review article nanotechnology-applied curcumin for

Review ArticleNanotechnology-Applied Curcumin forDifferent Diseases Therapy

Negar Ghalandarlaki1 Ali Mohammad Alizadeh1 and Soheil Ashkani-Esfahani2

1 Cancer Research Center Tehran University of Medical Sciences Tehran Iran2 Student Research Committee Shiraz University of Medical Sciences Shiraz Iran

Correspondence should be addressed to Ali Mohammad Alizadeh aalizadehrazitumsacir

Received 4 February 2014 Revised 21 April 2014 Accepted 25 April 2014 Published 5 June 2014

Academic Editor Yoshinori Marunaka

Copyright copy 2014 Negar Ghalandarlaki et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Curcumin is a lipophilic molecule with an active ingredient in the herbal remedy and dietary spice turmeric It is used by differentfolks for treatment of many diseases Recent studies have discussed poor bioavailability of curcumin because of poor absorptionrapid metabolism and rapid systemic elimination Nanotechnology is an emerging field that is potentially changing the way wecan treat diseases through drug delivery with curcumin The recent investigations established several approaches to improve thebioavailability to increase the plasma concentration and to enhance the cellular permeability processes of curcumin Severaltypes of nanoparticles have been found to be suitable for the encapsulation or loading of curcumin to improve its therapeuticeffects in different diseases Nanoparticles such as liposomes polymeric nanoparticles micelles nanogels niosomes cyclodextrinsdendrimers silvers and solid lipids are emerging as one of the useful alternatives that have been shown to deliver therapeuticconcentrations of curcumin This review shows that curcuminrsquos therapeutic effects may increase to some extent in the presenceof nanotechnology The presented board of evidence focuses on the valuable special effects of curcumin on different diseases andcandidates it for future clinical studies in the realm of these diseases

1 Introduction

Curcumin 17-bis(4-hydroxy-3-methoxyphenyl)-16-hepta-dien-35-dione is a lipophilic molecule that rapidly per-meates cell membrane [1] Typical extract of Curcumalonga L contains the structures I to III (I) diferuloyl-methanecurcumin (curcumin I 75) (II) demethoxycur-cumin (curcumin II 20) and (III) bisdemethoxycurcumin(curcumin III 5) [2 3] (Figure 1) Curcumin is an activeingredient in the herbal remedy and dietary spice turmeric[4] It has a long history of administration by different folks ofChina India and Iran for the treatment ofmanydiseases suchas diabetes liver diseases rheumatoid diseases atheroscle-rosis infectious diseases cancers and digestive disorderssuch as indigestion dyspepsia flatulence and gastric andduodenal ulcers [5 6] Many researchers have worked oncurcumin due to its various therapeutic effects on differentdiseases Shortly curcumin has received attentionmostly due

to its antioxidant anti-inflammatory antitumoral apoptosis-inducing and antiangiogenesis effects which were reportedin many investigations It acts on multiple targets in cel-lular pathways making this agent able to perform multipleactions [7] The simple molecular structure along with therelative density of functional groups in curcumin providesresearchers with an outstanding target for structure-activityrelationship and lead optimization studies The structuralanalogues of curcumin have been reported to enhance therate of absorption with a peak plasma half-life [8ndash10] Recentinvestigations have considered curcumin a lead compoundfor designing new chemotherapeutic agents for treatment ofcancers including colon cancers [11] prostate cancers [12]and other conditions with indication of chemotherapy [1314]

Curcumin is remarkably well tolerated but its bioavail-ability is poor It does not appear to be toxic to animals[15] or humans [16] even at high doses Recent studies have

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 394264 23 pageshttpdxdoiorg1011552014394264

2 BioMed Research International

OHHO

OO

Curcumin (I)

Demethoxycurcumin (II)

Bisdemethoxycurcumin (III)

Equilibrating keto-enol tautomers

OCH3H3CO

OHHO

O

OCH3H3CO

OHHO

OO

OCH3

OH

OH

OHHO

O

OCH3H3CO

OH

HO

OO

Figure 1 Curcumin I II and III (curcumin demethoxycurcumin and bisdemethyoxycurcumin) and curcumin keto-enol tautomers

discussed poor bioavailability of curcumin because of poorabsorption rapid metabolism and rapid systemic elimina-tion [17 18] however comprehensive pharmacokinetic dataare still missing In a study done by Yang et al [19] theyreported 1 bioavailability for oral administration of cur-cumin in rats On the elimination of curcumin an investiga-tion in rat model demonstrated that after oral administrationof 1 gkg of curcumin more than 75 was excreted in fecesand negligible amount of curcumin was detected in urine[20] Additionally FDA has declared curcumin as ldquogenerallysaferdquo Although curcumin showed a wide variety of usefulpharmacological effects and has been found to be quite safe inboth animals and humans there are some studies concerning

its toxicity [21] In spite of these advantages curcumin haspoor water solubility as a consequence it reveals solubility-limited bioavailability which makes it a class II drug inthe biopharmaceutics classification system [22] Additionallydue to its rapid intestinal and hepatic metabolism about 60to 70 of an oral dose of curcumin gets eliminated by thefeces [23]

As mentioned above curcumin has been proven to beeffective in treatment of different diseases with low toxicityto human and animals It is extremely safe upon oral admin-istration even at very high doses however it is limited dueto its poor bioavailability stability low solubility and rapiddegradation and metabolism Overcoming these problems

BioMed Research International 3

has been the main goal of many studies over the past threedecades Since curcumin was demonstrated to have poorbioavailability and selectivity [17 24] numerous analoguesof this material have been introduced and tested in order toevaluate their activities against known biological targets andto also improve their bioavailability selectivity and stability[25ndash28] In addition several approaches were introduced toimprove the bioavailability to increase the plasma concentra-tion and to enhance the cellular permeability and resistanceto metabolic processes of curcumin Using nanoparticlesfor targeting drug delivery appeared to provide curcuminwith longer circulation better permeability and strongerresistance to metabolic processes

2 Nanotechnology Approaches for Curcumin

Nanotechnology is increasingly considered to be the technol-ogy of the future Among the wide applications of nanotech-nology is the use of nanoparticles for enhancing the bioavail-ability and the solubility of lipophilic compounds such as cur-cumin in drug delivery systemsTherefore applying nanopar-ticles gained immense popularity in the last decade due totheir potential to improve the therapeutic effects of the encap-sulated drugs by protecting drugs from enzymatic degrada-tion providing their controlled release and prolonged bloodcirculation changing their pharmacokinetics decreasingtheir toxicity and limiting their nonspecific uptake [29] Overa period of time numerous emphases have been given todevelop the biodistribution of natural curcumin but it is onlyjust recently that the application of the field of nanotech-nology has considerably enhanced its therapeutic effectsNanoparticles such as liposomes polymeric nanoparticlesmicelles nanogels niosomes cyclodextrins dendrimers sil-vers and solid lipids are emerging as one of the usefulalternatives that have been shown to deliver therapeutic con-centrations of curcumin The use of the above nanoparticlehas improved main problems of curcumin such as low solu-bility instability poor bioavailability and rapid metabolismin cancers wound healing Alzheimerrsquos disease epilepticusischemia diseases inflammatory diseases and so on (Table 1)

3 Liposomes

Liposomes are synthetic vesicles with globular character thatcan be produced from natural phospholipids [82] They areself-assembling closed colloidal constructions composed oflipid bilayers and they have a spherical shape in whichan outer lipid bilayer surrounds a central aqueous space[83] The liposome diameter varies from 25 nm to 25mm(Table 1) They are stated to act as immunological adjuvantsand drug carriers Liposomes can encapsulate drugs withwidely varying solubility or lipophilicity entrapped eitherin the aqueous core of the phospholipid bilayer or at thebilayer interface [84] Moreover they are able to deliverdrugs into cells by fusion or endocytosis and practicallyany drug irrespective of its solubility can be entrapped intoliposomes (Figure 2) In this regard to enhance the solubilityof curcumin Rahman et al [30] prepared 120573-cyclodextrin-curcumin inclusion complexes that entrapped both native

curcumin and the complexes separately into liposomes Allcurcumin-containing formulations were effective in inhibit-ing cell proliferation in in vitro cell culture In another studyShi et al [31] developed a water-soluble liposomal curcuminto examine curcuminrsquos preventive effects on lung fibrosis viaintravenous administration in mice by using enzyme-linkedimmunosorbent assay method (ELISA) Results showed thatliposomal curcumin can effectively diminish radiation pneu-monitis and fibrosis of lung and sensitize LL2 cells toirradiation These data suggest that the systemic administra-tion of liposomal curcumin with enhanced solubility is safeand deserves to be investigated for further clinical applica-tion

Some studies showed that the drugs encapsulated inliposomes are expected to be transported without rapiddegradation and result in minimum side effects and showmore signs of stability in the recipients In this regardto assess curcumin tissue distribution Matabudul et al[32] questioned whether different durations of intravenousinfusions of Lipocurc can alter curcumin metabolism and itstissue distribution and whether treating necropsied tissues ofBeagle dogs with phosphoric acid prior to measuring cur-cumin and its metabolite (tetrahydrocurcumin) can stabilizethe compounds allowing for accurate analytical measure-ments Results demonstrated that the addition of liposomesmay inhibit or saturate a putative reductase enzyme thatconverts curcumin to tetrahydrocurcumin and stabilizes thelevels of curcumin Tetrahydrocurcumin in some tissues(lung spleen and liver) but not all the examined tissues(lung spleen liver pancreas kidney and urinary bladder)raised issues of tissue-specific curcumin and tetrahydrocur-cumin stability via a transporter-dependent mechanism thatelevated tissue concentrations of curcumin Additionallyto obtain better understanding of curcumin interactionmechanisms with lipid membranes and improve the stabilityof curcumin Karewicz et al [33] banded curcumin toegg yolk phosphatidylcholine dihexadecyl phosphate andcholesterol then in order to determine curcumin bindingconstant to liposomes they used absorption and fluorescencetechniques The egg yolk phosphatidylcholinedihexadecylphosphatecholesterol liposomal bilayer curcumin stabilizedthe system proportionally to its content while the egg yolkphosphatidylcholinedihexadecyl phosphate system destabi-lized upon drug loading The three-component lipid compo-sition of the liposome seems to be themost promising systemfor curcumin delivery Furthermore an interaction of freeand liposomal curcumin with egg yolk phosphatidylcholineand mixed monolayers was also studied by using Langmuirbalance measurements Condensing effects of curcumin onegg yolk phosphatidylcholine and egg yolk phosphatidyl-cholinedihexadecyl phosphate monolayers and looseninginfluence on egg yolk phosphatidylcholinedihexadecyl phos-phatecholesterol ones were observed It was also demon-strated that curcumin-loaded egg yolk phosphatidylcholineliposomes are more stable upon interaction with the modellipid membrane than the unloaded ones In another studyChen et al [85] reported the effects of different lipo-somal formulations on curcumin stability in phosphatebuffered saline human blood plasma and culture medium

4 BioMed Research InternationalTa

ble1Nanop

articles-conjugated

curcum

incharacteriz

ationford

ifferentd

iseases

treatment

Type

ofnano

particles

Form

Size

(nm)

Usedmod

els

Metho

dsRe

sults

Reference

Lipo

some

Globu

lar

25ndash205

(i)Breastcancer

(ii)M

elano

ma

(iii)Re

nalischemia

(iv)M

alaria

Invitro

Invivo

(dog

andmice)

(i)Increasedsolubilitytissued

istrib

utionandsta

bility

(ii)E

nhancedantitum

orandantia

ngiogenesis

effects

(iii)Show

edantim

elanom

aanti-inflammatoryand

antim

alarialeffects

[30ndash

33]

[34ndash

37]

[3839]

Micelle

Spheric

al10ndash100

(i)Lu

ngtumor

(ii)B

reastcancer

Invitro

Invivo

(mice)

(i)Increasedsolubilityandbioavailability

(ii)Improved

antio

xidativ

eand

antitum

oreffects

(iii)Prolon

gedcirculationtim

e(iv

)Enh

ancedflu

orescencee

ffect

[40]

[41]

[42]

[43]

[44]

[45]

[46]

Noisome

Lamellar

190ndash

1140

(i)Albinoratskin

(ii)C

ancerous

cells

Invitro

Invivo

(snake

andmice)

(i)Increasedskin

penetration

(ii)P

rolonged

deliverysyste

m(iii)Anti-infectio

nandantic

ancere

ffects

(iv)E

nhancedflu

orescenceintensity

[47]

[48]

[49]

OO

O O O

O

OO

OOO

O

n

OR 6

OR 6

OR 2O

R 2

OR 6

OR 6O

R 3

OR 3

OR 3

R 6O

R 2OR 3

OR 3

O

R 3OR 2

O

R 6O

R 2O

OR 2

Cyclo

dextrin

Cyclic

150ndash

500

(i)Bo

weldisease

(ii)B

reastlung

pancreaticand

prostatecancer

Invitro

Invivo

(ratandmice)

(i)Im

proved

solubility

(ii)E

nhancedantip

roliferationeffects

(iii)Increasedantic

ancera

ndanti-inflammatoryeffects

(iv)D

evelop

edbioavailability

[30]

[50ndash

56]

Dendrim

erGlobu

lar

polymer

15ndash150

(i)Breastcancer

(ii)C

olon

cancer

Invitro

Invivo

(mice)

(i)Im

proved

stability

(ii)Increased

antitum

orandantip

roliferativee

ffects

[5758]

[59ndash

63]

Nanogel

Cross-lin

ked

polymer

network

10ndash200

(i)Melanom

a(ii)B

reastand

pancreaticcancer

cells

Invitro

(i)Increasedstability

(ii)E

nhancedflu

orescencee

ffects

(iii)Develop

edbioavailability

(iv)Improved

antic

ancere

ffects

(v)G

etbette

rcon

trolledrelease

(vi)Prolon

gedhalf-life

(vii)

Enhanced

treatmento

fmelanom

a

[64]

[65]

Chito

san

Linear

polysaccha-

ride

compo

sed

100ndash

250

(i)Wou

nds

(ii)M

elanom

atum

ors

Invitro

Invivo

(ratandmice)

(i)Im

proved

chem

icalstability

(ii)S

howed

wou

ndhealingeffects

(iii)Increasedantitum

oreffects

(iv)Improved

antio

xidant

effects

(v)P

rolonged

bloo

dcirculation

[66ndash

71]

Gold

Globu

lar

200ndash

250

Cancerou

scells

Invitro

(i)Im

proved

solubility

(ii)E

nhancedantio

xidant

andantic

ancere

ffects

[72]

[73]

Silver

Film

layer

sim15

(i)Infections

(ii)S

kinwou

nds

Invitro

(i)Sh

owed

antim

icrobialeffects

(ii)Improved

wou

ndhealing

(iii)Increasedantiv

iraland

antic

ancere

ffects

[74]

[75]

Lipi

d(s

olid

)Solid

lipid

Spheric

al50ndash100

0

(i)Cerebralischemia

(ii)C

olitis

(iii)Allergy

(iv)B

reastcancer

Invitro

Invivo

(ratandmice)

(i)Prolon

gedcirculationof

bloo

d(ii)Increased

anti-inflammatoryeffects

(iii)Im

proved

braindelivery

[76ndash

78]

[79ndash

81]


Curcumin Liposome

Enter cell

Fusion

Endocytosis

Lysosome

OH

O O

H3COOCH3

HO

Figure 2 A schematic figure of how curcumin is located in liposomes and enters into cells Curcumin is encapsulated inside the liposomalcontainer and covalently bound to liposome so it is protected from destruction on the way to the target The liposome membrane isusually made of phospholipids which constitute biological membranes and can deliver curcumin into cells by two different ways fusionand endocytosis

Liposomal curcumin showed a higher stability than freecurcumin in phosphate buffered saline (PBS) Liposomaland free curcumin showed similar stability in humanblood plasma and culture medium In addition resultson the toxicity of concanavalin-A showed that dimyris-toylphosphatidylcholine and dimyristoylphosphatidylglyc-erol were toxic on lymphoblastoid cell lines However addi-tion of cholesterol to the lipids at dimyristoylphosphatidyl-cholinedimyristoylphosphatidylglycerolcholesterol almostcompletely eliminated the lipid toxicity to these cells Liposo-mal curcumin had similar or even stronger inhibitory effectson concanavalin-A-stimulated human lymphocyte spleno-cyte and lymphoblastoid cell proliferation They concludedthat liposomal curcumin may be useful for intravenousadministration to improve the bioavailability and efficacyfacilitating the in vivo studies that could ultimately lead toclinical application of curcumin

In addition liposomal curcuminrsquos potential was evaluatedagainst cancer models of osteosarcoma and breast cancerby Dhule et al [34] with curcumin-loaded 120574-cyclodextrinliposomal nanoparticles The results showed promising anti-cancer potential of liposomal curcumin both in vitro andin vivo against osteosarcoma and breast cancer cell linesvia the caspase cascade that leads to apoptotic cell death

The efficiency of the liposomal curcumin nanoparticles wasalso confirmed by using a xenograft osteosarcoma modelin vivo Li et al [9] encapsulated curcumin in a liposo-mal delivery system for intravenous administration Theyalso showed the liposome-encapsulated curcumin effectson proliferation apoptosis signaling and angiogenesis byusing human pancreatic carcinoma cells in vitro and in vivoLiposome-encapsulated curcumin suppressed pancreatic car-cinoma growth in murine xenograft models and inhibitedtumor angiogenesis in vivo It also downregulated the NF-120581B pathway suppressed growth and induced apoptosis ofhuman pancreatic cells in vitro and showed antitumor andantiangiogenesis effects in vivo [35 36] Chen et al [37]studied in vitro skin permeation and in vivo antineoplasticeffects of curcumin by using liposomes as the transdermaldrug-delivery system Curcumin-loaded liposomes exhibitedability to inhibit the growth of melanoma cells A con-siderable effect on antimelanoma action was detected withcurcumin-loaded liposomes These results similar to theresults of other studies suggest that liposomes would be ahopeful delivery service for curcumin in cancer management[30 86 87] These data indicate a significant liposomalcurcumin potential as delivery vehicles for the treatment ofdifferent cancers (Table 1)


