nano-drug delivery systems and applications in … · 2020. 8. 31. · (cdds) are particulate or...

Natarajan. World Journal of Pharmacy and Pharmaceutical Sciences

www.wjpps.com Vol 9, Issue 9, 2020.

1313

NANO-DRUG DELIVERY SYSTEMS AND APPLICATIONS IN

DERMATOLOGY

Dr. Mariappan Natarajan*

Consultant Plastic Surgeon, Chennai, India.

ABSTRACT

Dermatology clinical practice has become an important aspect of

human healthcare with the prevalence of skin diseases exceed that of

obesity, hypertension, and cancer added together. Skin diseases

account for more than 12 % of primary care hospital visits, and one out

of every three person has a skin disease at any given time. Skin is

accessible to traditional clinical examination and various imaging

modalities are also available for diagnosis. Conventional formulations

of many drugs available for treatment of dermatological conditions act

via different mechanisms of action are not satisfactory due to poor water solubility, low

biological efficacy, non-targeting, and drug resistance. Limitations of conventional

formulations must be addressed to enhance efficiency of the drug, reduce toxicity and avoid

damage to normal adjacent healthy tissues. Most skin conditions are characterized by

chronicity and associated with psychological effects. Advances in nanotechnology provide

new drug delivery methods for treatment of various skin conditions. Nano-drug delivery

systems (NDDSs) have great advantages in solving the problems and limitations faced by

conventional formulations. But problems related to NDDSs such as cytotoxicity,

environmental issues and long term effects must always be kept in mind. This review aims at

understanding the types and targeting strategies of NDDSs, new research progress in the

diagnosis, therapy and monitoring of skin disorders in recent years. Future prospective for

nano-carriers in drug delivery includes gene therapy, in order to provide more ideas for the

improvement of drugs used for skin problems. Safety and environmental concerns are also

discussed in this review.

KEYWORDS: bioactive molecules, nanoparticulate carrier system, oligomeric film,

cosmetics, Iontophoresis; self-assembly, conformational integrity, sonophoresis,

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 9, 1313-1360 Review Article ISSN 2278 – 4357

*Corresponding Author

Dr. Mariappan Natarajan

Consultant Plastic Surgeon,

Chennai, India.

Article Received on

12 July 2020,

Revised on 01 August 2020,

Accepted on 22 August 2020

DOI: 10.20959/wjpps20209-17173



1314

microneedles, cell therapy, transdermal delivery system, chemical enhancers, controlled

release, Drug delivery devices, Gene therapy, personalized medicine, protein/peptide

delivery, targeted drug delivery.

1. INTRODUCTION

Management of dermatological disorders include an efficient drug action and monitoring of

therapies also. Early detection, treatment and monitoring of management process are crucial

for complete recovery that include inflammatory and infective lesions and skin cancers. A

treatment strategy that combines therapeutics with diagnostics is known as Theragnostics.

Beneficial and harmful effects of new medications can be identified, and targeted drug

therapy technologies for individual patients can be developed. Progress of molecular

theragnostics depends on molecular biology tools like, bioinformatics, genomics, proteomics,

and functional genomics, that generate genetic and protein information required for

development of diagnostic assays.[1]

Theragnostics include personalized medicine,

pharmacogenomics, and molecular imaging. They help develop efficient new targeted

therapies with adequate benefit/risk to patients and to optimize drug selection based on better

molecular understanding. Theragnostics have the following advantages and potential.

Aim to increase drug efficacy, safety, and monitor response to the treatment,

Eliminate unnecessary treatment of patients for whom therapy may not be appropriate,

A significant drug cost savings for the healthcare system.

Theragnostic tests as a routine in health care is based on cost-effectiveness and the

availability of appropriate accessible testing systems.

Theragnostics may change pharmaceutical business model towards targeted therapies,

from classic blockbuster model.

2. Basics of Skin barrier function and moisturization

The Stratum Corneum has been considered as a brick wall-like structure with the keratin-rich

corneocytes being the ―bricks‖ and the intercellular lipid matrix being the ―mortar‖. During

formation of SC by epidermal differentiation, the lipid composition changes from polar to

neutral in nature. Composition of SC lipids are neutral (60–80%), with sphingolipids (15–

35%) and a small number of polar lipids comprising the rest. Both saturated and unsaturated

fatty chains form part of the neutral lipids and unsaturated chains predominate in SC except

for the free fatty acid fraction. Lipids form 20% volume of SC, are in continuous lipid phase

and arranged in multiple lamellar structures. SC does not contain phospholipids; and has



1315

ceramides (41%), cholesterol (27%), and cholesteryl esters (10%) together with fatty acids

(9%) and cholesteryl sulfate (1.9%). These components form broad intercellular lipid

lamellae in the initial layers of the SC.[2]

They form into lipid bilayers, with the hydrocarbon

chains aligned and the polar head groups dissolved in an aqueous layer. Different domains

within the lipid bilayers are formed by hydrocarbon chains arranged into regions of

crystalline, lamellar gel, and lamellar liquid crystal phases.

Ibn Sina, a Persian physician described the concept that certain drugs can cross the skin and

proposed that dermal application of drugs have local effect, affect tissue immediately beneath

the skin as well as in more remote areas. This is considered as one of the most ancient

description of transdermal drug delivery. Two main routes of skin permeation defined for

molecules applied to the skin include (1). In Trans-epidermal transport, molecules cross intact

horny layer, two potential micro-routes of entry include transcellular (or intracellular) and the

inter-cellular pathway and (2). Trans-follicular route (Shunt pathway) comprises transport via

the sweat glands and the hair follicles with their associated sebaceous glands. Three possible

pathways for SC epidermal penetration of active compounds are appendageal (intercellular)

penetration through the hair follicle or via the sebaceous and/or sweat glands, Transcellular

(intracellular) permeation through the corneocytes and through intercellular lipid

matrix[Figure:1].

Figure 1: Transcellular and intercellular routes of drug delivery via the skin [Escobar-

Chávez et al. (2012)].

Intercellular route through appendages (hair follicles and glands) offer high permeability but

offer only approximately 0.1% of total skin for permeation and their contribution to

epidermal permeation is very small. This route seems to be most important for ions and large



1316

polar molecules which hardly permeate through the stratum corneum. Intercellular lipid

matrix allows a straight path through SC into the lower levels of epidermis, and finally, the

dermis below.[3]

Transcellular route comprises the main trans-epidermal pathway. A

molecule traversing transcellular route must partition into and diffuse through the

corneocytes, and move between corneocytes. The molecule must diffuse through 4 to 20 lipid

lamellae between each of these cells, that requires negotiation of multiple hydrophilic and

hydrophobic domains. Transdermal permeation is based on passive diffusion.[4]

The main

objective of transdermal drug delivery system is to deliver drugs into systemic circulation

through skin at predetermined rate with minimal inter and intra patient variation. Thus, the

intercellular lipid matrix plays a major role in the barrier function of the SC. As a result, the

majority of research is aimed at optimizing the permeation of the skin by actives has focused

on the contribution of lipids to barrier function, manipulation of the solubility of the lipid

domain, and alteration of the ordered structure of the SC.

Keratohyalin is a protein structure in cytoplasmic granules of keratinocytes in stratum

granulosum of the epidermis. Keratohyalin granules (KHG) mainly consist of keratin,

profilaggrin, loricin and trichohyalin proteins which contribute to cornification or

keratinization, the process of formation of epidermal cornified cell envelope. During

keratinocyte differentiation, these granules mature and expand in size, and leads to the

conversion of keratin tonofilaments into a homogenous keratin matrix, an important step in

cornification. Keratohyalin granules can be divided in three classes: Globular KHG (in

quickly dividing epithelia, the oral mucosae), Stellate KHG (in slowly dividing

normal epidermis) and KHG of Hassall‘s corpuscles or type VI epithelia-reticular cells of

thymus gland. The exact purpose of keratinization of Hassall's corpuscles is unknown. During

skin differentiation process, keratohyaline granules discharge their contents at the junction

between stratum granulosum and stratum corneum cell layers that form the barrier. At the

same time, the inner side of the cell membrane thickens forming the cornified cell envelope.