Rogers et al [38] also administered liposomes contain-ing curcumin to target delivery to renal tubular epithelialand antigen-presenting cells in mice renal ischemia modelLiposomal curcumin significantly improved serum crea-tinine reduced histological injury and cellular apoptosisand lowered toll-like receptor-4 heat shock protein-70 andtumor necrosis factor alpha (TNF-120572) mRNA expression andit also decreased neutrophil infiltration and inflammatoryinterleukins expression In this regard Basnet et al [39]developed vaginal administration of liposomal curcuminLiposomal curcumin was found to be twofold to sixfold morepotent than corresponding free curcumin Results showedthat liposomal delivery systems enhance anti-inflammatoryproperties of curcumin Also evaluation of liposomal cur-cumin cytochrome P450 inhibition was conducted by Machet al [88] in liver tissues Results demonstrated that thereis low potential for CYP450 mediated drug interactions atphysiologic serum concentrations of liposomal curcuminIt will not interact with other chemotherapy agents thatare metabolized andor eliminated via the primary drugmetabolizing cytochrome P450 pathways [88]

The therapeutic efficacies of novel liposomal deliverysystems based on artemisinin or artemisinin-based combi-nation therapy with curcumin have been investigated andreported by Isacchi et al [89]They reported that artemisininalone began to decrease parasitaemia levels only 7 daysafter the start of the treatment and it appears to have afluctuant trend in blood concentration which is reflectedin the antimalarial effectiveness By contrast treatmentswith artemisinin loaded with liposomal delivery systemsappeared to have an immediate antimalarial effect whichcured all malaria-infected mice within the same postinocu-lation period of time In particular artemisinin loaded withliposomal curcumin seems to give the most pronouncedand statistically significant therapeutic effect in this murinemodel of malaria The enhanced permanency in bloodof artemisinin loaded with liposomal curcumin suggestsapplication of these nanosystems as suitable passive targetedcarriers for parasitic infections [89] This strong effect offormulation is added up to the mechanism of action ofartemisinin which acts in the erythrocyte cycle stage ofhuman host as a blood schizonticide Agarwal et al [90] alsoassessed the acute effects of liposome-entrapped curcumin onincreasing current electroshock seizures pentylenetetrazole-induced seizures and status epilepticus in mice Liposome-entrapped curcumin demonstrated significant increase inseizure threshold current and latency to myoclonic andgeneralized seizures increasing current electroshock andpentylenetetrazole-induced seizures respectively It alsoincreased the latency to the onset and decreased the durationof seizures during status epilepticus Therefore liposomal-entrapped curcumin can possess anticonvulsant activityagainst status epilepticus in mice (Table 1)

To put it briefly the above data suggest that the admin-istration of liposomal curcumin has numerous beneficialeffects which could lead to required clinical applicationsThese better outcomes take place by means of enhancedsolubility more safety and minimum side effects moresigns of stability in the blood increased bioavailability and

efficacy owning a potential role as delivery vehicles for thetreatment of different cancers potent anti-inflammatory andantimalaria response and finally anticonvulsant activity

4 Micelles

A typical micelle is a surfactant molecule aggregate dispersedin a liquid colloid It is a nanosized vesicular membranewhich becomes soluble in water by gathering the hydrophilicheads outside in contact with the solvent and hydrophobictails inside which is known as emulsification Micelles arelipid molecules that arrange themselves in a spherical formin aqueous solutions with a very narrow range from 10to 100 nm in size which makes them more stable towarddilution in biological fluids [84] The shape or morphologyof micelles is from amphiphilic block copolymers such asspherical rodlike and starlike as well as vesicles (Table1) The self-assembly of amphiphilic block copolymer is areversible process and the shape varies with the copolymersrsquocomposition and length ratio [91] The functional propertiesofmicelles are based on amphiphilic block copolymers whichcome together to form a nanosized coreshell structure inaqueous media The hydrophobic core area hands out asa pool for hydrophobic drugs while the hydrophilic shellarea stabilizes the hydrophobic core and makes the polymerswater soluble Polymeric micelles can serve as transporters ofwater-insoluble drugs such as curcumin which can augmentthe drugrsquos efficiency by targeting definite cells or organstherefore fewer drugs accumulate in healthy tissues andtheir toxicity reduces and occasionally higher doses can beadministered [92] In this regard to overcome the poor watersolubility of curcumin Liu et al [93] prepared curcumin-loaded biodegradable self-assembled polymeric micelles bysolid dispersion method which was simple and easy toscale up Release profile showed a significant differencebetween rapid release of free curcumin and much slowerand sustained release of curcumin-loaded micelles In addi-tion the preparation of curcumin-loaded micelles basedon amphiphilic Pluronicpolycaprolactone block copolymerwas investigated by Raveendran et al [40] which provedto be efficient in enhancing curcuminrsquos aqueous solubilitySome other studies also deliberated on highly surface-activecompounds such as poloxamers or Pluronic that can self-assemble into spherical micelle In vitro results showedthat spherical curcumin-loaded mixed micelles might serveas a potential nanocarrier to improve the solubility andbiological activity of curcumin [94ndash96] In another studythe aqueous solubility of the curcumin was increased byencapsulation within the micelles [97] Solubilization wasdirectly related to the compatibility between the solubilizateand polycaprolactone as determined by the Flory-Hugginsinteraction parameter Molecular modeling study suggestedthat curcumin tended to interact with polycaprolactoneserving as a core embraced by polyethylene glycol as a shellIn addition Yu et al [41] showed the structure of modified120576-polylysine micelles and their application in improvingcellular antioxidant activity of curcuminoids Results of theirinvestigation revealed that modified 120576-polylysine micelleswere able to encapsulate curcuminoids and improve their


water solubility and cellular antioxidative activity comparedwith free curcuminoids They suggested that these micellesmay be used as new biopolymermicelles for delivering poorlysoluble drugs such as curcumin Another study synthesizedcurcumin in sodium dodecyl sulfate and cetyltrimethylam-monium bromide micelles to overcome the poor watersolubility of curcumin and demonstrated antioxidative effectsof curcumin analogues against the free-radical-induced per-oxidation of linoleic acid in these micelles [98 99] Kineticanalysis of the antioxidation processes demonstrated thatthese compounds exhibited extraordinarily higher antioxida-tive activity in micelles due to their solubility being higherthan free curcumin [98]

Drug release frommicelles is governed by different issuesincluding micelle stability the rate of copolymer biodegrada-tion and drug diffusion By the way Sahu et al [100] reportedthe potential of the two most common Pluronic triblockcopolymer micelles Pluronic F127 and F68 for curcuminencapsulation efficiency and stability Pluronic F127 showedbetter encapsulation efficiency and good stability for long-term storage than Pluronic F68 Atomic force microscopy(AFM) study revealed that the drug-encapsulatedmicelles arespherical in shape with diameters below 100 nm Pluronic-encapsulated curcumin demonstrated slower and sustainedrelease of curcumin from the micelles and considerableanticancer activity in comparison with free curcumin in vitrocytotoxicity study In addition Podaralla et al [42] reporteda natural protein core-based polymeric micelle and demon-strated its application for the delivery of hydrophobic anti-cancer drugs specifically curcumin They synthesized novelbiodegradable micelles by conjugatingmethoxy polyethyleneglycol and zein a biodegradable hydrophobic plant proteinwhich can be found in Maize and then encapsulating withcurcumin Polyethylene glycol zein micelles sustained thecurcumin release up to 24 hrs in vitro and significantlyenhanced its aqueous solubility and stability with the 3-fold reduction in IC50 value of curcumin So since thecurcumin is finely protected from possible inactivation bytheir micellar surroundings its retention and bioavailabilitycan be enhanced (Table 1)

Aiming to modify the pharmacokinetics of curcuminSong et al [43] synthesized a poly(DL-lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(DL-lactide-co-glycolide)(PLGA-PEG-PLGA) with micelles PLGA-PEG-PLGAmicelles provided higher area under the concentrationcurve (AUC) and enhanced residence time clearance anddistribution half-life in comparison with curcumin solutionThe prolongation of half-life enhanced residence time anddecreased total clearance indicated that curcumin-loadedmicelles could prolong acting time of curcumin in vivoTheseresults may be related to the curcumin location within themicelles and increased viscosity of copolymer solution at thebody temperature The variation of AUC indicated that thecurcumin-loaded micelles provided higher bioavailabilitythan curcumin solution and the biodistribution studyshowed that the micelles had decreased drug uptake byliver and spleen and enhanced drug distribution in lungand brain These results suggested that PLGA-PEG-PLGAmicelles would be a potential carrier for curcumin In

addition Ma et al [94] demonstrated the pharmacokineticsof both solubilized curcumin and its polymeric micellarformulation in rats by using a simple rapid and reliableHPLC method They concluded that encapsulation ofcurcumin in the polymeric micellar formulation led toincrease in curcuminrsquos half-life and distribution volume

In addition curcumin-micelles can be affected by physic-ochemical characteristics concentration and location withinthe micelles The polymeric micelles have a prolonged cir-culation time due to their small size and hydrophilic shellthat reduce the drug uptake by the mononuclear phagocytesystem [101] Leung et al [44] reported that encapsulatedcurcumin in cationic micelles suppresses alkaline hydrolysisthat was studied in three types of micelles composed ofthe cationic surfactants cetyltrimethylammonium bromide(CTAB) and dodecyltrimethylammonium bromide (DTAB)and the anionic surfactant sodium dodecyl sulfate (SDS)Curcumin underwent rapid degradation in the SDS micellarsolution by alkaline hydrolysis at pH of 13 while it wassignificantly suppressed with a yield of suppression closeto 90 in the presence of either CTAB or DTAB micellesResults from fluorescence spectroscopic studies revealed thatcurcumin is dissociated from the SDSmicelles to the aqueousphase at this pH while curcumin remains encapsulatedin CTAB and DTAB micelles at pH 13 The absence ofencapsulation and stabilization in the SDS micellar solutionresulted in rapid hydrolysis of curcumin Some other studiesshowed other curcumin-loaded micelles properties Wanget al [102] introduced the sensitive fluorometric methodfor the determination of curcumin using the enhancementof mixed micelle This method had the advantages of highsensitivity selectivity and stability The fluorescence of cur-cumin was greatly enhanced by mixed micelle of sodiumdodecylbenzenesulfonate and cetyltrimethylammoniumbro-mide (SDBS-CTAB) This study indicated that fluorescencequantum yield of curcumin in SDBS-CTAB micelle wasabout 55-fold larger than that of aqueous solution con-taining 10 ethanol which was in agreement with theirfluorescence intensity ratio As a result curcumin can beused as a fluorophore in fluorescence polarization anisotropymeasurement to determine the criticalmicellar concentrationof surfactant and to study the interaction between themIn addition Adhikary et al [45] performed femtosecondfluorescence upconversion experiments on the naturallyoccurringmedicinal pigment curcumin in anionic cationicand neutral micelles These micelles were composed of SDSdodecyltrimethylammonium bromide (DTAB) and TritonX-100 They revealed the curcuminrsquos excited-state kinetics inmicelles with fast (3ndash8 ps) and slow (50ndash80 ps) componentsWhile deuteration of curcumin had a negligible effect onthe fast component the slow component exhibited a pro-nounced isotope impact of approximately 16 which indi-cates thatmicelle-captured curcumin undergoes excited-stateintramolecular hydrogen atom transfer Moreover Beganet al [46] had attached curcumin to phosphatidylcholinemicelles followed by fluorescence measurements Curcuminin aqueous solution did not inhibit dioxygenation of fattyacids by lipoxygenase 1 but it inhibited the oxidation offatty acids when bound to phosphatidylcholine micelles


Results demonstrated that 86 120583M of curcumin bound to thephosphatidylcholine micelles is required for 50 inhibitionof linoleic acid peroxidation Lineweaver-Burk plot analysishad indicated that curcumin is a competitive inhibitor oflipoxygenase 1 with Ki of 17 120583M for linoleic acid and 43 120583Mfor arachidonic acid respectively By using spectroscopicmeasurement they revealed that the inhibition of lipoxyge-nase 1 activity by curcumin can be due to binding to activecenter iron and curcumin after binding to the phosphatidyl-choline micelles acts as an inhibitor of lipoxygenase 1 In arecent investigation the critical micelle concentration of theamphiphilic polymer was determined by using fluorescentprobe Outcomes indicated that Pluronicpolycaprolactonemicelles may be a promising candidate for curcumin deliveryto cancer cells of colorectal adenocarcinoma [40] In anotherpharmacokinetic study curcumin micelles demonstratedhigher concentration and longer retention time in plasmaand tumor sites so they had stronger inhibitory effects onproliferation migration invasion and tube formation ofcarcinoma cells than free curcumin for example curcuminmicelles were shown to be more effective presumably dueto higher concentration in inhibiting tumor growth andprolonged survival in both subcutaneous and pulmonarymetastatic tumor models [103]

Investigating the influence of micelles on cytotoxicityof curcumin specifically in cancer therapy in vitro studyby Raveendran et al [40] showed that Pluronicpolycapro-lactonemicelles could be a promising candidate for curcumindelivery to cancer cells regarding the cytotoxicity and cellularuptake of the curcumin-loaded micelles in colorectaladenocarcinoma cells An investigation by Wang et al [104]revealed that the encapsulated curcuminmaintains its potentantitumor effects however curcumin-loaded micelles weremore effective in inhibiting tumor growth and spontaneouspulmonary metastasis in subcutaneous 4T1 breast tumormodel and prolonged survival of tumor-bearingmice Immu-nofluorescent and immunohistochemical studies alsoshowed that tumors of curcumin-loaded micelle-treatedmice had more apoptotic cells fewer microvessels and fewerproliferation-positive cells [104] In addition Yang et al[19] had conjugated methoxypolyethylene glycol-polylacticacid (mPEG-PLA) micelle to multiple curcumin mole-cules the cytotoxicity study results showed that the effect ofIC50 of mPEG-PLA-Tris-curcumin on human hepatocellularcarcinoma cells was similar to unmodified curcuminThe cel-lular uptake study demonstrated that these carriers could suc-cessfully transport the drug to the cytoplasm of hepatic cellsMicelles containing multiple drug molecules were an effi-cient means to increase loading and intracellular deliveryof low-potency curcumin [19] Moreover Mohanty et al[105] reported that curcumin encapsulated in methoxypoly(ethylene glycol)poly-epsilon-caprolactone diblockcopolymeric (MePEGPCL) micelle by varying the cop-olymer ratio (40 60MePEGPCL ratio was selected due toits high encapsulation) had increased bioavailability due tointensified uptake 295 times more with comparative cyto-toxic effects by induction of apoptosis in contrast withunmodified curcumin at equimolar concentrations Over-all these data obviously showed the commitment of a

micellar system for efficient solubilization stabilization andcontrolled delivery of the hydrophobic drug such as cur-cumin for cancer therapy

Concisely curcumin-loadedmicelles can boost the drugrsquosefficiency by targeting definite cells and result in less drugaccumulation in healthy tissues and reduction of toxicityCurcuminrsquos aqueous solubility and much slower and sus-tained release of drug caused by curcumin-loaded micellesalso get in use in several conditions The retention andbioavailability of curcumin could be elevated since the cur-cumin is protected from possible inactivation by its micellarsurroundings Locating the curcumin in the micelles can alsoenhance half-life and residence time and decrease total clear-ance leading to prolongation of acting time of curcuminCurcumin micelles can be influenced by physicochemicalfeatures including their size and electrical charges concentra-tion and location within the micelles These data obviouslyshowed the commitment of a micellar system for efficientsolubilization stabilization and controlled delivery of thehydrophobic drug such as curcumin for cancer therapy(Table 1)

5 Niosomes

Niosomes aremicroscopic lamellar constructions of nonionicsurfactant of alkyl or dialkyl polyglycerol ether category withcholesterol that were first introduced in the 70s [106 107]Niosomes can provide a container for drug molecules witha wide range of solubilities due to presence of hydrophilicamphiphilic and lipophilic moieties in the constitution(Table 1)They behave similar to liposomes in vivo and can beused as an effective alternative to liposomal drug carriers andthose properties depend on the composition of the bilayer aswell as the method of their production [108] Surfactant typeencapsulated drug nature storage temperature detergentsand use of membrane spanning lipids can affect niosomesstability [107] Niosomes are also planned for use in a numberof potential therapeutic applications such as anticancer andanti-infective drug targeting agents [84] They can improvethe therapeutic indices of drugs by restricting their actionon the target cells They also improve oral bioavailability ofpoorly absorbed drugs such as curcumin to design the noveldrug delivery system and increase the skin penetration ofdrugs [47] In this regard in an in vitro study which wasperformed using albino rat skin proniosomes of curcuminwere prepared by encapsulation of the drug in a mixtureof Span 80 cholesterol and diethyl ether to investigatetransdermal drug delivery system [109]The planned systemsdistinguished between size drug entrapment repose anglehydration rate and vesicular stability under different storagesettings Results showed that proniosomes are very stable andpromising prolonged delivery systems for curcumin [109]Mandal et al [48] also designed a comparative study withdifferent microenvironments for photophysical propertiesof curcumin inside niosomes by means of steady statetime resolved fluorescence spectroscopy and dynamic lightscattering techniques Outcomes showed that more rigidand confined microenvironments of niosomes improve thesteady state fluorescence intensity alongwith the fluorescence


lifetime of curcumin The data indicated that niosomes are agood tool for delivery system to suppress the level of degrada-tion of curcumin [48] In another study by Rungphanichkulet al curcuminoid niosomes were developed with a seriesof nonionic surfactants to enhance skin permeation of cur-cuminoids [49] Results were evaluated based on entrapmentefficiency and in vitro penetration of curcuminoids via snakeskin Niosomes drastically enhanced permeation of curcum-inoids compared with a vehicle solution of curcuminoids[49] The fluxes of curcumin desmethoxycurcumin andbisdesmethoxycurcumin also were consistent with the quali-fied hydrophobicity of curcumin desmethoxycurcumin andbisdesmethoxycurcumin respectively Data indicated thatcurcuminoids can be fruitfully prepared as niosomes andsuch formulations have superior properties for transdermaldrug delivery system [49]