The nuclei, ribosomes and mitochondria disappear after release of the granules and the cells

become densely packed with filaggrin and cover more surface. After final dehydration, the

cell desquamates. Release of keratohyalin granules plays an important role in the skin

moisturization. Filaggrin undergoes chemical modification and proteolytic processing which

leads to the formation of natural moisturizing factor (NMF), hygroscopic amino acids and

derivatives which function as UV protectant, modulate stratum corneum pH and water

retention. Role of NMF in stratum corneum: The NMF consists primarily of amino acids or



1317

their derivatives such as pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA)

together with lactic acid, urea, citrate, and sugars. These compounds are collectively present

at high concentrations within the cell and may represent 20 to 30% of the dry weight of the

SC.[5]

The constituent chemicals, particularly the PCA and lactic acid salts, are intensely

hygroscopic and these salts absorb atmospheric water and dissolve in their own water of

hydration, thereby acting as very efficient humectants.

3. Drug delivery Systems

Drug delivery Systems (DDS) is “a formulation or a device that enables the introduction of

a therapeutic substance into the body and improves its efficacy and safety by controlling

the rate, time, and place of release of drugs in the body”.[6]

Advances in nanotechnology

and nanomaterials have led to development of newer drug delivery systems in biomedicine.

Drug formulations for drug delivery and targeted drug delivery utilize various routes of drug

administration. New biotechnology-based therapeutics deliver proteins and peptides; cell and

gene therapies are sophisticated methods of delivery of therapeutics[Table:1].

Table 1: Classification of Pharmaceutical Carriers.

Particulate carrier (also

known as a colloidal

carrier system)

Lipid Particles (Low and High Density Lipoprotein-LDL and

HDL),

Microspheres, Nanoparticles,

Polymeric Micelles and vesicular Like Liposomes, Niosomes,

Pharmacosomes, Virosomes etc .

Polymeric carrier

HPMA (polymer-drug) and PEG (polymer-protein),

poly(glutamic acid), PEI, dextran, dextrin, chitosans, poly(L-

lysine), and poly(aspartamides) as polymeric carriers.

Macromolecular carrier

Liposomes, Polymer micelles (PM), Dendrimers, and

Calix[n]arenes (Calix[n]arenes are cyclic oligomers-3rd

generation of supramolecular chemistry, synthesised from

phenol and formaldehyde in an acidic or basic medium).

Carbon nanotubes, Cyclodextrin, Polymer-drug conjugates,

and Azo polymer.

Cellular carriers

Immune cells as drug carriers- macrophages, T cells;

Blood cells as drug carriers (Platelets, Red blood cells and red

blood cell mimics); Stem cells as drug carriers;

Exosomes as drug carriers; and Adipocytes as drug carriers.

Nanoparticles are important for refining drug delivery as vehicles for drug delivery, as

pharmaceuticals and as diagnostics. Most of the advances in targeted drug delivery have

occurred in cancer therapy.[7]

The challenge of drug delivery into the central nervous system

(CNS) is due to the blood brain barrier (BBB). Biodegradable and non-cytotoxic



1318

nanomaterials help cross the BBB as efficient drug delivery systems. Poly (PEG, PLA, and

PLGA) covalent-attached to nanoparticles strategies, lipid nanocarrier DDS strategies,

polymeric/dendritic nanocarrier DDS strategies, magnetic nanocarrier DDS strategies, and

other (carbon nanotubes, viral, gold, silica etc.) nanocarrier DDS strategies are useful and

promising for developing special brain drug delivery systems. Refinements in drug delivery

will facilitate the development of personalized medicine. Colloidal drug delivery systems

(CDDS) are particulate or vesicular dosage form in nano-meter size range, that include

liposomes, niosomes, nanospheres, multiple emulsion, and ceramics. CDDS are essential for

effective transportation of loaded drug to the target site. Colloidal drug carriers such as

liposomes and NPs modify the distribution of an associated substance and are used to

improve therapeutic index of drugs by increasing their efficacy and/or reducing their toxicity.

Nanosponges are new nanotechnology-based colloidal, discrete functionalized particles with

precise carrier function of controlled drug delivery for topical use.[8]

Poor permeability, skin

irritation and allergic reactions are challenges for topical drug delivery systems. Nanosponges

are tiny sponges with size of a virus, that can be filled with a variety of drugs. Aqueous

solubility of nanosponge is an important feature, drugs can be released at specific target sites

instead of circulating throughout the body and both lipophillic and hydrophilic drugs can be

incorporated. The outer surface is typically porous, allowing controlled release of the drug.

Nanosponge systems enhance solubility and bioavailability, reduce side effects, modify drug

release and are effective for drugs with poor solubility.