Briefly niosomes can be a potential delivery system forcurcumin in order to suppress the degradation of this agentand increase its life time It has also been demonstrated thatniosomes boost the permeation of curcumin through skin(Table 1)

6 Cyclodextrins

Cyclodextrins (Cds) are a family of complexes prepared fromsugar molecules bound together in cyclic oligosaccharides[110] They are created from starch by using enzymaticswitch Cds are cyclic oligomers of glucose that can formwater-soluble inclusion complexes with small molecules andportions of large complexes [111] They are exceptionalmolecules with pseudoamphiphilic construction which areused industrially in pharmaceutical requirements [84] Cdsare also used in agriculture and in environmental engineeringin food drug delivery systems and chemical industries [110]They have an interior hydrophobic surface which can providea place for residence of poorly water-soluble molecules whilethe external hydrophilic area makes its solubility possible inthe aqueous setting with high stability (Table 1)

To improve the water solubility and the hydrolytic stabil-ity of curcumin Toslashnnesen et al [50] prepared cyclodextrin-curcumin complexes by using HPLC and UVVIS scan-ning spectrophotometer techniques [50] (Figure 3) Resultsshowed that the hydrolytic stability of curcumin was sturdilyimproved by the complex and also the photodecompositionrate was enhanced in organic solvents compared to the freecurcumin As a result the cavity size and charge of cyclodex-trin side-chains influenced the stability and degradation rateof curcumin [50] In addition other investigations on thesolubility phase distribution and hydrolytic and photochem-ical stability of curcumin showed that curcumin derivativesweremore stable towards hydrolytic degradation in cyclodex-trin solutions than free curcumin [51] The photochemicalstudies illustrated that curcumin is universally more stablethan its other derivatives Solubility and phase-distributionstudies showed that curcuminoids with side groups on thephenyl moiety have higher affinity for the hydroxypropyl-120574-cyclodextrin (HP-120574-CD) than the cyclodextrins The rad-ical scavenging investigations confirmed that curcumin ismore active than its curcuminoids derivatives and the

free phenolic hydroxyl group may possibly be necessaryfor the scavenging properties [51] In another study toincrease the solubility of curcumin Darandale and Vavia [52]employed cyclodextrin-based nanosponges they formulatedthe complex of curcumin with 120573-cyclodextrin nanospongeobtained with dimethyl carbonate as a cross-linker Theloaded nanosponges have shown more solubilization effi-ciency compared to free curcumin and 120573-cyclodextrin com-plex The characterization of curcumin nanosponge complexconfirmed the interactions of curcumin with nanospongesMoreover in vitro drug release of curcumin was controlledover a prolonged time period and the complex was non-hemolytic [52] Therefore it seems that CDs are permittingvehicles that can be used for oral delivery to develop thebioavailability of insoluble drugs bymolecular dispersion anddegradation protection and for intravenous delivery to supplyas solubilizers for multifaceted hydrophobic drugs withoutaltering their pharmacokinetic properties [84]

Yadav et al [53] developed a new cyclodextrin com-plex of curcumin to increase solubility of curcumin andstudied its anti-inflammatory and antiproliferative effectsThey showed that cyclodextrin-curcumin complex was moreactive than free curcumin in inhibiting the inflammatorytranscription factor such as nuclear factor kappa-b (NF-120581B)In addition it suppressed cyclin D1 as a cell proliferationmarker matrix metallopeptidase 9 (MMP-9) as an invasionmarker in metastasis and vascular endothelial growth factor(VEGF) as an angiogenesis marker Cyclodextrin-curcumincomplex was alsomore active in inducing the death receptorsand apoptosis of leukemic cells as well as other cancer celllinesThese suggest that cyclodextrin-curcumin complex hassuperior characteristics compared to free curcumin for celluptake and antiproliferative and anti-inflammatory effects[53] Yadav et al [54] have also planned curcumin complexesby common methods to evaluate the anti-inflammatoryeffects of cyclodextrin-curcumin complex for the treatmentof inflammatory bowel disease (IBD) in an animal rat modelIn vivo results showed that curcumin has higher affinity forhydroxypropyl-120573-cyclodextrin than other cyclodextrins Inaddition hydroxypropyl-120573-cyclodextrin-curcumin complexproved to be a powerful antiangiogenesis complex In vivodata also confirmed that the scale of colitis was appreciablyattenuated by cyclodextrin-curcumin In summary cyclodex-trin complex was shown to be valuable in the therapeuticapproaches for IBD patients being a nontoxic natural dietaryyield [54]

Additionally Cds can augment bioavailability of insolubledrugs such as curcumin by rising drug solubility and dissolu-tion [84] They also amplify the permeability of hydrophobicagents by making them accessible at the surface of the mem-branersquos biological barrier A 120573-cyclodextrin-encapsulatedcurcumin drug delivery systemwas developed by Yallapu andcolleagues in order to get better curcumin hydrophilic anddrug delivery characteristics [55] Encapsulated-curcuminefficiency was shown to be improved through increasingthe ratio of curcumin to cyclodextrin Then an optimizedcyclodextrin-curcumin complex was assessed for intracellu-lar uptake and anticancer effects Cell proliferation and clono-genic examinations showed that 120573-cyclodextrin-curcumin


OndashCH3 H3CndashO

Curcumin

+

Cyclodextrin

OOH

OHHO

HOO

CC

CC

C CC

HO

OMeOMe

OH

1

2

3

4

5

6

7

8

9

10

2998400

3998400

4998400

5998400

6998400

7998400

8998400

9998400

10998400

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OHOH

OH

O

O

O

O

O

OOO

O

O

O

O

OO

HOCH3

HOCH3

CH3OH CH3OH

CH3OH

CH3OH

CH3OH

6

2

3

Figure 3 A schematic figure of curcumin connection to the cyclodextrin nanoparticles

self-assembly augmented curcumin delivery and improvedits therapeutic efficacy in prostate cancer cells [55] More-over curcumin-loaded 120574-cyclodextrin liposomal nanoparti-cles as delivery vehicles were also explored by Dhule et al[34] and evaluated against cancer models The resulting 2-hydroxypropyl-120574-cyclodextrincurcumin-liposome complexshowed promising anticancer potential both in vitro and invivo against osteosarcoma and breast cancer Liposomal cur-cumin initiated the caspase cascade that led to apoptoticcell death in vitro In addition the efficiency of the lipo-somal curcumin formulation was confirmed in vivo byusing a xenograft osteosarcoma model Data showed thatcurcumin-loaded 120574-cyclodextrin liposomes indicated con-siderable potential as delivery vehicles for cancer cure [34]Rahman et al [30] prepared 120573-cyclodextrin-curcumin com-plexes as a hydrophilic curcumin They entrapped both

native curcumin as a hydrophobic agent and the complexesseparately into liposomes and then assessed them for theircytotoxicity in cancerous cell lines The aqueous solubilityof 120573-cyclodextrin-curcumin complexes enhanced noticeablyand successful entrapment of complexes into prepared lipo-somes was also achieved The median effective dose for allcurcumin formulations was found to be in a low range forboth lung and colon cancer cell lines [30] Outcomes guar-anteed that 120573-cyclodextrin-curcumin complexes of weaklywater-soluble drugs such as curcumin can be tricked withinbiocompatible vesicles such as liposomes and this does notprevent their anticancer effects [30] In another study anovel curcumin analogue (difluorinated curcumin CDF) andCDF-120573-cyclodextrin-curcumin complex were synthesized toenhance anticancer effects against pancreatic cancer [56]Results showed that CDF-120573-cyclodextrin was found to lower


IC50 value by half when tested against multiple cancercell lines Following intravenous administration of CDF-120573-cyclodextrin it was specially accumulated in pancreatic tissue10 times higher than in serum As a result novel curcuminanalogue CDF outstanding gathering in pancreas tissue ledto its persuasive anticancer effects against pancreatic cancercells So synthesis of such CDF-120573-cyclodextrin self-assemblyis a successful approach to improve its bioavailability andtissue distribution Further evaluations on CDF delivery inclinical settings for treatment of human malignancies weresuggested by these authors [56] Moreover a novel poly(120573-cyclodextrin)-curcumin self-assembly was approached toimprove curcuminrsquos delivery to prostate cancer cells byYallapu et al [112] Intracellular uptake of the self-assemblywas evaluated by means of flow cytometry and immunoflu-orescence microscopy The therapeutic values were estab-lished by cell proliferation and colony formation tests onprostate cancer cells Results recommended that the poly(120573-cyclodextrin)-curcumin formulation could be a valuablesystem for developing curcumin delivery and its therapeu-tic effectiveness in prostate cancer [112] Additionally inorder to improve solubility and drug delivery of curcuminLomedasht et al [113] exploited a 120573-cyclodextrin-curcumininclusion complex and evaluated its cytotoxic effects byMTT assay in vitro Breast cancer cells were treated withequal concentration of 120573-cyclodextrin-curcumin and freecurcumin Then telomerase gene expression was comparedby real-time PCR in two groups In vitro results showedthat 120573-cyclodextrin-curcumin increased curcumin deliveryin breast cancer cells [113] Telomerase gene expression waslower in 120573-cyclodextrin-curcumin-treated cells than freecurcumin-treated cells As a result 120573-cyclodextrin-curcumincomplex wasmore effectual than free curcumin in telomeraseexpression inhibition Rocks et al [114] have used cyclodex-trins as an excipient permitting a significant enhancementof curcumin solubility and bioavailability Then complexrsquoseffects were evaluated in cell cultures as well as in vivoin an orthotopic lung tumor mouse model Cell prolifer-ation in the presence of curcumin-cyclodextrin complexwas decreased while apoptosis rates were increased in lungepithelial tumor cells in vitro For in vivo experimentscells were grafted into lungs of C57Bl6 mice treated byan oral administration of a nonsoluble form of curcuminCds alone or curcumin-CD complexes combined with ornot combined with gemcitabine [114] In addition the sizeof orthotopically implanted lung tumors was noticeablyreduced by curcumin complex administration in compar-ison with nonsolubilized curcumin Moreover curcumin-cyclodextrin complex potentiated the gemcitabine-mediatedantitumor effects Results underlined a prospective preser-vative effect of curcumin with gemcitabine thus providinga proficient remedial alternative for anti-lung cancer treat-ment [114] Moreover for noninvasive imaging encapsu-lated 4-[35-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic-acid] (CLEFMA) was developed by usinghydroxypropyl 120573-cyclodextrin [115] CLEFMA possessedmore persuasive antiproliferative effects in lung adenocar-cinoma without any impact on normal lung fibroblasts Itseems that CLEFMA liposomes retained the antiproliferative

effectiveness of free CLEFMA while sustaining its nontoxiccharacter in normal lung fibroblasts In addition tumorvolume extensively reduced after treatment with CLEFMAto 94 in rat xenograft tumors Outcomes revealed theusefulness of liposomes to supply as a carrier for CLEFMAand this study was the first to exhibit the efficacy of novelcurcuminoid CLEFMA in a preclinical model [115]

To sum up these collected data show that Cds helpincrease the hydrolytic stability of curcumin photodecompo-sition rate protection against decomposition bioavailabilityand molecular dispersion compared to the free curcuminwithout altering their pharmacokinetic characteristics (Table1) These data also confirm that cyclodextrin-curcumin com-plex has a priority against free curcumin in cell uptakeantiproliferative and anti-inflammatory effects by suppres-sion of cyclin D1 MMP-9 and VEGF and induction of deathreceptors and apoptosis

7 Dendrimers

Dendrimers are a group of greatly branched globular poly-mers which are created with structural control rivalingtraditional biomolecules They were introduced in the mid-1980s and are referred to as synthetic proteins Dendrimersare a series of polymeric architectures with different chem-ical and surface-related properties They have much moreaccurately controlled structures with a globular shape anda single molecular weight rather than a distribution ofmolecular weights in comparison with the traditional lin-ear polymers [116] A number of properties put togetherdendrimersrsquo exceptional nanostructures with the interior-surface architecture or generations (Table 1) The dendrimerstructure consisting of a core branched interiors andnumerous surface functional groups serves as a platform towhich additional substrates can be added to this sphericalmolecule in a highly controlled manner This nanospacerepresents an isolated environment thus decreasing toxicityassociated with the payload The well-defined organizationdense spherical form size monodispersity and controllableldquosurfacerdquo functionalities of dendrimers make them brilliantapplicants for assessment as drug delivery services [117]In addition the biocompatibility silhouette of dendrimersdonates to their effectiveness in molecular imaging Thisbiocompatibility can be increased via functionalization withsmallmolecules Increased biocompatibility is also associatedwith lower generation branch cells with anionic or neutralgroups compared to similar branch cells of higher generationswhich have cationic surface groups

To test whether dendrimer curcumin displays both cyto-toxicity and water solubility Debnath et al [57] generateddendrimer curcumin conjugate a water-soluble and effectivecytotoxic agent against breast cancer cell lines In vitro resultsshowed that dendrimer curcumin conjugate dissolved inwaterwas significantlymore effective in inducing cytotoxicityagainst SKBr3 and BT549 human breast cancer cells andeffectively induced cellular apoptosis measured by caspase-3 activation In another study the interaction of curcumindendrimers with cancer cells serum proteins and human redblood cells was studied by Yallapu et al [58] They assessed


dendrimersrsquo potential application for in vivo preclinical andclinical studies Protein interaction studies were conductedusing particle size analysis zeta potential and western blottechniques To evaluate its acute toxicity and hemocompati-bility curcumin-dendrimer was incubated with human redblood cells In addition the cellular uptake of curcumin-dendrimer was assessed by using curcumin levels in can-cer cells using ultraviolet-visible spectrophotometry Resultsshowed a remarkable capacity of the dendrimer curcuminnanoformulation to bind to plasma protein However no sig-nificant changes were observed in the zeta potential and theextensive hemolysis of the dendrimer curcumin formulationResults showed that the positively charged amino surfacegroups cause destabilize the cell membrane and cell lysisThistype of lytic effect on erythrocytosis is extremely dangerouswhen administered in vivo Therefore polyethylene glycolconjugation of dendrimer formulations may be required todecrease this activity [118 119]

Cao et al [59] investigated the interactions betweenpolyamidoamine-C (a dendrimers) and curcumin by usingfluorescence spectroscopy andmolecularmodelingmethodsResults showed that the polyamidoamine-C12 25 formationtogether with curcumin induced the fluorescence quenchingof polyamidoamine-C12 25 Curcumin entered the inter-face of polyamidoamine-C12 25 with mainly five classesof binding sites by hydrophobic bonds hydrogen bondsand van der Waals forces interactions The larger valuesof binding constants indicated that polyamidoamine-C1225 holds the curcumin strongly Furthermore in anotherstudy polyamidoamine encapsulated curcumin inhibitedtelomerase activity in human breast cancer cell line [60]These researchers also used telomerase repeat amplificationprotocol (TRAP) assay and determined relative telomeraseactivity (RTA) In vitro results demonstrated that den-drimers have no cytotoxicity in human breast cancer cellline Also polyamidoamine encapsulating curcumin con-centration increased while RTA decreased These resultssuggested that polyamidoamine encapsulating curcumin hada dose-dependent cytotoxicity effect on breast cancer cell linethrough downregulation and inactivation of telomerase andinducing apoptosis by enhancing curcumin uptake by cells(Table 1) So polyamidoamine can be considered as a finecarrier especially for hydrophobic agents

The stability of curcumin and its antitumor propertieswere improved by using dendrosomal nanoparticles in vitroand in vivo by our teamrsquos work [61ndash63 120] The made den-drosomal nanoparticle-curcumin is a neutral amphipathicand biodegradable nanomaterial with variable monomerssuitable for inert cell drug porters It is a new type of bio-compatible polymeric particle taken from plant fatty acidswhich keeps curcumin size at 80 nm (Table 1) Acute andchronic toxicity of dendrosomal nanoparticle-curcumin wasinvestigated in mice Our results shed new light on den-drosomal nanoparticle-curcuminrsquos potential biocompatibilityfor in vitro and in vivo biological systems In additionthe protective and the therapeutic effects of dendrosomalnanoparticle-curcumin were assessed on an animal modelof breast cancer through apoptosis proliferation andangiogenesis pathways In our study dendrosomal

nanoparticle-curcumin significantly suppressed proliferationof human andmouse carcinoma cells In vitro results showednot only that dendrosomes have significantly increased theuptake of curcumin but also that dendrosomal nanoparticle-curcumin inhibited the growth of cancer cells rather thannormal ones by inducing apoptosis In toxicity profilebased on hematological blood chemical and histologicalexaminations minimal hepatic and renal toxicity wereseen with high dendrosomal nanoparticle-curcumin dosesIn addition in vivo results showed that tumor incidenceweight and size were significantly declined in dendrosomalnanoparticle-curcumin-treated group Dendrosomal nano-particle-curcumin also induced the expression of proapop-totic Bax protein and reduced antiapoptotic Bcl-2 proteinexpression relative to the control group Moreover prolife-rative and angiogenic markers were lowered in dendrosomalnanoparticle-curcumin-treated animalsThese findings pointto the features of the polymeric carrier as a promising drug-delivery system for cancer therapy In another study we alsoevaluated the antiproliferative and anticarcinogenic effectsof dendrosomal nanoparticle-curcumin in rat colon cancerOur results demonstrated the potential anticancer effectsof dendrosomal nanoparticle-curcumin in a typical animalmodel of colon cancer The results provide evidence thatnanoparticle-curcumin exerts significant chemoprotectiveand chemotherapeutic effects on colon cancer through inhi-bition of cell proliferation and apoptosis induction [61 63]These tunable properties make dendrimers more attractiveagents for biomedical applications compared to other nano-vectors such as micelles liposomes or emulsion droplets(Table 1) Therefore they are being preferred as carrierswhich are the foundation for new types of anticancer entitiesAlthough the application of dendrimers as drug-deliveryinstruments has been advertised as a major area of theirpotential application this part has really been little studied[121]

So mentioned studies suggest that dendrimer curcuminconjugate in water was significantly more effective in induc-ing cytotoxicity through downregulation and inactivation oftelomerase activity and in inducing apoptosis by induction ofthe expression of proapoptotic Bax protein and reduction ofantiapoptotic Bcl-2 protein expression since curcuminuptakeenhances