Polymers form the backbone of drug delivery systems, three main components of polymer-

drug conjugate include, a soluble polymer foundation, a biodegradable linker and covalently

attached therapeutic agents. Macromolecules have optimal drug loading potential, smooth

drug releasing ability and bio-compatibility and have a wide range of applications in targeted

drug delivery systems. Cellular carriers include a variety of cell or cell membrane-based

drug delivery systems (Carrier RBC, MSC, NSC, Whole blood cells, RBC MVs); Tumour

cell-derived MPs; Exosomes for immuno-therapy and drug delivery and exosome-mimetic

vesicles; Semipermeable protein-loaded RBCs (as bioreactors); Shedding vesicles (RBC-

derived micro-vesicles; tumour Cell-derived microparticles and MSC-based micro-vesicles)

and RBC membrane coated NPs.

Drug delivery research is moving from the micro to nanoscale and nanotechnology is

emerging as a significant therapeutic benefit tool in the field of medicine with advantages of



1319

drug delivery particularly for oral drugs. It allows (1) delivery of poorly water-soluble drugs

(2) targeting of drugs to specific parts of the gastrointestinal tract (3) transcytosis of drugs

across the tight intestinal barrier and (4) the intra-cellular and transcellular delivery of large

macromolecules. Nanodrug delivery systems such as nano-emulsions, lipid or polymeric

NPs, and liposomes are functional drug carriers for treating a wide range of therapies

including cardiovascular diseases, autoimmune diseases and cancer. Nanosized devices or

drug carriers (nanocarriers or nano-vehicles) provide advantages for effective drug delivery.

Nanotechnology holds the promise for future of controlled drug delivery and monitoring of

concentration of delivered drugs. Research in this direction with efforts from scientists from

different disciplines and in combination with nanotechnology applicable in key areas will

benefit patients in the near future.

3.1. Controlled-release technology

Controlled release drug delivery is defined as release of the drug in a predesigned manner

that achieve therapeutic benefits and time reducing toxic effects at the same and minimize

unwanted fluctuation of drug levels.[9]

Foaming and unwanted preferential flow paths in the

subsurface are generated by wasteful big bursts of oxygen that simply ―bubble off‖.

Controlled Release Technology (CRT) limit rate of oxygen release from solid oxygen

sources, by intercalating (embedding) phosphates into the crystal structure of solid peroxygen

molecules. This slows the reaction that yields oxygen within the crystal, and minimize bubble

off which can waste the majority of oxygen available in common solid peroxygen chemicals.

Advances in development of various drugs have produced new devices, concepts and

technique called controlled-release technology. Examples of CRTs include trans-dermal and

transmucosal controlled-release delivery systems, encapsulated cells, nasal and buccal

aerosol sprays, drug-impregnated lozenges, oral soft gels and iontophoretic devices to

administer drugs through skin. A variety of programmable and implantable drug-delivery

devices are also included in CRT, that help overcome problems associated with conventional

drug administration methods. Pharmacokinetic and pharmacodynamic studies of action and

nature of potent opioid analgesics, inhalation anaesthetic agents, sedative/hypnotics and

muscle relaxants help study drug delivery mechanisms. Skin, buccal and nasal mucous

membranes are used as alternate routes for drug delivery of analgesic and anaesthetic drugs.

Self-assembly is a prominent thermodynamically favourable phenomenon observed in nature.

Several natural and synthetic materials are used to develop functional systems for various



1320

biomedical applications, including drug delivery. Two crucial features for controlled and

targeted drug release are tunability and multifunctionality that are the added advantages of

Layered self-assembled systems, and Layer-by-layer (LbL) deposition is the most popular

technique for layered self-assemblies. Recently metal-phenolic networks (MPNs) and

Liesegang rings are also utilized for controlled drug delivery. Blending sophisticated self-

assembly phenomena with material science and technological advances achieve powerful

tools, that develop smart drug carriers in a scalable manner.

The organic CRT has the disadvantage of ‗the burst effect‟ i.e. the drug is suddenly released

in large quantities than required therapeutically, without any control.[10]

The iCRT platform

includes inorganic materials that offer solutions for challenges in drug delivery, formulation

tools development for cosmetics, personal care and novel materials for medical devices. Their

chemical and physical properties are delivered by materials manipulated via novel manufac-

turing processes and compositions. A new delivery platform technology, iCRT-deter provides

abuse deterrent controlled release for pharmaceutical application. iCRT platform has distinct

advantages that are used in medical devices, pharmaceuticals and consumer products. They

control release of actives, protect functional ingredients, optimize and add features to

products, improve formulation stability, and increase bioactivity of medical materials.

Mechanism of controlled release is achieved by diffusion, degradation, swelling followed by

diffusion, and active efflux.

3.1.2. Classification and Mechanism of ‘Controlled drug release’ of Drugs

The controlled release systems are divided based on release pattern. (1) Rate pre-programmed

drug delivery system. (2) Activated modulated drug delivery system. (3) Feedback regulated

drug delivery system and (4) Site targeting drug delivery system[Table:2]. The temperature

of solid tumour is very high due to the uncontrolled cellular differentiation and growth that

liberates more amount of energy. Cancerous cells have hypoxia and undergo anaerobic

respiration resulting in accumulation of lactic acid and hence an acidic pH. In a

biochemically more active tumour, pH is lower and temperature is higher. Controlled

release of drug from the carrier is based on changes in pH(lower in biochemically more

active tumour), temperature (higher in the tumour), redox potential or biological

macromolecules (enzymes, glucose, antigens, etc.) by stimuli like light, magnetic field,

ultrasound either in a single mode or in combination of the stimuli.[11]

External or internal



1321

stimuli mechanisms or a combination of stimuli can be used. Useful diagnostic modalities are

MRI that use T1 and/or T2 sensitive agents, fluorescein markers and radionuclides.

Table 2: Classification of controlled release delivery systems.

Physical

systems

Diffusion controlled systems; Monolithic systems; Dissolved drugs;

Dispersed drugs; Porous systems; Hydrogels; Biodegradable system;

Reservoir system; Constant activity; Non constant activity; Unsteady state;

Ion exchange resin system; Osmotically control system; Hydra-dynamically

balanced system; Other physical systems

Chemical

systems

Immobilization of the drugs

Prodrugs

Biological

system Gene therapy

3.1.3.Advantages and disadvantages of controlled drug therapy

The delivery systems improve patient compliance especially with long-term treatments for

chronic diseases, with reduction in dose and dosing frequencies. Conventional dosage forms

produce fluctuations in plasma drug concentration, depending on drug kinetics within the

body like absorption, distribution, metabolism and excretion. Controlled release eliminates

these fluctuations and maintain plasma concentration of the required drug, thus eliminates

failure of drug therapy and improves efficiency of treatment. A suitable delivery system for

drugs having a short biological half-life (3-4 hrs) ensures the drug is rapidly eliminated from

the body. Disadvantages of CRDDS include dumping, a rapid release of a relatively large

quantity of drug from a controlled release formulation.[12]

This phenomenon becomes

hazardous with potent drugs. It has a poor in-vivo and in-vitro correlations and is difficult to

optimize the accurate dose and dosing interval. Patient variability affects the release rate like

GI emptying rate, residential time, fasting or non-fasting condition, etc.

3.2. Mechanisms of Drug Release

Drug delivery technologies modify drug release profile, absorption, distribution and

elimination of drugs for an improved product efficacy, safety, patient convenience and

compliance. Drug delivery refers to approaches, formulations, technologies, and systems for

transporting pharmaceutical compound in the body; NPs achieve safe and desired therapeutic

effect. Common routes of administration include the enteral (gastrointestinal tract), parenteral

(via injections), inhalation, transdermal, topical and oral routes. Drug release involves

multiple steps that include diffusion, disintegration, de-aggregation and dissolution;

degradation, swelling, and affinity-based mechanisms are also involved. Site-targeting within



1322

the body, systemic pharmacokinetics concerned with both quantity and duration of drug

presence are characteristic features. Chemical formulation of drug, medical devices or drug-

device combination are utilized. Drug delivery concept is heavily integrated with dosage

form and route of administration. Peptide and protein, antibody, vaccine and gene-based

drugs undergo enzymatic degradation, or may not be absorbed into systemic circulation

efficiently due to molecular size and charge. Protein and peptide drugs are delivered by

injection or by nanoneedle array. Protein drugs delivered by injection can usually reach the

extra-cellular space and targeting the intracellular space with protein drugs and delivery of

proteins into cells (e.g. into the cytosol) still remains a challenge.