8 Nanogels

Nanogels are self-possessed of cross-linked three-dimen-sional polymer chain networks which are created throughcovalent linkages and can be customized to gel networkswith biocompatible and degradable properties The porosityamong these cross-linked networks not only provides aperfect reservoir for loading drugs but also keeps them fromenvironmental degradation [58] The swelling of nanogels inan aqueous setting is controlled by using the polymer chem-ical structure cross-linking degree and the polyelectrolytegelrsquos charge density andor by pH value ionic strength andchemical nature of low molecular mass (Table 1) Further-more nanogels can be chemically modified to incorporate


various ligands for targeted drug delivery triggered drugrelease or preparation of composite materials [122]

Nanogels are developed as carriers for drug delivery andcan be planned to spontaneously absorb biologically activemolecules via creation of salt bonds hydrogen bonds orhydrophobic interactions that can enhance oral and brainbioavailability of low-molecular-weight drugs and biomacro-molecules [122] An important criterion for a nanogel carrierwith widespread biomedical abilities is to have good stabilityin biological fluids which would prohibit aggregation In thisregard Goncalves et al (2012) applied a self-assembled dex-trin nanogel as curcumin delivery system by using dynamiclight scattering andfluorescencemeasurementsThey showedthat the stability and loading efficiency of curcumin-loadednanogel depend on the nanogelcurcumin ratio The in vitrorelease profile in HeLa cell cultures indicated that dextrinnanogel may act as a suitable carrier for the controlled releaseof curcumin [123] Various nanogel properties can be attainedby altering the chemical functional groups cross-linking den-sity and surface-active and stimuli-responsive elements [58]Nanogels demonstrate excellent potential for systemic drugdelivery that should have a few common features includinga smaller particle size (10ndash200 nm) biodegradability andorbiocompatibility prolonged half-life high stability higheramount of drug loading andor entrapment and moleculesprotection from immune system [58] Mangalathillam et al(2011) loaded curcumin into chitin nanogels and analyzed itby dynamic light scattering (DLS) scanning electron micro-scope (SEM) and Fourier transform infrared spectroscopy(FTIR) Then the nanogelrsquos cytotoxicity was analyzed onhuman dermal fibroblast and human melanoma cells Thecurcumin-chitin nanogels showed higher release at acidicpH compared to neutral pH The in vitro results showedthat curcumin-chitin nanogels have had a specific toxic-ity on melanoma cells in a concentration range of 01ndash10mgmL but less toxicity towards normal cells [64] Theconfocal analysis confirmed the high uptake of curcumin-chitin nanogels by human melanoma cells In addition itwas indicated that curcumin-chitin nanogels at the higherconcentration of the cytotoxic range may show comparableapoptosis in comparison with free curcumin The curcumin-chitin nanogels also showed a 4-fold increase in steadystate transdermal flux of curcumin in comparison with freecurcumin The histopathology studies showed loosening ofthe horny layer of the epidermis facilitating penetrationwith no observed signs of inflammation in the group treatedwith curcumin-chitin nanogels [64] These results suggestedthe formulated curcumin-chitin nanogelsrsquo explicit advantagefor the treatment of melanoma by effective transdermalpenetration

Drug release from nanogelsrsquo networks depends on theinteraction of hydrophobic and hydrogen complicationandor coordination of drug molecules with the polymerchain networks Preclinical studies suggest that nanogels canbe used for the efficient delivery of biopharmaceuticals in cellsas well as for increasing drug delivery across cellular barriers[124] Wu et al [125] designed a class of water-dispersiblehybrid nanogels for intracellular delivery of hydrophobiccurcumin They synthesized hybrid nanogels by coating

the AgAu bimetallic nanoparticles with a hydrophobicpolystyrene gel layer as internal shell and a subsequent thinhydrophilic nonlinear poly(ethylene glycol-) based gel layeras external shell The AgAu core nanoparticles not onlyemitted well-built fluorescence for imaging and monitoringat the cellular level but also exhibited burly absorption in thenear-infrared region for photothermal conversion and signif-icantly improved the therapeutic efficacy Furthermore whilethe internal polystyrene gel layer was introduced to providestrong hydrophobic interactionswith curcumin for high drugloading yields the external nontoxic and thermoresponsivepoly(ethylene glycol) analog gel layer was designed to triggerthe release of the preloaded curcumin by either variationof surrounding temperature or exogenous irradiation withnear-infrared light These results suggest that such designedmultifunctional hybrid nanogels are properly suited for invivo and clinical trials by promising natural medicine ofcurcumin to the forefront of therapeutic agents for cancersand other diseases In addition hyaluronic acid- (HA-) basednanogel-drug conjugates with enhanced anticancer activitywere designed by Wei et al for the targeting of CD44-positive and drug-resistant tumors [65] These authors syn-thesized nanogel-drug conjugates based on membranotropiccholesteryl-HA for efficient targeting and suppression ofdrug-resistant tumors This class of tumors expresses CD44receptors cellular glycoproteins which bind to HA Thesenanogel conjugates have significantly increased the bioavail-ability of poorly soluble drugs such as curcumin In this studythe small nanogel particles with a hydrophobic core andhigh drug loads were formed after ultrasonication [65]Thesenanogel particles demonstrated a sustained drug releasefollowing the hydrolysis of biodegradable ester linkageImportantly cholesteryl-HA-drug nanogels demonstrated a2ndash7 times higher cytotoxicity in CD44-expressing drug-resistant human breast and pancreatic adenocarcinoma cells[65] These nanogels were efficiently internalized via CD44receptor-mediated endocytosis and simultaneous interactionwith the cancer cellmembrane [65] Anchoring by cholesterolmoieties in cellular membrane caused more efficient drugaccumulation in cancer cells The cholesteryl-HA nanogelswere able to penetrate multicellular cancer spheroids andexhibited a higher cytotoxic effect in the system modelingtumor environment than both HA-drug conjugates and freedrugs [65]

Overall the proposed design of nanogel-drug conjugatescan allow significantly enhancing drug bioavailability sta-bility loading efficiency effective transdermal penetrationcancer cell targeting and treatment efficacy against drug-resistant cancer cells and multicellular spheroids (Table 1)

9 Chitosans

Chitosan is a linear polysaccharide composed of randomlydisseminated deacetylated and acetylated units It is madecommercially by deacetylation of chitin which is the struc-tural component of crustaceansrsquo exoskeleton and fungi cellwalls Unlike other biodegradable polymers chitosan is theonly one exhibiting a cationic character due to its primaryamino groups that responsible for various effects in drug


delivery systems [126] It displays particular properties forexample solubility in various media polyoxysalt creationpolyelectrolyte behavior metal chelations and structuraluniqueness (Table 1) One study showed that the fluorescenceintensity of curcumin can be greatly improved in the presenceof chitosan by bovine and human serum albumin [104] Themethod has been profitably used for the determination ofhuman serum albumin in real samples Data analysis recom-mended that the highly enhanced fluorescence of curcuminresulted from synergic effects of favorable hydrophobicmicroenvironment provided by bovine serum albumin andchitosan and efficient intermolecular energy transfer betweenbovine serum albumin and curcumin Bovine serum albuminmay bind to chitosan through hydrogen bonds which causesthe protein conformation to switch from 120573-fold to 120572-helixCurcumin can combine with bovine serum albumin from 120573-fold to 120572-helix and can also combine with the bovine serumalbumin-chitosan complex via its center carbonyl carbonTherefore chitosan plays a key role in promoting the energytransfer process by shortening the distance between bovineserum albumin and curcumin [104]

Polycaprolactone nanocarriers decorated with amucoad-hesive polysaccharide chitosan containing curcumin werealso developed [127] In order to optimize the preparationconditions these nanocarriers were prepared by the nano-precipitation method by using different molar masses andconcentrations of chitosan and triblock surfactant polox-amer Chitosan-coated nanocarriers revealed positive surfacecharge and a mean particle radius ranging between 114and 125 nm confirming the decoration of the nanocarrierswith the mucoadhesive polymer through hydrogen bondsbetween ether and amino groups from poloxamer andchitosan respectively Dynamic light scattering studies haveshown monodisperse nanocarriers Furthermore colloidalsystems showed mean drug content about 460 lgmL andencapsulation efficiency higher than 99 In summary thesenanocarriers showed a vast ability to interact with mucinalso indicating their suitability formucoadhesive applicationswhen coated with chitosan [127]

On the other hand curcumin-phytosome-loaded chi-tosan microspheres were developed by combining polymer-and lipid-based delivery systems to improve the bioavailabil-ity and prolong the retention time of curcumin [66] Thesecomplexes were produced by encapsulating curcumin phy-tosomes in chitosan microspheres using ionotropic gelationDifferential scanning calorimetry and FUTI spectroscopyrevealed that the integrity of the phytosomes was pro-tected within the polymeric matrix of the microspheresIn vitro release rate of curcumin from the curcumin-phytosome-loaded chitosan microspheres was slower thancurcumin-loaded chitosan microspheres Pharmacokineticstudies showed an increase in curcumin absorption incurcumin-phytosome-loaded chitosan microspheres com-pared with curcumin phytosomes and curcumin-loadedchitosan microspheres Moreover half-life of curcumin inoral administration of curcumin-phytosome-loaded chitosanmicrospheres was longer than the two other ones Theseresults indicated that the novel curcumin-phytosome-loadedchitosan microspheres combined system has the advantages

of both the chitosanmicrospheres and the phytosomes whichhad better effects of promoting oral absorption and prolong-ing retention time of curcumin than single curcumin phyto-somes or curcumin-loaded chitosanmicrospheresThereforethe phytosome chitosan microspheres may be used as asustained delivery system for lipophilic compounds withpoorwater solubility and loworal bioavailability [66] A studyshowed that curcumin bound to chitosan nanoparticles wasnot rapidly degraded in comparison to free curcumin andthe uptake of curcumin-loaded chitosan NPs by mousersquos redblood cells (RBC) was much better than free curcumin [67]Oral delivery of curcumin-loaded chitosan NPs improvedthe bioavailability of curcumin both in plasma and in RBCLike chloroquine conjugated curcumin inhibited parasitelysate induced heme polymerization in vitro in a dosedependentmanner and it had a lower IC50 value than chloro-quine Additionally feeding of curcumin-loaded chitosanNPs caused a higher survival in mice infected with a lethalstrain of Plasmodium yoelii Therefore binding of curcuminto chitosan NPs improves its chemical stability and bioavail-ability In vitro data also suggest that this complex can inhibithemozoin synthesis which is lethal for the parasite [67]

In another study chitosan showed promising features asauxiliary agent in drug delivery (eg slimming wound dress-ing and tissue engineering) An in situ injectable nanocom-posite hydrogel curcumin was effectively developed for useas a treatment in the dermal wound repair process [68] Invitro release studies disclosed that the encapsulated nanocur-cumin was slowly released from the NO-carboxymethylchitosanoxidized alginate hydrogel with the controllablediffusion behavior Additionally in vivo wound healingstudies revealed that application of nanocurcuminNO-carboxymethyl chitosanoxidized alginate hydrogel couldsignificantly improve the reepithelialization of epidermis andcollagen deposition on rat dorsal wounds DNA proteinand hydroxyproline content in wound tissue indicated thatmaking a combination by using nanocurcumin and NO-carboxymethyl chitosanoxidized alginate hydrogel couldsignificantly accelerate the process of wound healing Soresults suggested that the developed nanocurcuminNO-carboxymethyl chitosanoxidized alginate hydrogel as apromising wound dressing might have potential applicationin the wound healing [68]

Water-soluble nanocarriers of curcumin were synthe-sized characterized and applied as a stable detoxifyingagent for arsenic poisoning [69] The therapeutic efficacy ofencapsulated curcumin nanocarriers was investigated againstarsenic-induced toxicity in an animal model In this regardsodium arsenite and encapsulated curcumin were orallyadministered to male Wistar rats for 4 weeks Arsenic dra-matically declined blood d-aminolevulinic acid dehydrataseactivity and glutathione and increased blood reactive oxygenspecies These alterations were accompanied by increasesin hepatic total ROS oxidized glutathione and thiobar-bituric acid-reactive substance levels By contrast hepaticglutathione superoxide dismutase and catalase activitieswere considerably declined after arsenic exposure indicativeof oxidative stress Brain amines levels such as dopaminenorepinephrine and 5-hydroxytryptamine also showed


considerable changes after arsenic exposure Coadministra-tion of encapsulated curcumin nanocarriers providedobvious favorable effects on the adverse changes in oxidativestress parameters induced by arsenicThe results revealed thatencapsulated curcumin nanocarriers have better antioxid-ant and chelating potential compared to free curcuminTherefore the significant neurochemical and immunohisto-chemical protection afforded by encapsulated curcumin nan-ocarriers shows their neuroprotective effectiveness [69]Chitosan also explains fungistatic haemostatic and anti-tumor effects [70] In this regard stable vesicles for efficientcurcumin encapsulation delivery and controlled releasehave been obtained by coating of liposomes with thin layerof newly synthesized chitosan derivatives [71] Some spe-cial derivatives of chitosan were studied such as the cationichydrophobic and cationic-hydrophobic derivatives Zetapotential data proved effectual coating of liposomes withall these derivatives In this regard the liposomes coatedwith cationic-hydrophobic chitosan derivatives were themain promising curcumin carriers They can easily entercell membrane and release curcumin in a controlledapproach and the biological investigations showed that suchorganizations are nontoxic for normal murine fibroblastswhile toxic for murine melanoma tumors [71]

In a recent study Pluronic F127 was used to enhance thesolubility of curcumin in the alginate-chitosan NPs [128]Atomic force and scanning electron microscopic analysisdemonstrated that the particles were almost spherical inshape (100 plusmn 20 nm) Fourier transform infrared analysisshowed impending interactions among the components inthe composite NPs Furthermore encapsulated curcuminefficiency confirmed considerable increase over alginate-chitosan NPs without Pluronic Cytotoxicity assay explainedthat composite NPs at a concentration of 500120583gmL werenontoxic for HeLa cells Moreover cellular internalizationof curcumin-loaded complex was confirmed by green flu-orescence inside the HeLa cells [128] Curcumin-loadedbiodegradable thermoresponsive chitosan-g-poly copoly-mericNPswere prepared by using ionic cross-linkingmethod[129] The results showed that these NPs were nontoxic todifferent cancerous cell lines whereas the curcumin loadedwith NPs showed a specific toxicity for the abovementionedcell lines Additionally these results were further approvedby flow cytometry analysis which proved increased apoptosison these cell lines in a concentration-dependent mannerFurthermore the blood compatibility assay showed the pos-sibility of an IV injection with this formulation Preliminarystudy provided clear evidence for the thermal targetingof curcumin by being loaded with novel thermosensitivechitosan-g-PNIPAAm NPs and efficacies were achieved incancer therapy These results indicated that thermorespon-sive chitosan-g-poly copolymeric NPs can be a potentialnanocarrier for curcumin drug delivery [129] Novel cationicpoly(butyl) cyanoacrylate (PBCA) NPs coated with chitosanwere synthesized with curcumin The transmission electronmicroscopy showed the spherical shape of prepared NPsalong with the particle size Curcumin NPs demonstratedmore therapeutic efficacy than free curcumin against apanel of human hepatocellular cancer cell lines Encapsulated

curcumin with PBCA NPs caused a profound change inthe pharmacokinetics of the drug The elimination half-life of curcumin was increased 52-fold in loaded form withPBCA NPs and ultimately its clearance was also decreased25-fold Additionally the higher plasma concentration ofcurcumin for curcumin-PBCA NPs might be a result of theNPs size and chitosan coating to keep drug in the bloodcirculation for a more extended period Besides the meanresidence time of curcumin-PBCA NPs was longer thanfree curcumin These results might be due to accumulationof NPs in endoplasmic reticulum system of organs andsustained release of the drug from them Furthermore thecarriersrsquo properties for instance shape size charge andhydrophilicity can prolong the retention of them in theblood circulation There was also a substantial increase inthe distribution volume (51-fold) that was quite unexpectedObviously it was possible that the larger micellar carri-ers were sequestered by the reticuloendothelial system orother tissues and truly led to improved distribution volume[130] Additionally treatment with curcumin NPs resultedin reduced tumor size and visible blanching of tumors[131]

So far curcumin-loaded chitosan NPs improve thebioavailability and prolong the retention time of curcumindue to accumulation of NPs in endoplasmic reticulum systemand the carriersrsquo features such as shape size charge andhydrophilicity (Table 1) Gathered data also propose that thiscomplex can be lethal for the parasite because of hemozoinsynthesis inhibition Some in vivo experiments also resultedin better wound healing after application of curcumin-loadedchitosan NP polymers by means of better reepithelializationof epidermis and collagen deposition This complex couldalso be administered in order to detoxify arsenic throughbetter antioxidant and chelating potential These compoundsgained some achievements in cancer therapy as well

10 Gold Nanoparticles

Metal nanoparticles have been known since very old timesand gold nanoparticles (AuNPs) with optical and electro-chemical uniqueness have proven to be a potent appara-tus in nanomedicinal requests [132] They have also beenlargely used in immunochemistry immunohistochemistryand immunoblotting for electron microscopy They are oftengenerated in various shapes [132] and their properties arestrongly dependent on the conditions in which they are pre-pared Moreover the stability of AuNPs and their capabilityto combine with biomolecules are their other outstandingproperties AuNPs are studied broadly as imperative drugdelivery vectors due to some of their characteristic aspectssuch as low cytotoxicity tunable surface features and stabilityin in vivo conditions and can be easily synthesized andfunctionalized (Table 1) They can also act as drug pool forsmall drugmolecules proteins DNA or RNAwith improvedlong life in the blood circulation Rajesh et al [133] usedpolyvinyl pyrrolidone (PVP) as a proven drug carrier tocurcumin conjugation with AuNPs to enhance solubility ofcurcumin Results showed a superior assurance for suchconjugates as therapeutic-curcumin-imaging materials in


biomedical field [134] Kumar et al (2012) also preparedthe chitosan-curcumin nanocapsules with AuNPs via solventevaporation method Scanning electron microscopy andtransmission electron microscopy were done to describethe drug entrapped nanocapsules The average diameter ofAuNPs was found to be in the range of 18ndash20 nm andthe nanocapsules were found to be in the range of 200ndash250 nm Furthermore the Fourier transform infrared analysisrevealed no possible interactions among the constituentswith the chitosan nanoparticles The drug release studiesrevealed that curcumin encapsulated chitosan with AuNPswas controlled and steadied when compared with curcuminencapsulated chitosan nanoparticles Use of in vitro drugrelease in various kinetic equations indicated a matrix modelwith uniform distribution of curcumin in the nanocapsules[135] Additionally the tunability of AuNPs allows for com-plete control of surface properties for targeting and sustainedrelease of the bioactive molecules [136]

In a study by Singh et al [72] curcumin was bound on thesurface of AuNPs in order to increase the bioavailability ofit The AuNPs were synthesized by direct decline of HAuCl4by curcumin in aqueous part Curcumin acted as both areducing and capping agent and a stabilizing gold sol formany months Furthermore these curcumin-capped AuNPsshowed an excellent antioxidant activity which was estab-lished by 22-diphenyl-l-picrylhydrazyl radical test Conse-quently the practical surface of AuNPs with curcumin maysuggest a new way of use of curcumin towards possible drugdelivery and therapeutics [72] In another study effect ofcurcumin-conjugated-AuNPs was investigated on peripheralblood lymphocytes [137] The treated lymphocytes showedtypical characteristics of apoptosis which included chromatincondensation and membrane blebbing and occurrence ofapoptotic bodies Results revealed that these conjugatednanoparticles may be used as drugs in nontoxic range[137] In order to target cancer at a single cell level gold-citrate nanoparticles were also synthesized with diametersof 13 nm [73] AuNPs were coated with sodium citrateOutcomes revealed that cancerous cells were more proneto absorb nanomaterials coated with citrate than normalsomatic cells Moreover the damage was reversible withAuNPs and the normal dermal fibroblast cells were able toregenerate stress fibers which were lost during exposureHowever cancer cells were unable to recover from the dam-age inflicted by Aucitrate nanoparticle exposure [73] Manjuand Sreenivasan [136] also formulated a simple method forthe fabrication of water-soluble curcumin conjugated AuNPsto target various cancer cell lines Curcumin conjugatedto hyaluronic acid to get a water-soluble compound Theywere made AuNPs by diminishing chloroauric acid usinghyaluronic acid-curcumin which played dual roles of areducing and a stabilizing agent and subsequently anchoredfolate conjugated PEG Their interaction with various can-cer cell lines was followed by flow cytometry and confo-cal microscopy Blood-materials interactions studies provedthat the nanoparticles are extremely hemocompatible Flowcytometry and confocal microscopy results demonstratedconsiderable cellular uptake and internalization of the par-ticles by various cancer cells [136]

In conclusion curcumin conjugated AuNPs exhibitedmore cytotoxicity compared to free curcumin (Table 1)AuNPs also cause targeting and sustained release of curcuminand an excellent antioxidant activity

11 Silvers

Silver has usually been utilized as an incredibly efficientmate-rial for antimicrobial utility [138] In small concentrations itis safe for human cells but lethal for the majority of bacteriaand viruses [139] With development of nanotechnologyit has become the metal of choice in restricting microbialgrowth and expansion in a variety of nanoparticle-relatedrequests [138] Silver nanoparticles are identified for theirbrilliant optoelectronic properties originated from surfaceplasmon resonance They can be used in optoelectronicsbiological labeling and biological and chemical sensing(Table 1) They have shown excellent antimicrobial activitycompared to other available silver antimicrobial agents

Sodium carboxylmethyl cellulose silver nanocompositefilms were attempted for antibacterial applications so toimprove their applicability novel film-silver nanoparticle-curcumin complexes have been developed [74] These filmswere described by FTIRUV-visible X-ray diffraction (XRD)thermogravimetric analysis (TGA) differential scanningcalorimetry (DSC) and TEM techniques The structuredsilver nanoparticles had a typical particle size of 15 nm Cur-cumin loading into sodium carboxylmethyl cellulose silvernanocomposite films was achieved by diffusion mechanismThe UV analysis showed superior encapsulation of curcuminin the films with higher sodium carboxylmethyl cellulosecontent Additionally it was surveyed that the presence ofsilver nanoparticles in the films improved the encapsulationof curcumin demonstrating an interaction between themMoreover results showed that the sodium carboxylmethylcellulose films produced with silver nanoparticles have asynergistic effect in the antimicrobial activity against Ecoli Furthermore curcumin loaded with sodium carboxyl-methyl cellulose silver nanocomposite films extended consid-erable inhibition of E coli growth compared with the silvernanoparticles and curcumin alone film Therefore the studyobviously supplied novel antimicrobial films which werepotentially helpful in preventingtreating infections [74] Inanother study novel hydrogel-silver nanoparticle-curcumincomposites have been built up to increase its applicabilityThese were first synthesized by polymerizing acrylamide inthe presence of polyvinyl sulfonic acid sodium salt and atrifunctional cross-linker (246-triallyloxy 135-triazine) byusing redox initiating system Silver nanoparticles were thenproduced throughout the hydrogel networks by using in situmethod incorporating the silver ions and following dropwith sodium borohydride Curcumin loading into hydrogel-silver nanoparticles complex was earned by diffusion mech-anism An attractive arrangement of silver nanoparticles(shining sun ball in range 5 nm) with apparent smaller grownnanoparticles (1 nm) was detected A comparative antimicro-bial study was performed for hydrogel-silver nanocompositesand hydrogel-silver nanoparticle-curcumin composites Theresults indicated that hydrogel-AgNPs-curcumin composites


have exhibited greater reduction of E coli growth com-pared with Ag NPs loaded hydrogels The current workdemonstrated that combining hydrogel nanotechnology andcurcumin is promising for developing novel antimicrobialagents with potential applications in dressing of varioustypes of skin wounds The entrapped silver nanoparticlesand curcumin molecules showed sustained release whichadvises enormous prolonged therapeutic values [74] Inaddition silver nanoparticles could protect cells against HIV-1 infection and help with the wound healing process and alsohave essential function as an anti-inflammation an antiviraland an anticancer agent [75] So the combination of silvernanoparticles and curcumin besides prolonged therapeuticoutcomes and sustained release has several other usefuleffects such as anti-inflammatory anti-infection anticancerand wound healing (Table 1)

12 Solid Lipids

Solid lipid nanoparticles (SLNs) are one of the novel potentialcolloidal carrier systems as alternative materials to poly-mers for parenteral nutrition SLNs have typically sphericaland submicron colloidal carriers (50 to 1000 nm) and arecomposed of physiologically tolerated lipid components withsolid shape at room temperature (Table 1)They are one of themost fashionable advances to develop the oral bioavailabilityof poorly water-soluble drugs [76] Advantages of SLNs arehigh and improved drug content ease of scaling up andsterilizing better control over release kinetics of encap-sulated compounds enhanced bioavailability of entrappedbioactive compounds chemical protection of incorporatedcompounds much easier manufacturing than biopolymericnanoparticles conventional emulsion manufacturing meth-ods and applicability and very high long-term stabilityapplication versatility [76]

Kakkar et al [77] loaded curcumin into SLNs to improveits oral bioavailability Curcumin-SLNs with an average par-ticle size of 1346 nm and a total drug content of lt92 wereproduced by using a microemulsification technique In vivopharmacokinetics was performed after oral administrationof curcumin-SLNs by using a validated LC-MSMS methodin ratrsquos plasma Results revealed significant improvementin bioavailability times after administration of curcumin-SLNs with respect to curcumin-solid lipid Data confirmedthat enhanced and reliable bioavailability will help in estab-lishing its therapeutic impacts [77] Furthermore Kakkaret al [78] incorporated curcumin into SLNs to achieve asignificant bioavailability of curcumin Then the plasma andbrain cryosections were observed for fluorescence underfluorescentconfocal microscope Biodistribution study wasalso performed using 99m Tc-labeled curcumin-SLNs andcurcumin-solid lipid in mice after oral and intravenousadministration Presence of yellow fluorescent particles inplasma and brain indicated effective delivery of curcumin-SLNs across the gut wall and the blood brain barrierBlood AU coral value for curcumin-SLNs was 8135 timesgreater than curcumin-solid lipid confirming a prolongedcirculation of the formerThe ratio of bloodAUC intravenouscurcumin-SLNcurcumin-solid lipid in blood was le1 while

the ratio in brain promisingly indicates 30 times higher pref-erential distribution of curcumin-SLNs into brain confirmingtheir direct delivery [78]

Dadhaniya et al (2011) examined the adverse effects ofa new solid lipid curcumin particle in rats Administrationof the conjugated curcumin showed no toxicologically sig-nificant treatment-related changes in the clinical parame-ters including behavioral observations ophthalmic exami-nations body weights and weight gains food consumptionand organ weights or the paraclinical parameters includinghematology serum chemistry and urinalysis In additionterminal necropsy revealed no treatment-related gross orhistopathology findings [140] Expansion of SLNs is one ofthe promising fields of lipid nanotechnology with severalpotential applications in drug delivery system and clinicalmedicine and research The experimental paradigm of cere-bral ischemia in rats by curcumin-SLNs was prepared therewas an improvement of 90 in cognition and 52 inhibitionof acetylcholinesterase versus cerebral ischemic and neuro-logical scoring which improved by 79 [78] Levels of super-oxide dismutase catalase glutathione and mitochondrialcomplex enzyme activities were also significantly increasedwhile lipid peroxidation nitrite and acetylcholinesterase lev-els decreased after curcumin-SLNs administration Gamma-scintigraphic studies showed 164 and 30 times improvementin brain bioavailability upon oral and intravenous admin-istration of curcumin-SLNs versus curcumin-silver Resultsindicated the protective role of curcumin-SLNs against cere-bral ischemic insult suggesting that it is packaged suitablyfor improved brain delivery [78] Moreover simultaneouscurcumin treatment during the induction of neurotoxicityby aluminum was reported by Kakkar and Kaur (2011)They prepared solid lipid nanoparticles of curcumin withenhanced bioavailability and examined its therapeutic effectsin alleviating behavioral biochemical and histochemicalchanges in mice Adverse effects of aluminum were com-pletely reversed by oral administration of curcumin-SLNsTreatment with free curcumin showed lt15 recovery inmembrane lipids and 22 recovery in acetylcholinesterasewith respect to aluminum treated group Histopathology ofthe brain sections of curcumin-SLNs treated groups also indi-cated significant improvement [141] This study emphasizedthe potential of curcumin-SLNs for treatment of Alzheimerrsquosdisease though the therapeutic potential of curcumin interms of reversing the neuronal damage once induced islimited due to its compromised bioavailability [141]

Yadav et al (2009) also developed a novel formulationapproach for treating experimental colitis in the rat modelby a colon-specific delivery approach Solid lipid micropar-ticles of curcumin were prepared with palmitic acid stearicacid and soya lecithin with an optimized percentage ofpoloxamer 188 Then the colonic delivery system of solidlipid microparticles formulations of curcumin was furtherinvestigated for their antiangiogenic and anti-inflammatoryactivities by using chick embryo and rat colitis models Datashowed that solid lipid microparticles of curcumin proved tobe a potent angioinhibitory compound in the chorioallantoicmembrane assay Rats treated with curcumin and its solidlipid microparticle complex showed a faster weight gain


compared with dextran sulfate solution control rats Theincrease in whole colon length appeared to be signifi-cantly greater in solid lipid microparticle-treated rats whencompared with free curcumin and control rats Moreoverdecreased mast cell numbers was observed in the colonmucosa of curcumin-solid lipid microparticle treated ratsThe degree of colitis caused by administration of dextran sul-fate solution was significantly attenuated by colonic deliveryof curcumin-solid lipid microparticles [79] Being a nontoxicnatural dietary product it seems that curcumin can be usefulin the therapeutic strategy for inflammatory bowel diseasepatients Wang et al (2012) aimed to formulate curcumin-SLNs to improve its therapeutic efficacy in an ovalbumin-induced allergic rat model of asthma in vitro tests wereperformed in order to check Physiochemical properties ofcurcumin-SLNs and its release experiments The pharma-cokinetics in tissue distribution and the therapeutic effectswere studied in mice X-ray diffraction analysis revealedthe amorphous nature of the encapsulated curcumin Thecurcumin concentrations in plasma suspension were consid-erably superior to free curcumin and all the tissue concen-trations of curcumin increased after curcumin-SLNs admin-istration especially in lung and liver In addition curcumin-SLNs efficiently suppressed airway hyperresponsiveness andinflammatory cell infiltration It also inhibited the expressionof T-helper-2-type cytokinesin bronchoalveolar lavage fluidsignificantly compared to free curcumin These observationsimply that curcumin-SLNs can be a promising candidate forasthma therapy [80] In another study transferrin-mediatedSLNs were prepared to increase photostability and anticanceractivity of curcumin against breast cancer cells in vitro [81]Microplate analysis and flow cytometry techniques were usedfor cytotoxicity and apoptosis studiesThe physical character-ization showed the suitability of preparation method Trans-mission electron microscopy and X-ray diffraction studiesrevealed the spherical nature and entrapment of curcuminin amorphous form respectively Annexin V-FITCPI doublestaining DNA analysis and reducedmitochondrial potentialconfirmed the occurrence of apoptosis The flow cytometricstudies disclosed that the anticancer activity of curcuminis enhanced with transferrin-mediated SLNs compared tofree curcumin and apoptosis is the mechanism underlyingthe cytotoxicity (Table 1) Results indicated the potential oftransferrin-mediated SLNs in enhancing the anticancer effectof curcumin in breast cancer cells in vitro [81]

13 Conclusion and Future Perspectives

The use of nanotechnology in medicine and more purposelydrug delivery is set to spread quickly Currently manysubstances are under investigation for drug delivery andmorespecifically for cancer therapy Fascinatingly pharmaceuticalsciences are using nanoparticles to reduce toxicity and sideeffects of drugs Moreover nanoparticles augment solubilityand stability of some substances like curcumin It is now clearthat further development of traditional natural compoundswith chemopreventive and chemotherapeutic potential suchas curcumin will be dictated by the advanced drug delivery

systemsNanotechnology is assumed to be a fundamental set-ting in drug delivery system and human therapeutics How-ever considerable challenges remain in driving this field intoclinically practical therapies Curcumin an excellent repre-sentative derived from traditional natural compounds hasbeen proven to be effectual in long-term application andpreclinical trials There is no doubt that advance of noveldelivery systems of curcumin with better therapeutic effectswill be vital for future improvement of curcumin as a thera-peutic agentThus it is an enormous implication to overcomethe current limitations of curcumin It seems that only bymultidisciplinary collaboration we can bring these promis-ing traditional natural compounds to the forefront of ther-apeutic agents for different diseases Therefore the promiseof nanotechnology-based medicine may become a realitywith sufficient efforts and further researches Human trialsneed to be conducted to establish curcuminrsquos effectiveness inclinical applications as an improved therapeutic modality fortreatment of different diseases

Conflict of Interests

The authors report no conflict of interests The authors aloneare responsible for the content of the paper

Acknowledgment

This study was supported by Tehran University of MedicalSciences

References

[1] E Jaruga S Salvioli J Dobrucki et al ldquoApoptosis-like revers-ible changes in plasmamembrane asymmetry and permeabilityand transientmodifications inmitochondrialmembrane poten-tial induced by curcumin in rat thymocytesrdquo FEBS Letters vol433 no 3 pp 287ndash293 1998

[2] S Sreejayan and M N A Rao ldquoCurcuminoids as potent inhi-bitors of lipid peroxidationrdquo Journal of Pharmacy and Pharma-cology vol 46 no 12 pp 1013ndash1016 1994

[3] R S Ramsewak D L DeWitt and M G Nair ldquoCytotoxicityantioxidant and anti-inflammatory activities of curcumins I-IIIfrom Curcuma longardquo Phytomedicine vol 7 no 4 pp 303ndash3082000

[4] J Milobedzka S V Kostanecki and V Lampe ldquoZur Kenntnisdes Curcuminsrdquo Berichte der Deutschen Chemischen Gesells-chaft vol 43 no 2 pp 2163ndash2170 1910

[5] H P Ammon and M A Wahl ldquoPharmacology of Curcumalongardquo Planta Medica vol 57 no 1 pp 1ndash7 1991

[6] N K Pandeya ldquoOld wivestales modern miraclesmdashturmeric astraditionalmedicine in IndiardquoTrees for Life Journal vol 1 article3 2005

[7] B B Aggarwal and B Sung ldquoPharmacological basis for the roleof curcumin in chronic diseases an age-old spice with moderntargetsrdquo Trends in Pharmacological Sciences vol 30 no 2 pp85ndash94 2009

[8] B A Bharat and K B Harikumar ldquoPotential therapeutic effectsof curcumin the anti-inflammatory agent against neurode-generative cardiovascular pulmonary metabolic autoimmune


and neoplastic diseasesrdquo International Journal of Biochemistryand Cell Biology vol 41 no 1 pp 40ndash59 2009

[9] L Li F S Braiteh and R Kurzrock ldquoLiposome-encapsulatedcurcumin in vitro and in vivo effects on proliferation apop-tosis signaling and angiogenesisrdquo Cancer vol 104 no 6 pp1322ndash1331 2005

[10] K Maiti K Mukherjee A Gantait B P Saha and P KMukherjee ldquoCurcumin-phospholipid complex preparationtherapeutic evaluation and pharmacokinetic study in ratsrdquoInternational Journal of Pharmaceutics vol 330 no 1-2 pp 155ndash163 2007

[11] L Lin Q Shi A K Nyarko et al ldquoAntitumor agents 250Design and synthesis of new curcumin analogues as potentialanti-prostate cancer agentsrdquo Journal of Medicinal Chemistryvol 49 no 13 pp 3963ndash3972 2006