3.2.1.Diffusion

Diffusion is defined as a process of mass transfer of individual molecules of the substance

brought about by random molecule motion and associated with a driving force such as

concentration gradient.[13]

Diffusion takes place on a macroscopic scale through pores in the

device matrix and at the same time on a molecular level by passing between matrix

molecules. Diffusion occurs as drug passes from polymer matrix into external surrounding. In

a controlled release system drug has to travel longer distance and needs a large diffusion time

to release; hence as drug release increases, diffusion rate decreases. Diffusion is a very

significant phenomenon in pharmaceutical science e.g. diffusion of drug across a biological

membrane is needed for a drug to be absorbed into and excreted from the body. Diffusion is a

relatively slow process and result of a random molecular motion and concentration gradient is

the driving force. Fick‟s Law of Diffusion: Fick realized that the mathematical equation of

heat conduction by Fourier can be applied to mass transfer, the fundamental relationships

indicate the diffusion process in pharmaceutical systems. Amount M, of the material passing

through a unit cross section S, in a time interval t is known as flux J: J= dM/S.dt (Ficks first

law of diffusion equation). Flux J is directly proportional to concentration gradients dc/dx. ( J

= -D dc/dx; D = diffusion coefficient of a drug; C= concentration (g/cm 2); S = surface area

(cm2); t = time in seconds; and J = g/cm

2 second.

3.2.2. Endothelium Targeting

Nanoparticle-based drug delivery has improved the treatment of solid tumours. Integrins are

proteins that have mechanical function to attach cell cytoskeleton to extracellular matrix and

biochemical function help confirm adhesion by sensing.[14]

Transmembrane heterodimers are

formed by alpha and beta subtypes of integrin family of proteins. Integrins are adhesion



1323

receptors for extracellular ligands and transduce bio-chemical signals into the cell, through

downstream effector proteins. Cadherins are transmembrane proteins with adhesion tension

function, signalling function, and mechanical scaffolding functions. Syndecans belong to a

family of transmembrane heparan sulphate proteoglycans, that function as cell proliferation

and cell–matrix and cell–cell adhesion processes. They modulate the ligand-dependent

activation of primary signalling receptors at the cell surface and principal functions of the

syndecan core proteins are to target the heparan sulphate chains to the appropriate plasma-

membrane compartment and to interact with components of the actin-based

cytoskeleton. Selectins are carbohydrate-binding molecules that bind to fucosylated and

sialylated glycoprotein ligands, and are found on endothelial cells, leukocytes and platelets.

They are involved in trafficking of cells of the innate immune system, T lymphocytes and

platelets. Selectins are multi-functional adhesion molecules that mediate the initial

interactions between circulating leukocytes and the endothelium.

Integrins along with other proteins such as cadherins, the immunoglobulin superfamily cell

adhesion molecules, selectins and syndecans to mediate cell-cell and cell-matrix interaction.

They function bidirectionally i.e. they can transmit information both outside-in and inside-

out. Signal transduction pathways that mediate cellular signals like regulation of cell cycle on

binding to ligands are activated by integrins, play key roles in regulation of angiogenesis and

lymphangiogenesis during normal development. Integrins have an important role in

angiogenesis of tumour vasculature and molecular biology methods identify them as potential

targets. Integrin expression and/or function is involved in every stage of cancer

development, influence primary tumour formation, cancer cell extravasation and formation of

metastasis. They are responsible for primary tumour, tumour microenvironment, migration

and invasion of tumour, metastasis and anchorage, metastatic niche and colonization, and

play a crucial role in the development of drug resistance. Integrin signalling is linked to the

acquisition of drug resistance. Integrins and integrin-dependent functions are potential

therapeutic targets in cancer therapy. Loss of integrin α3 prevents skin tumour formation by

promoting epidermal turnover and depletion of slow-cycling cells. Tripeptide Arginine-

Glycine-Aspartate, the amino acid sequence within the extracellular matrix protein

fibronectin, mediates cell attachment. Laminin and vitronectin, other extra-cellular matrix

proteins also have RGD cell binding sequence. Integrins belong to the family of membrane

proteins, act as receptors for these cell adhesion molecules via the RGD motif.[15]

A subset of

the integrins (αvβ3, α5β1 and αIIbβ3) recognize RGD motif within their ligands and the



1324

binding mediates both cell-substratum and cell-cell interactions. Integrins bind to tripeptide

Arg-Gly-Asp (RGD) inclusive sequences and are included into a cyclic nano-peptide RGD-

4C. This complex binds to integrins v 3 in v 5 without any cross-reactivity with thrombocyte

integrins and receptors found everywhere. The applications of integrins in cancer therapy

include

Efficacy of doxorubicin increases with coupling with RGD-4C and has decreased

hepatotoxicity and cardiotoxicity.