[12] H Ohtsu Z Xiao J Ishida et al ldquoAntitumor agents 217 Cur-cumin analogues as novel androgen receptor antagonists withpotential as anti-prostate cancer agentsrdquo Journal of MedicinalChemistry vol 45 no 23 pp 5037ndash5042 2002

[13] B K Adams E M Ferstl M C Davis et al ldquoSynthesis andbiological evaluation of novel curcumin analogs as anti-cancerand anti-angiogenesis agentsrdquo Bioorganic and Medicinal Chem-istry vol 12 no 14 pp 3871ndash3883 2004

[14] R Benassi E Ferrari R Grandi S Lazzari and M SaladinildquoSynthesis and characterization of new 120573-diketo derivativeswith iron chelating abilityrdquo Journal of Inorganic Biochemistryvol 101 no 2 pp 203ndash213 2007

[15] T N Shankar N V Shantha H P Ramesh I A Murthy andV S Murthy ldquoToxicity studies on turmeric (Curcuma longa)acute toxicity studies in rats guinea pigs amp monkeysrdquo IndianJournal of Experimental Biology vol 18 no 1 pp 73ndash75 1980

[16] K B Soni and R Kuttan ldquoEffect of oral curcumin administra-tion on serum peroxides and cholesterol levels in human vol-unteersrdquo Indian Journal of Physiology and Pharmacology vol 36no 4 pp 273ndash275 1992

[17] PAnandA BKunnumakkara RANewman andB BAggar-wal ldquoBioavailability of curcumin problems and promisesrdquoMolecular Pharmaceutics vol 4 no 6 pp 807ndash818 2007

[18] R A Sharma W P Steward and A J Gescher ldquoPharma-cokinetics and pharmacodynamics of curcuminrdquo Advances inExperimental Medicine and Biology vol 595 pp 453ndash470 2007

[19] R Yang S Zhang D Kong X Gao Y Zhao and Z WangldquoBiodegradable polymer-curcumin conjugate micelles enhancethe loading and delivery of low-potency curcuminrdquo Pharma-ceutical Research vol 29 no 12 pp 3512ndash3525 2012

[20] BWahlstrom andG Blennow ldquoA study on the fate of curcuminin the ratrdquoActa Pharmacologica et Toxicologica vol 43 no 2 pp86ndash92 1978

[21] M Lopez-Lazaro ldquoAnticancer and carcinogenic properties ofcurcumin considerations for its clinical development as a can-cer chemopreventive and chemotherapeutic agentrdquo MolecularNutrition and Food Research vol 52 no 1 pp S103ndashS127 2008

[22] N A KasimMWhitehouse C Ramachandran et al ldquoMolecu-lar properties ofWHO essential drugs and provisional biophar-maceutical classificationrdquoMolecular Pharmaceutics vol 1 no 1pp 85ndash96 2004

[23] M-H Pan T-M Huang and J-K Lin ldquoBiotransformationof curcumin through reduction and glucuronidation in micerdquoDrug Metabolism and Disposition vol 27 no 4 pp 486ndash4941999

[24] F Payton P Sandusky and W L Alworth ldquoNMR study of thesolution structure of curcuminrdquo Journal of Natural Productsvol 70 no 2 pp 143ndash146 2007

[25] J Ishida H Ohtsu Y Tachibana et al ldquoAntitumor agentsmdashpart 214 synthesis and evaluation of curcumin analogues ascytotoxic agentsrdquo Bioorganic and Medicinal Chemistry vol 10no 11 pp 3481ndash3487 2002

[26] C Selvam S M Jachak RThilagavathi and A K ChakrabortildquoDesign synthesis biological evaluation and molecular dock-ing of curcumin analogues as antioxidant cyclooxygenase inhi-bitory and anti-inflammatory agentsrdquo Bioorganic andMedicinalChemistry Letters vol 15 no 7 pp 1793ndash1797 2005

[27] A SunM Shoji Y J Lu D C Liotta and J P Snyder ldquoSynthesisof EF24-tripeptide chloromethyl ketone a novel curcumin-related anticancer drug delivery systemrdquo Journal of MedicinalChemistry vol 49 no 11 pp 3153ndash3158 2006

[28] H Ohori H Yamakoshi M Tomizawa et al ldquoSynthesisand biolgical analysis of new curcumin analogues bearing anenhanced potential for the medicinal treatment of cancerrdquoMolecular Cancer Therapeutics vol 5 no 10 pp 2563ndash25712006

[29] R A Freitas Jr ldquoWhat is nanomedicinerdquo NanomedicineNanotechnology Biology and Medicine vol 1 no 1 pp 2ndash92005

[30] S Rahman S Cao K J Steadman M Wei and H S ParekhldquoNative and 120573-cyclodextrin-enclosed curcumin entrapmentwithin liposomes and their in vitro cytotoxicity in lung andcolon cancerrdquo Drug Delivery vol 19 no 7 pp 346ndash353 2012

[31] H S Shi X Gao D Li et al ldquoA systemic administrationof liposomal curcumin inhibits radiation pneumonitis andsensitizes lung carcinoma to radiationrdquo International Journal ofNanomedicine vol 7 pp 2601ndash2611 2012

[32] D Matabudul K Pucaj G Bolger B Vcelar M Majeed andL Helson ldquoTissue distribution of (Lipocurc) liposomal cur-cumin and tetrahydrocurcumin following two- and eight-hourinfusions in Beagle dogsrdquo Anticancer Research vol 32 no 10pp 4359ndash4364 2012

[33] A Karewicz D Bielska B Gzyl-Malcher M Kepczynski RLach andM Nowakowska ldquoInteraction of curcumin with lipidmonolayers and liposomal bilayersrdquo Colloids and Surfaces BBiointerfaces vol 88 no 1 pp 231ndash239 2011

[34] S S Dhule P Penfornis T Frazier et al ldquoCurcumin-loaded120574-cyclodextrin liposomal nanoparticles as delivery vehiclesfor osteosarcomardquoNanomedicine Nanotechnology Biology andMedicine vol 8 no 4 pp 440ndash451 2012

[35] W SOrr JWDenboK R Saab et al ldquoLiposome-encapsulatedcurcumin suppresses neuroblastoma growth through nuclearfactor-kappa B inhibitionrdquo Surgery vol 151 no 5 pp 736ndash7442012

[36] D Wang M S Veena K Stevenson et al ldquoLiposome-encap-sulated curcumin suppresses growth of head and neck squa-mous cell carcinoma in vitro and in xenografts through theinhibition of nuclear factor kappaB by an AKT-independentpathwayrdquo Clinical Cancer Research vol 14 no 19 pp 6228ndash6236 2008

[37] Y Chen Q Wu Z Zhang L Yuan X Liu and L Zhou ldquoPre-paration of curcumin-loaded liposomes and evaluation of theirskin permeation and pharmacodynamicsrdquoMolecules vol 17 no5 pp 5972ndash5987 2012

[38] N M Rogers M D Stephenson A R Kitching J DHorowitz andP THCoates ldquoAmelioration of renal ischaemia-reperfusion injury by liposomal delivery of curcumin to renal


tubular epithelial and antigen-presenting cellsrdquoTheBritish Jour-nal of Pharmacology vol 166 no 1 pp 194ndash209 2012

[39] P Basnet H Hussain ITho andN Skalko-Basnet ldquoLiposomaldelivery system enhances anti-inflammatory properties of cur-cuminrdquo Journal of Pharmaceutical Sciences vol 101 no 2 pp598ndash609 2012

[40] R Raveendran G Bhuvaneshwar and C P Sharma ldquoIn vitrocytotoxicity and cellular uptake of curcumin-loaded Pluro-nicPolycaprolactone micelles in colorectal adenocarcinomacellsrdquo Journal of Biomaterials Applications vol 27 no 7 pp 811ndash827 2013

[41] H Yu J Li K Shi andQHuang ldquoStructure ofmodified 120576-poly-lysine micelles and their application in improving cellular anti-oxidant activity of curcuminoidsrdquo Food and Function vol 2 no7 pp 373ndash380 2011

[42] S Podaralla R Averineni M Alqahtani and O Perumal ldquoSyn-thesis of novel biodegradable methoxy poly(ethylene glycol)-zein micelles for effective delivery of curcuminrdquo MolecularPharmaceutics vol 9 no 9 pp 2778ndash2786 2012

[43] Z Song R Feng M Sun et al ldquoCurcumin-loaded PLGA-PEG-PLGA triblock copolymericmicelles preparation pharmacoki-netics and distribution in vivordquo Journal of Colloid and InterfaceScience vol 354 no 1 pp 116ndash123 2011

[44] M H M Leung H Colangelo and T W Kee ldquoEncapsulationof curcumin in cationicmicelles suppresses alkaline hydrolysisrdquoLangmuir vol 24 no 11 pp 5672ndash5675 2008

[45] R Adhikary P J Carlson TW Kee and JW Petrich ldquoExcited-state intramolecular hydrogen atom transfer of curcumin insurfactantmicellesrdquo Journal of Physical Chemistry B vol 114 no8 pp 2997ndash3004 2010

[46] G Began E Sudharshan and A G Appu Rao ldquoInhibitionof lipoxygenase 1 by phosphatidylcholine micelles-bound cur-cuminrdquo Lipids vol 33 no 12 pp 1223ndash1228 1998

[47] S Jain P Singh V Mishra and S P Vyas ldquoMannosylated nio-somes as adjuvant-carrier system for oral genetic immunizationagainst hepatitis Brdquo Immunology Letters vol 101 no 1 pp 41ndash49 2005

[48] S Mandal C Banerjee S Ghosh J Kuchlyan and N SarkarldquoModulation of the photophysical properties of curcumin innonionic surfactant (Tween-20) forming micelles and nio-somes a comparative study of different microenvironmentsrdquoJournal of Physical Chemistry B vol 117 no 23 pp 6957ndash69682013

[49] N Rungphanichkul U Nimmannit W Muangsiri and PRojsitthisak ldquoPreparation of curcuminoid niosomes forenhancement of skin permeationrdquo Pharmazie vol 66 no 8pp 570ndash575 2011

[50] H H Toslashnnesen M Masson and T Loftsson ldquoStudies of cur-cumin and curcuminoids XXVII Cyclodextrin complexationsolubility chemical and photochemical stabilityrdquo InternationalJournal of Pharmaceutics vol 244 no 1-2 pp 127ndash135 2002

[51] M A Tomren M Masson T Loftsson and H H ToslashnnesenldquoStudies on curcumin and curcuminoids XXXI Symmetric andasymmetric curcuminoids stability activity and complexationwith cyclodextrinrdquo International Journal of Pharmaceutics vol338 no 1-2 pp 27ndash34 2007

[52] S S Darandale and P R Vavia ldquoCyclodextrin-based nano-sponges of curcumin formulation and physicochemical char-acterizationrdquo Journal of Inclusion Phenomena and MacrocyclicChemistry vol 75 no 3-4 pp 315ndash322 2013

[53] V R Yadav S Prasad R Kannappan et al ldquoCyclodextrin-com-plexed curcumin exhibits anti-inflammatory and antiprolifer-ative activities superior to those of curcumin through highercellular uptakerdquo Biochemical Pharmacology vol 80 no 7 pp1021ndash1032 2010

[54] V R Yadav S Suresh K Devi and S Yadav ldquoEffect of cyclo-dextrin complexation of curcumin on its solubility and antian-giogenic and anti-inflammatory activity in rat colitis modelrdquoAAPS PharmSciTech vol 10 no 3 pp 752ndash762 2009

[55] M M Yallapu M Jaggi and S C Chauhan ldquo120573-cyclodextrin-curcumin self-assembly enhances curcumin delivery in prostatecancer cellsrdquo Colloids and Surfaces B Biointerfaces vol 79 no1 pp 113ndash125 2010

[56] P R Dandawate A Vyas A Ahmad et al ldquoInclusion complexof novel curcumin analogue CDF and 120573-cyclodextrin (12)and its enhanced in vivo anticancer activity against pancreaticcancerrdquo Pharmaceutical Research vol 29 no 7 pp 1775ndash17862012

[57] S Debnath D Saloum S Dolai et al ldquoDendrimer-curcuminconjugate a water soluble and effective cytotoxic agent againstbreast cancer cell linesrdquoAnti-Cancer Agents inMedicinal Chem-istry vol 13 no 10 pp 1531ndash1539 2013

[58] M M Yallapu M C Ebeling N Chauhan M Jaggi and SC Chauhan ldquoInteraction of curcumin nanoformulations withhuman plasma proteins and erythrocytesrdquo International Journalof Nanomedicine vol 6 pp 2779ndash2790 2011

[59] J Cao H Zhang Y Wang J Yang and F Jiang ldquoInvestigationon the interaction behavior between curcumin and PAMAMdendrimer by spectral and docking studiesrdquo SpectrochimicaActa A Molecular and Biomolecular Spectroscopy vol 108 pp251ndash255 2013

[60] M Mollazade N Zarghami M Nasiri K Nejati M Rahmatiand M Pourhasan ldquoPolyamidoamine (PAMAM) encapsulatedcurcumin inhibits telomerase activity in breast cancer cell linerdquoClinical Biochemistry vol 44 no 13 supplement p S217 2011

[61] M N Sarbolouki A M Alizadeh M Khaniki S Azizianand M A Mohaghgheg ldquoProtective effect of dendrosomal cur-cumin combination on colon cancer in ratrdquo Tehran UniversityMedical Journal vol 69 no 11 pp 678ndash685 2012

[62] A M Alizadeh M Khaniki S Azizian M A MohaghgheghiM Sadeghizadeh and F Najafi ldquoChemoprevention of azoxy-methane-initiated colon cancer in rat by using a novel poly-meric nanocarriermdashcurcuminrdquo European Journal of Pharma-cology vol 689 no 1ndash3 pp 226ndash232 2012

[63] E Babaei M Sadeghizadeh Z M Hassan M A H Feizi FNajafi and S M Hashemi ldquoDendrosomal curcumin signifi-cantly suppresses cancer cell proliferation in vitro and in vivordquoInternational Immunopharmacology vol 12 no 1 pp 226ndash2342012

[64] S Mangalathillam N S Rejinold A Nair V-K LakshmananS V Nair and R Jayakumar ldquoCurcumin loaded chitin nanogelsfor skin cancer treatment via the transdermal routerdquoNanoscalevol 4 no 1 pp 239ndash250 2012

[65] X Wei T H Senanayake G Warren and S V Vino-gradov ldquoHyaluronic acid-based nanogel-drug conjugates withenhanced anticancer activity designed for the targeting ofCD44-positive and drug-resistant tumorsrdquo Bioconjugate Chem-istry vol 24 no 4 pp 658ndash668 2013

[66] J Zhang Q Tang X Xu and N Li ldquoDevelopment and evalua-tion of a novel phytosome-loaded chitosan microsphere systemfor curcumin deliveryrdquo International Journal of Pharmaceuticsvol 448 no 1 pp 168ndash174 2013


[67] F Akhtar M M A Rizvi and S K Kar ldquoOral delivery of cur-cumin bound to chitosan nanoparticles cured Plasmodiumyoelii infected micerdquo Biotechnology Advances vol 30 no 1 pp310ndash320 2012

[68] X Li S Chen B Zhang et al ldquoIn situ injectable nano-compositehydrogel composed of curcumin NO-carboxymethyl chitosanand oxidized alginate for wound healing applicationrdquo Interna-tional Journal of Pharmaceutics vol 437 no 1-2 pp 110ndash1192012

[69] A Yadav V Lomash M Samim and S J Flora ldquoCurcuminencapsulated in chitosan nanoparticles a novel strategy for thetreatment of arsenic toxicityrdquo Chemico-Biological Interactionsvol 199 no 1 pp 49ndash61 2012

[70] S K Shukla A K Mishra O A Arotiba and B BMamba ldquoChitosan-based nanomaterials a state-of-the-artreviewrdquo International Journal of Biological Macromolecules vol59 pp 46ndash58 2013

[71] AKarewiczD BielskaA Loboda et al ldquoCurcumin-containingliposomes stabilized by thin layers of chitosan derivativesrdquoColloids and Surfaces B Biointerfaces vol 109 pp 307ndash316 2013

[72] D K Singh R Jagannathan P Khandelwal P M Abrahamand P Poddar ldquoIn situ synthesis and surface functionalizationof gold nanoparticles with curcumin and their antioxidantproperties an experimental and density functional theoryinvestigationrdquo Nanoscale vol 5 no 5 pp 1882ndash1893 2013

[73] A Moten ldquoThe use of gold-citrate nanoparticles and curcuminnanomedicine to target cancer at a single cell levelrdquo in Proceed-ings of the NSTI Nanotechnology Conference and Trade ShowJune 2008

[74] K Varaprasad Y Murali Mohan K Vimala and K MohanaRaju ldquoSynthesis and characterization of hydrogel-silver nano-particle-curcumin composites for wound dressing and antibac-terial applicationrdquo Journal of Applied Polymer Science vol 121no 2 pp 784ndash796 2011

[75] H Zhou X Wu W Xu J Yang and Q Yang ldquoFluorescenceenhancement of the silver nanoparticalesmdashcurcumin-cetyl-trimethylammonium bromide-nucleic acids system and itsanalytical applicationrdquo Journal of Fluorescence vol 20 no 4 pp843ndash850 2010

[76] P Ekambaram andH S Abdul ldquoFormulation and evaluation ofsolid lipid nanoparticles of ramiprilrdquo Journal of Young Pharm-acists vol 3 no 3 pp 216ndash220 2011

[77] V Kakkar S Singh D Singla and I P Kaur ldquoExploring solidlipid nanoparticles to enhance the oral bioavailability of cur-cuminrdquo Molecular Nutrition and Food Research vol 55 no 3pp 495ndash503 2011

[78] V Kakkar S K Muppu K Chopra and I P Kaur ldquoCur-cumin loaded solid lipid nanoparticles an efficient formulationapproach for cerebral ischemic reperfusion injury in ratsrdquoEuropean Journal of Pharmaceutics and Biopharmaceutics vol85 no 3 pp 339ndash345 2013

[79] V R Yadav S Suresh K Devi and S Yadav ldquoNovel formulationof solid lipid microparticles of curcumin for anti-angiogenicand anti-inflammatory activity for optimization of therapy ofinflammatory bowel diseaserdquo Journal of Pharmacy and Pharm-acology vol 61 no 3 pp 311ndash321 2009

[80] W Wang R Zhu Q Xie et al ldquoEnhanced bioavailabilityand efficiency of curcumin for the treatment of asthma by itsformulation in solid lipid nanoparticlesrdquo International Journalof Nanomedicine vol 7 pp 3667ndash3677 2012

[81] R S Mulik J Monkkonen R O Juvonen K R Mahadik andA R Paradkar ldquoTransferrin mediated solid lipid nanoparticles

containing curcumin enhanced in vitro anticancer activity byinduction of apoptosisrdquo International Journal of Pharmaceuticsvol 398 no 1-2 pp 190ndash203 2010

[82] A H Faraji and P Wipf ldquoNanoparticles in cellular drugdeliveryrdquo Bioorganic and Medicinal Chemistry vol 17 no 8 pp2950ndash2962 2009

[83] K Cho XWang S Nie Z Chen and D M Shin ldquoTherapeuticnanoparticles for drug delivery in cancerrdquo Clinical CancerResearch vol 14 no 5 pp 1310ndash1316 2008

[84] F Aqil R Munagala J Jeyabalan and M V Vadhanam ldquoBio-availability of phytochemicals and its enhancement by drugdelivery systemsrdquo Cancer Letters vol 334 no 1 pp 133ndash1412013

[85] C Chen T D Johnston H Jeon et al ldquoAn in vitro study ofliposomal curcumin stability toxicity and biological activityin human lymphocytes and Epstein-Barr virus-transformedhumanB-cellsrdquo International Journal of Pharmaceutics vol 366no 1-2 pp 133ndash139 2009

[86] M Pandelidou K Dimas A Georgopoulos S Hatziantoniouand C Demetzos ldquoPreparation and characterization of lyo-philised EGG PC liposomes incorporating curcumin and eval-uation of its activity against colorectal cancer cell linesrdquo Journalof Nanoscience andNanotechnology vol 11 no 2 pp 1259ndash12662011

[87] C N Sreekanth S V Bava E Sreekumar and R J AntoldquoMolecular evidences for the chemosensitizing efficacy of lipo-somal curcumin in paclitaxel chemotherapy inmousemodels ofcervical cancerrdquo Oncogene vol 30 no 28 pp 3139ndash3152 2011

[88] C M Mach J H Chen S A Mosley R Kurzrock and J ASmith ldquoEvaluation of liposomal curcumin cytochrome P450metabolismrdquo Anticancer Research vol 30 no 3 pp 811ndash8142010

[89] B Isacchi M C Bergonzi M Grazioso et al ldquoArtemisinin andartemisinin plus curcumin liposomal formulations enhancedantimalarial efficacy against Plasmodium berghei-infectedmicerdquo European Journal of Pharmaceutics and Biopharmaceu-tics vol 80 no 3 pp 528ndash534 2012

[90] N B Agarwal S Jain D Nagpal N K Agarwal P K Medi-ratta and K K Sharma ldquoLiposomal formulation of curcuminattenuates seizures in different experimental models of epilepsyin micerdquo Fundamental amp Clinical Pharmacology vol 27 no 2pp 169ndash172 2013

[91] H K Cho I W Cheong J M Lee and J H Kim ldquoPolymericnanoparticles micelles and polymersomes from amphiphilicblock copolymerrdquo Korean Journal of Chemical Engineering vol27 no 3 pp 731ndash740 2010

[92] M-C Jones and J-C Leroux ldquoPolymeric micellesmdasha newgeneration of colloidal drug carriersrdquo European Journal ofPharmaceutics and Biopharmaceutics vol 48 no 2 pp 101ndash1111999

[93] L Liu L Sun Q Wu et al ldquoCurcumin loaded polymericmicelles inhibit breast tumor growth and spontaneous pulmo-nary metastasisrdquo International Journal of Pharmaceutics vol443 no 1-2 pp 175ndash182 2013

[94] Z Ma A Haddadi O Molavi A Lavasanifar R Lai and JSamuel ldquoMicelles of poly(ethylene oxide)-b-poly(120576-caprolac-tone) as vehicles for the solubilization stabilization and con-trolled delivery of curcuminrdquo Journal of Biomedical MaterialsResearch A vol 86 no 2 pp 300ndash310 2008

[95] L Zhao J Du Y Duan et al ldquoCurcumin loadedmixedmicellescomposed of Pluronic P123 and F68 preparation optimization


and in vitro characterizationrdquo Colloids and Surfaces B Biointer-faces vol 97 pp 101ndash108 2012

[96] M Gou KMen H Shi et al ldquoCurcumin-loaded biodegradablepolymeric micelles for colon cancer therapy in vitro and invivordquo Nanoscale vol 3 no 4 pp 1558ndash1567 2011

[97] K Letchford R Liggins and H Burt ldquoSolubilization of hydro-phobic drugs by methoxy poly(ethylene glycol)-block-poly-caprolactone diblock copolymer micelles theoretical andexperimental data and correlationsrdquo Journal of PharmaceuticalSciences vol 97 no 3 pp 1179ndash1190 2008

[98] F Dai W-F Chen B Zhou L Yang and Z-L Liu ldquoAntiox-idative effects of curcumin and its analogues against the free-radical-induced peroxidation of linoleic acid in micellesrdquo Phy-totherapy Research vol 23 no 9 pp 1220ndash1228 2009

[99] S Mondal and S Ghosh ldquoRole of curcumin on the determina-tion of the critical micellar concentration by absorbance fluo-rescence and fluorescence anisotropy techniquesrdquo Journal ofPhotochemistry and Photobiology B vol 115 pp 9ndash15 2012

[100] A Sahu N Kasoju P Goswami and U Bora ldquoEncapsulationof curcumin in Pluronic block copolymer micelles for drugdelivery applicationsrdquo Journal of Biomaterials Applications vol25 no 6 pp 619ndash639 2011

[101] M Yokoyama ldquoClinical applications of polymeric micelle car-rier systems in chemotherapy and Image diagnosis of solidtumorsrdquo Journal of Experimental and Clinical Medicine vol 3no 4 pp 151ndash158 2011

[102] FWang XWu FWang S Liu Z Jia and J Yang ldquoThe sensitivefluorimetric method for the determination of curcumin usingthe enhancement of mixedmicellerdquo Journal of Fluorescence vol16 no 1 pp 53ndash59 2006

[103] CGong SDengQWuet al ldquoImproving antiangiogenesis andanti-tumor activity of curcumin by biodegradable polymericmicellesrdquo Biomaterials vol 34 no 4 pp 1413ndash1432 2013

[104] F Wang W Huang L Jiang and B Tang ldquoQuantitative deter-mination of proteins based on strong fluorescence enhance-ment in curcumin-chitosan-proteins systemrdquo Journal of Fluo-rescence vol 22 no 2 pp 615ndash622 2012

[105] C Mohanty S Acharya A K Mohanty F Dilnawaz and S KSahoo ldquoCurcumin-encapsulated MePEGPCL diblock copoly-meric micelles a novel controlled delivery vehicle for cancertherapyrdquo Nanomedicine vol 5 no 3 pp 433ndash449 2010

[106] MMalhotra andN K Jain ldquoNiosomes as drug carriersrdquo IndianDrugs vol 31 no 3 pp 81ndash86 1994

[107] M Karim A Mandal N Biswas et al ldquoNiosome a future oftargeted drug delivery systemsrdquo Journal of Advanced Pharma-ceutical Technology and Research vol 1 no 4 pp 374ndash380 2010

[108] M N Azmin A T Florence R M Handjani-Vila J F StuartG Vanlerberghe and J S Whittaker ldquoThe effect of non-ionicsurfactant vesicle (niosome) entrapment on the absorption anddistribution of methotrexate in micerdquo Journal of Pharmacy andPharmacology vol 37 no 4 pp 237ndash242 1985

[109] K Kumar and A K Rai ldquoDevelopment and evaluation ofproniosome- encapsulated curcumin for transdermal adminis-trationrdquoTropical Journal of Pharmaceutical Research vol 10 no6 pp 697ndash703 2011

[110] S Menuel J-P Joly B Courcot J Elysee N-E Ghermani andA Marsura ldquoSynthesis and inclusion ability of a bis-120573-cyclo-dextrin pseudo-cryptand towards Busulfan anticancer agentrdquoTetrahedron vol 63 no 7 pp 1706ndash1714 2007

[111] M E Davis and M E Brewster ldquoCyclodextrin-based phar-maceutics past present and futurerdquo Nature Reviews DrugDiscovery vol 3 no 12 pp 1023ndash1035 2004

[112] M M Yallapu M Jaggi and S C Chauhan ldquoPoly(120573-cyclo-dextrin)curcumin self-assembly a novel approach to improvecurcumin delivery and its therapeutic efficacy in prostate cancercellsrdquo Macromolecular Bioscience vol 10 no 10 pp 1141ndash11512010

[113] F Lomedasht A Rami and N Zarghami ldquoComparison ofinhibitory effect of curcumin nanoparticles and free curcuminin human telomerase reverse transcriptase gene expression inbreast cancerrdquo Advanced Pharmaceutical Bulletin vol 3 no 1pp 127ndash130 2013

[114] N Rocks S Bekaert I Coia et al ldquoCurcumin-cyclodextrincomplexes potentiate gemcitabine effects in an orthotopicmouse model of lung cancerrdquoThe British Journal of Cancer vol107 no 7 pp 1083ndash1092 2012

[115] H Agashe K Sahoo P Lagisetty and V Awasthi ldquoCyclodex-trin-mediated entrapment of curcuminoid 4-[35-bis(2-chloro-benzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] orCLEFMA in liposomes for treatment of xenograft lung tumorin ratsrdquo Colloids and Surfaces B Biointerfaces vol 84 no 2 pp329ndash337 2011

[116] H Namazi and M Adeli ldquoDendrimers of citric acid and poly(ethylene glycol) as the new drug-delivery agentsrdquoBiomaterialsvol 26 no 10 pp 1175ndash1183 2005

[117] M Longmire P L Choyke and H Kobayashi ldquoDendrimer-based contrast agents for molecular imagingrdquo Current Topics inMedicinal Chemistry vol 8 no 14 pp 1180ndash1186 2008

[118] W Shi S Dolai S Rizk et al ldquoSynthesis of monofunctionalcurcumin derivatives clicked curcumin dimer and a PAMAMdendrimer curcumin conjugate for therapeutic applicationsrdquoOrganic Letters vol 9 no 26 pp 5461ndash5464 2007

[119] E Markatou V Gionis G D Chryssikos S HatziantoniouA Georgopoulos and C Demetzos ldquoMolecular interactionsbetween dimethoxycurcumin and Pamam dendrimer carriersrdquoInternational Journal of Pharmaceutics vol 339 no 1-2 pp 231ndash236 2007

[120] M Khaniki S Azizian AMAlizadehHHemmati N Emam-ipour and M A Mohagheghi ldquoThe antiproliferative and anti-cancerogenic effects of nano-curcumin in rat colon cancerrdquoTehran University Medical Journal vol 71 no 5 pp 277ndash2842013

[121] I Haririan M S Alavidjeh M R Khorramizadeh M SArdestani Z Z Ghane and H Namazi ldquoAnionic linear-glo-bular dendrimer-cis-platinum (II) conjugates promote cytotox-icity in vitro against different cancer cell linesrdquo InternationalJournal of Nanomedicine vol 2 no 5 pp 63ndash75 2010

[122] A V Kabanov and S V Vinogradov ldquoNanogels as pharmaceuti-cal carriers finite networks of infinite capabilitiesrdquo AngewandteChemiemdashInternational Edition vol 48 no 30 pp 5418ndash54292009

[123] C Goncalves P Pereira P Schellenberg P Coutinho and FGama ldquoSelf-assembled dextrin nanogel as curcumin deliverysystemrdquo Journal of Biomaterials and Nanobiotechnology vol 3no 2 pp 178ndash184 2012

[124] S Maya B Sarmento A Nair N S Rejnold S V Nair andR Jayakumar ldquoSmart stimuli sensitive nanogels in cancer drugdelivery and imaging a reviewrdquoCurrent Pharmaceutical Designvol 19 no 41 pp 7203ndash7218 2013

[125] W Wu J Shen P Banerjee and S Zhou ldquoWater-dispersiblemultifunctional hybrid nanogels for combined curcumin andphotothermal therapyrdquo Biomaterials vol 32 no 2 pp 598ndash6092011


[126] A Bernkop-Schnurch and S Dunnhaupt ldquoChitosan-baseddrug delivery systemsrdquo European Journal of Pharmaceutics andBiopharmaceutics vol 81 no 3 pp 463ndash469 2012

[127] L Mazzarino C Travelet S Ortega-Murillo et al ldquoElaborationof chitosan-coated nanoparticles loaded with curcumin formucoadhesive applicationsrdquo Journal of Colloid and InterfaceScience vol 370 no 1 pp 58ndash66 2012

[128] R K Das N Kasoju and U Bora ldquoEncapsulation of cur-cumin in alginate-chitosan-pluronic composite nanoparticlesfor delivery to cancer cellsrdquo Nanomedicine NanotechnologyBiology and Medicine vol 6 no 1 pp 153ndash160 2010

[129] N S Rejinold P R Sreerekha K P Chennazhi S V Nairand R Jayakumar ldquoBiocompatible biodegradable and thermo-sensitive chitosan-g-poly (N-isopropylacrylamide) nanocarrierfor curcumin drug deliveryrdquo International Journal of BiologicalMacromolecules vol 49 no 2 pp 161ndash172 2011

[130] S Kommareddy S B Tiwari and M M Amiji ldquoLong-circulating polymeric nanovectors for tumor-selective genedeliveryrdquo Technology in Cancer Research and Treatment vol 4no 6 pp 615ndash625 2005

[131] J Duan Y Zhang S Han et al ldquoSynthesis and in vitroin vivoanti-cancer evaluation of curcumin-loaded chitosanpoly(butylcyanoacrylate) nanoparticlesrdquo International Journal of Pharma-ceutics vol 400 no 1-2 pp 211ndash220 2010

[132] K Omidfar F Khorsand and M Darziani Azizi ldquoNew ana-lytical applications of gold nanoparticles as label in antibodybased sensorsrdquo Biosensors and Bioelectronics vol 43 pp 336ndash347 2013

[133] J Rajesh M Rajasekaran G Rajagopal and P Athappan ldquoAna-lytical methods to determine the comparative DNA bindingstudies of curcumin-Cu(II) complexesrdquo Spectrochimica Acta AMolecular and Biomolecular Spectroscopy vol 97 pp 223ndash2302012

[134] R Gangwar V Dhumale D Kumari et al ldquoConjugation ofcurcumin with PVP capped gold nanoparticles for improvingbioavailabilityrdquoMaterials Science and Engineering C vol 32 no8 pp 2659ndash2663 2012

[135] K Kumar D Gnanaprakash K Mayilvaganan C Arunrajand S Mohankumar ldquoChitosan-gold nanoparticles as deliverysystems for curcuminsrdquo International Journal of PharmaceuticalSciences amp Research vol 3 no 11 p 4533 2012

[136] S Manju and K Sreenivasan ldquoGold nanoparticles generatedand stabilized by water soluble curcumin-polymer conjugateblood compatibility evaluation and targeted drug delivery ontocancer cellsrdquo Journal of Colloid and Interface Science vol 368no 1 pp 144ndash151 2012

[137] K Sindhu R Indra A Rajaram K J Sreeram and R RajaramldquoInvestigations on the interaction of gold-curcumin nanopar-ticles with human peripheral blood lymphocytesrdquo Journal ofBiomedical Nanotechnology vol 7 no 1 p 56 2011

[138] M J Sweet and I Singleton ldquoSilver nanoparticles a microbialperspectiverdquo Advances in Applied Microbiology vol 77 pp 115ndash133 2011

[139] A Ravindran P Chandran and S S Khan ldquoBiofunctionalizedsilver nanoparticles advances and prospectsrdquo Colloids andSurfaces B Biointerfaces vol 105 pp 342ndash352 2013

[140] P Dadhaniya C Patel JMuchhara et al ldquoSafety assessment of asolid lipid curcumin particle preparation acute and subchronictoxicity studiesrdquo Food and Chemical Toxicology vol 49 no 8pp 1834ndash1842 2011

[141] V Kakkar and I P Kaur ldquoEvaluating potential of cur-cumin loaded solid lipid nanoparticles in aluminium induced

behavioural biochemical and histopathological alterations inmice brainrdquo Food and Chemical Toxicology vol 49 no 11 pp2906ndash2913 2011

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of


StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


Medicinal ChemistryInternational Journal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Autoimmune Diseases


Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of


Pharmaceutics


MEDIATORSINFLAMMATION

of


OHHO

OO

Curcumin (I)

Demethoxycurcumin (II)

Bisdemethoxycurcumin (III)

Equilibrating keto-enol tautomers

OCH3H3CO

OHHO

O

OCH3H3CO

OHHO

OO

OCH3

OH

OH

OHHO

O

OCH3H3CO

OH

HO

OO

Figure 1 Curcumin I II and III (curcumin demethoxycurcumin and bisdemethyoxycurcumin) and curcumin keto-enol tautomers

discussed poor bioavailability of curcumin because of poorabsorption rapid metabolism and rapid systemic elimina-tion [17 18] however comprehensive pharmacokinetic dataare still missing In a study done by Yang et al [19] theyreported 1 bioavailability for oral administration of cur-cumin in rats On the elimination of curcumin an investiga-tion in rat model demonstrated that after oral administrationof 1 gkg of curcumin more than 75 was excreted in fecesand negligible amount of curcumin was detected in urine[20] Additionally FDA has declared curcumin as ldquogenerallysaferdquo Although curcumin showed a wide variety of usefulpharmacological effects and has been found to be quite safe inboth animals and humans there are some studies concerning

its toxicity [21] In spite of these advantages curcumin haspoor water solubility as a consequence it reveals solubility-limited bioavailability which makes it a class II drug inthe biopharmaceutics classification system [22] Additionallydue to its rapid intestinal and hepatic metabolism about 60to 70 of an oral dose of curcumin gets eliminated by thefeces [23]

As mentioned above curcumin has been proven to beeffective in treatment of different diseases with low toxicityto human and animals It is extremely safe upon oral admin-istration even at very high doses however it is limited dueto its poor bioavailability stability low solubility and rapiddegradation and metabolism Overcoming these problems





3 Liposomes





ble1Nanop

articles-conjugated

curcum

incharacteriz

ationford

ifferentd

iseases

treatment

Type

ofnano

particles

Form

Size

(nm)

Usedmod

els

Metho

dsRe

sults

Reference

Lipo

some

Globu

lar

25ndash205

(i)Breastcancer

(ii)M

elano

ma

(iii)Re

nalischemia

(iv)M

alaria

Invitro

Invivo

(dog

andmice)


istrib

utionandsta

bility

(ii)E

nhancedantitum

orandantia

ngiogenesis

effects

(iii)Show

edantim

elanom


antim

alarialeffects

[30ndash

33]

[34ndash

37]

[3839]

Micelle

Spheric

al10ndash100

(i)Lu

ngtumor

(ii)B

reastcancer

Invitro

Invivo

(mice)


(ii)Improved

antio

xidativ

eand

antitum

oreffects

(iii)Prolon

gedcirculationtim

e(iv

)Enh

ancedflu

orescencee

ffect

[40]

[41]

[42]

[43]

[44]

[45]

[46]

Noisome

Lamellar

190ndash

1140

(i)Albinoratskin

(ii)C

ancerous

cells

Invitro

Invivo

(snake

andmice)

(i)Increasedskin

penetration

(ii)P

rolonged

deliverysyste

m(iii)Anti-infectio

nandantic

ancere

ffects

(iv)E

nhancedflu

orescenceintensity

[47]

[48]

[49]

OO

O O O

O

OO

OOO

O

n

OR 6

OR 6

OR 2O

R 2

OR 6

OR 6O

R 3

OR 3

OR 3

R 6O

R 2OR 3

OR 3

O

R 3OR 2

O

R 6O

R 2O

OR 2

Cyclo

dextrin

Cyclic

150ndash

500

(i)Bo

weldisease

(ii)B

reastlung

pancreaticand

prostatecancer

Invitro

Invivo

(ratandmice)

(i)Im

proved

solubility

(ii)E

nhancedantip

roliferationeffects

(iii)Increasedantic

ancera


(iv)D

evelop

edbioavailability

[30]

[50ndash

56]

Dendrim

erGlobu

lar

polymer

15ndash150

(i)Breastcancer

(ii)C

olon

cancer

Invitro

Invivo

(mice)

(i)Im

proved

stability

(ii)Increased

antitum

orandantip

roliferativee

ffects

[5758]

[59ndash

63]

Nanogel

Cross-lin

ked

polymer

network

10ndash200

(i)Melanom

a(ii)B

reastand

pancreaticcancer

cells

Invitro


(ii)E

nhancedflu

orescencee

ffects

(iii)Develop

edbioavailability

(iv)Improved

antic

ancere

ffects

(v)G

etbette

rcon

trolledrelease

(vi)Prolon

gedhalf-life

(vii)

Enhanced

treatmento

fmelanom

a

[64]

[65]

Chito

san

Linear

polysaccha-

ride

compo

sed

100ndash

250

(i)Wou

nds

(ii)M

elanom

atum

ors

Invitro

Invivo

(ratandmice)

(i)Im

proved

chem

icalstability

(ii)S

howed

wou

ndhealingeffects


oreffects

(iv)Improved

antio

xidant

effects

(v)P

rolonged

bloo

dcirculation

[66ndash

71]

Gold

Globu

lar

200ndash

250

Cancerou

scells

Invitro

(i)Im

proved

solubility

(ii)E

nhancedantio

xidant

andantic

ancere

ffects

[72]

[73]

Silver

Film

layer

sim15

(i)Infections

(ii)S

kinwou

nds

Invitro

(i)Sh

owed

antim

icrobialeffects

(ii)Improved

wou

ndhealing

(iii)Increasedantiv

iraland

antic

ancere

ffects

[74]

[75]

Lipi

d(s

olid

)Solid

lipid

Spheric

al50ndash100

0

(i)Cerebralischemia

(ii)C

olitis

(iii)Allergy

(iv)B

reastcancer

Invitro

Invivo

(ratandmice)

(i)Prolon

gedcirculationof

bloo

d(ii)Increased


(iii)Im

proved

braindelivery

[76ndash

78]

[79ndash

81]


Curcumin Liposome

Enter cell

Fusion

Endocytosis

Lysosome

OH

O O

H3COOCH3

HO










4 Micelles













5 Niosomes





6 Cyclodextrins







OndashCH3 H3CndashO

Curcumin

+

Cyclodextrin

OOH

OHHO

HOO

CC

CC

C CC

HO

OMeOMe

OH

1

2

3

4

5

6

7

8

9

10

2998400

3998400

4998400

5998400

6998400

7998400

8998400

9998400

10998400

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OHOH

OH

O

O

O

O

O

OOO

O

O

O

O

OO

HOCH3

HOCH3

CH3OH CH3OH

CH3OH

CH3OH

CH3OH

6

2

3








7 Dendrimers









8 Nanogels








9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





3 Liposomes





ble1Nanop

articles-conjugated

curcum

incharacteriz

ationford

ifferentd

iseases

treatment

Type

ofnano

particles

Form

Size

(nm)

Usedmod

els

Metho

dsRe

sults

Reference

Lipo

some

Globu

lar

25ndash205

(i)Breastcancer

(ii)M

elano

ma

(iii)Re

nalischemia

(iv)M

alaria

Invitro

Invivo

(dog

andmice)


istrib

utionandsta

bility

(ii)E

nhancedantitum

orandantia

ngiogenesis

effects

(iii)Show

edantim

elanom


antim

alarialeffects

[30ndash

33]

[34ndash

37]

[3839]

Micelle

Spheric

al10ndash100

(i)Lu

ngtumor

(ii)B

reastcancer

Invitro

Invivo

(mice)


(ii)Improved

antio

xidativ

eand

antitum

oreffects

(iii)Prolon

gedcirculationtim

e(iv

)Enh

ancedflu

orescencee

ffect

[40]

[41]

[42]

[43]

[44]

[45]

[46]

Noisome

Lamellar

190ndash

1140

(i)Albinoratskin

(ii)C

ancerous

cells

Invitro

Invivo

(snake

andmice)

(i)Increasedskin

penetration

(ii)P

rolonged

deliverysyste

m(iii)Anti-infectio

nandantic

ancere

ffects

(iv)E

nhancedflu

orescenceintensity

[47]

[48]

[49]

OO

O O O

O

OO

OOO

O

n

OR 6

OR 6

OR 2O

R 2

OR 6

OR 6O

R 3

OR 3

OR 3

R 6O

R 2OR 3

OR 3

O

R 3OR 2

O

R 6O

R 2O

OR 2

Cyclo

dextrin

Cyclic

150ndash

500

(i)Bo

weldisease

(ii)B

reastlung

pancreaticand

prostatecancer

Invitro

Invivo

(ratandmice)

(i)Im

proved

solubility

(ii)E

nhancedantip

roliferationeffects

(iii)Increasedantic

ancera


(iv)D

evelop

edbioavailability

[30]

[50ndash

56]

Dendrim

erGlobu

lar

polymer

15ndash150

(i)Breastcancer

(ii)C

olon

cancer

Invitro

Invivo

(mice)

(i)Im

proved

stability

(ii)Increased

antitum

orandantip

roliferativee

ffects

[5758]

[59ndash

63]

Nanogel

Cross-lin

ked

polymer

network

10ndash200

(i)Melanom

a(ii)B

reastand

pancreaticcancer

cells

Invitro


(ii)E

nhancedflu

orescencee

ffects

(iii)Develop

edbioavailability

(iv)Improved

antic

ancere

ffects

(v)G

etbette

rcon

trolledrelease

(vi)Prolon

gedhalf-life

(vii)

Enhanced

treatmento

fmelanom

a

[64]

[65]

Chito

san

Linear

polysaccha-

ride

compo

sed

100ndash

250

(i)Wou

nds

(ii)M

elanom

atum

ors

Invitro

Invivo

(ratandmice)

(i)Im

proved

chem

icalstability

(ii)S

howed

wou

ndhealingeffects


oreffects

(iv)Improved

antio

xidant

effects

(v)P

rolonged

bloo

dcirculation

[66ndash

71]

Gold

Globu

lar

200ndash

250

Cancerou

scells

Invitro

(i)Im

proved

solubility

(ii)E

nhancedantio

xidant

andantic

ancere

ffects

[72]

[73]

Silver

Film

layer

sim15

(i)Infections

(ii)S

kinwou

nds

Invitro

(i)Sh

owed

antim

icrobialeffects

(ii)Improved

wou

ndhealing

(iii)Increasedantiv

iraland

antic

ancere

ffects

[74]

[75]

Lipi

d(s

olid

)Solid

lipid

Spheric

al50ndash100

0

(i)Cerebralischemia

(ii)C

olitis

(iii)Allergy

(iv)B

reastcancer

Invitro

Invivo

(ratandmice)

(i)Prolon

gedcirculationof

bloo

d(ii)Increased


(iii)Im

proved

braindelivery

[76ndash

78]

[79ndash

81]


Curcumin Liposome

Enter cell

Fusion

Endocytosis

Lysosome

OH

O O

H3COOCH3

HO










4 Micelles













5 Niosomes





6 Cyclodextrins







OndashCH3 H3CndashO

Curcumin

+

Cyclodextrin

OOH

OHHO

HOO

CC

CC

C CC

HO

OMeOMe

OH

1

2

3

4

5

6

7

8

9

10

2998400

3998400

4998400

5998400

6998400

7998400

8998400

9998400

10998400

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OHOH

OH

O

O

O

O

O

OOO

O

O

O

O

OO

HOCH3

HOCH3

CH3OH CH3OH

CH3OH

CH3OH

CH3OH

6

2

3








7 Dendrimers









8 Nanogels








9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


ble1Nanop

articles-conjugated

curcum

incharacteriz

ationford

ifferentd

iseases

treatment

Type

ofnano

particles

Form

Size

(nm)

Usedmod

els

Metho

dsRe

sults

Reference

Lipo

some

Globu

lar

25ndash205

(i)Breastcancer

(ii)M

elano

ma

(iii)Re

nalischemia

(iv)M

alaria

Invitro

Invivo

(dog

andmice)


istrib

utionandsta

bility

(ii)E

nhancedantitum

orandantia

ngiogenesis

effects

(iii)Show

edantim

elanom


antim

alarialeffects

[30ndash

33]

[34ndash

37]

[3839]

Micelle

Spheric

al10ndash100

(i)Lu

ngtumor

(ii)B

reastcancer

Invitro

Invivo

(mice)


(ii)Improved

antio

xidativ

eand

antitum

oreffects

(iii)Prolon

gedcirculationtim

e(iv

)Enh

ancedflu

orescencee

ffect

[40]

[41]

[42]

[43]

[44]

[45]

[46]

Noisome

Lamellar

190ndash

1140

(i)Albinoratskin

(ii)C

ancerous

cells

Invitro

Invivo

(snake

andmice)

(i)Increasedskin

penetration

(ii)P

rolonged

deliverysyste

m(iii)Anti-infectio

nandantic

ancere

ffects

(iv)E

nhancedflu

orescenceintensity

[47]

[48]

[49]

OO

O O O

O

OO

OOO

O

n

OR 6

OR 6

OR 2O

R 2

OR 6

OR 6O

R 3

OR 3

OR 3

R 6O

R 2OR 3

OR 3

O

R 3OR 2

O

R 6O

R 2O

OR 2

Cyclo

dextrin

Cyclic

150ndash

500

(i)Bo

weldisease

(ii)B

reastlung

pancreaticand

prostatecancer

Invitro

Invivo

(ratandmice)

(i)Im

proved

solubility

(ii)E

nhancedantip

roliferationeffects

(iii)Increasedantic

ancera


(iv)D

evelop

edbioavailability

[30]

[50ndash

56]

Dendrim

erGlobu

lar

polymer

15ndash150

(i)Breastcancer

(ii)C

olon

cancer

Invitro

Invivo

(mice)

(i)Im

proved

stability

(ii)Increased

antitum

orandantip

roliferativee

ffects

[5758]

[59ndash

63]

Nanogel

Cross-lin

ked

polymer

network

10ndash200

(i)Melanom

a(ii)B

reastand

pancreaticcancer

cells

Invitro


(ii)E

nhancedflu

orescencee

ffects

(iii)Develop

edbioavailability

(iv)Improved

antic

ancere

ffects

(v)G

etbette

rcon

trolledrelease

(vi)Prolon

gedhalf-life

(vii)

Enhanced

treatmento

fmelanom

a

[64]

[65]

Chito

san

Linear

polysaccha-

ride

compo

sed

100ndash

250

(i)Wou

nds

(ii)M

elanom

atum

ors

Invitro

Invivo

(ratandmice)

(i)Im

proved

chem

icalstability

(ii)S

howed

wou

ndhealingeffects


oreffects

(iv)Improved

antio

xidant

effects

(v)P

rolonged

bloo

dcirculation

[66ndash

71]

Gold

Globu

lar

200ndash

250

Cancerou

scells

Invitro

(i)Im

proved

solubility

(ii)E

nhancedantio

xidant

andantic

ancere

ffects

[72]

[73]

Silver

Film

layer

sim15

(i)Infections

(ii)S

kinwou

nds

Invitro

(i)Sh

owed

antim

icrobialeffects

(ii)Improved

wou

ndhealing

(iii)Increasedantiv

iraland

antic

ancere

ffects

[74]

[75]

Lipi

d(s

olid

)Solid

lipid

Spheric

al50ndash100

0

(i)Cerebralischemia

(ii)C

olitis

(iii)Allergy

(iv)B

reastcancer

Invitro

Invivo

(ratandmice)

(i)Prolon

gedcirculationof

bloo

d(ii)Increased


(iii)Im

proved

braindelivery

[76ndash

78]

[79ndash

81]


Curcumin Liposome

Enter cell

Fusion

Endocytosis

Lysosome

OH

O O

H3COOCH3

HO










4 Micelles













5 Niosomes





6 Cyclodextrins







OndashCH3 H3CndashO

Curcumin

+

Cyclodextrin

OOH

OHHO

HOO

CC

CC

C CC

HO

OMeOMe

OH

1

2

3

4

5

6

7

8

9

10

2998400

3998400

4998400

5998400

6998400

7998400

8998400

9998400

10998400

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OHOH

OH

O

O

O

O

O

OOO

O

O

O

O

OO

HOCH3

HOCH3

CH3OH CH3OH

CH3OH

CH3OH

CH3OH

6

2

3








7 Dendrimers









8 Nanogels








9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Curcumin Liposome

Enter cell

Fusion

Endocytosis

Lysosome

OH

O O

H3COOCH3

HO










4 Micelles













5 Niosomes





6 Cyclodextrins







OndashCH3 H3CndashO

Curcumin

+

Cyclodextrin

OOH

OHHO

HOO

CC

CC

C CC

HO

OMeOMe

OH

1

2

3

4

5

6

7

8

9

10

2998400

3998400

4998400

5998400

6998400

7998400

8998400

9998400

10998400

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OHOH

OH

O

O

O

O

O

OOO

O

O

O

O

OO

HOCH3

HOCH3

CH3OH CH3OH

CH3OH

CH3OH

CH3OH

6

2

3








7 Dendrimers









8 Nanogels








9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of






4 Micelles













5 Niosomes





6 Cyclodextrins







OndashCH3 H3CndashO

Curcumin

+

Cyclodextrin

OOH

OHHO

HOO

CC

CC

C CC

HO

OMeOMe

OH

1

2

3

4

5

6

7

8

9

10

2998400

3998400

4998400

5998400

6998400

7998400

8998400

9998400

10998400

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OHOH

OH

O

O

O

O

O

OOO

O

O

O

O

OO

HOCH3

HOCH3

CH3OH CH3OH

CH3OH

CH3OH

CH3OH

6

2

3








7 Dendrimers









8 Nanogels








9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of












5 Niosomes





6 Cyclodextrins







OndashCH3 H3CndashO

Curcumin

+

Cyclodextrin

OOH

OHHO

HOO

CC

CC

C CC

HO

OMeOMe

OH

1

2

3

4

5

6

7

8

9

10

2998400

3998400

4998400

5998400

6998400

7998400

8998400

9998400

10998400

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OHOH

OH

O

O

O

O

O

OOO

O

O

O

O

OO

HOCH3

HOCH3

CH3OH CH3OH

CH3OH

CH3OH

CH3OH

6

2

3








7 Dendrimers









8 Nanogels








9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of




6 Cyclodextrins







OndashCH3 H3CndashO

Curcumin

+

Cyclodextrin

OOH

OHHO

HOO

CC

CC

C CC

HO

OMeOMe

OH

1

2

3

4

5

6

7

8

9

10

2998400

3998400

4998400

5998400

6998400

7998400

8998400

9998400

10998400

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OHOH

OH

O

O

O

O

O

OOO

O

O

O

O

OO

HOCH3

HOCH3

CH3OH CH3OH

CH3OH

CH3OH

CH3OH

6

2

3








7 Dendrimers









8 Nanogels








9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


OndashCH3 H3CndashO

Curcumin

+

Cyclodextrin

OOH

OHHO

HOO

CC

CC

C CC

HO

OMeOMe

OH

1

2

3

4

5

6

7

8

9

10

2998400

3998400

4998400

5998400

6998400

7998400

8998400

9998400

10998400

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OHOH

OH

O

O

O

O

O

OOO

O

O

O

O

OO

HOCH3

HOCH3

CH3OH CH3OH

CH3OH

CH3OH

CH3OH

6

2

3








7 Dendrimers









8 Nanogels








9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





7 Dendrimers









8 Nanogels








9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of







8 Nanogels








9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of







9 Chitosans




















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



















11 Silvers





12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



12 Solid Lipids













Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of








Acknowledgment


References




























































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of




















































































































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

review article nanotechnology-applied curcumin for

Documents