Adenoviral tropism for big blood vessel endothelial and smooth muscle cells is enhanced

by Histidine-tryptophan-glycine-phenylalanine (HWGF). Other binding sequences

actively binds to matrical metallo-proteinases 2 and 9.[16]

NGR hexapeptide molecule binds to N angiogenic endothelial cell peptidases. Coupling

doxorubicin and melphalan with TNF-α increases the chemo-reactivity of

chemotherapeutics against murine tumours eight to tenfold.

Targeted delivery of therapeutic genes complexed with cation nanoparticles in tumour

endothelial cells by synthetic v3 analogue is another antiangiogenic for treatment of solid

tumours.

Early identification of tumour angiogenesis is possible by location specific MR imaging

with v3 targeted paramagnetic nanoparticles.

The principles and mechanisms utilized in the treatment of tumours include (1) Selective

targeting of blood and lymphatic vessels with peptide covered quantum dots.[17]

(2) NGR

covered liposomes for tumour blood vessel obliteration. (3) Cell adhesion molecules (CAMs)

ICAM-1 and PECAM-1 act as endothelial targets for therapeutic drug delivery.[18]

Anti-CAM

nanoparticles can deliver compounds to pulmonary and heart endothelium in vivo studies,

and (4). NGR (Asn-Gly-Arg)-targeted delivery of coagulase to tumour vasculature arrests

cancer cell growth.

3.2.3.pH controlled drug release

Tissue environment has a lower pH than healthy tissues in the presence of inflammation or

cancer and pH differences acts as a stimulus to modulate properties of certain materials for

controlled drug release.[19]

Intravenous injection of Mesoporous Silica Nanoparticles

(MSNPs) release the incorporated drug before they reach target area; toxic drugs cause

damage to healthy cells before they reach cancer cells[Table:3]. Difference in pH acts as the

stimulus for controlled release of drug as pH sensitive molecules efficiently close the pores.



1325

The principle of controlled drug release involves blocking of pores in silica nanoparticles by

pH sensitive functional groups and unblocking occurs when pH reaches a low enough

value.[20]

Table 3: pH-responsive drug delivery systems based on nanomaterials.

Main classification Sub-

classification Mechanism of action and examples

1). Organic materials

based pH-responsive

drug delivery systems

Synthetic

polymers

Polymeric micelles, polymersomes, nanospheres,

hydrogels, liposomes, dendrimers and films.

Peptides Glutamic acid-alanine-leucine-alanine (GALA) ; RGD

peptide (H-(D- Val)-Arg-Gly-Asp-Glu-OH)

2).Inorganic materials

based pH-responsive

drug delivery systems

ZnO and quantum dots (QDs) ; CaP nanoparticles; and magnetic nano-grenades

(PMNs)

3). Hybrid nano-

materials based pH-

responsive drug delivery

systems

Hybrid pH-sensitive liposomes (DPPC: CHOL:pI-pAA: Curc :BEC-X) based on

dipalmitoyl-phosphathydil-choline : cholesterol (DPPC: CHOL).

Dexamethasone was loaded in the self- assembling NP system based on

chitosan/carboxymethyl-β-cyclodextrin, which formed within a (RADA)4 nano-

scaffold matrix: (Arginine-alanine-aspartic acid-alanine)4 ((RADA)4) nano-

scaffolds are excellent candidates for use as peptide delivery vehicles.

Hybrids based on grapheme oxide and magnetic nanomaterials

Multifunctional stable and pH-responsive super paramagnetic iron oxide (SPIO)

/ DOX-loaded polymer vesicles for combined and tumour-targeted drug delivery

and ultrasensitive MR imaging.

4) Redox-responsive

nanomaterials

Redox potential differs between cancerous and healthy tissues, as well as

between the extracellular and intracellular compartments.

Disulfide bonds, as well as di-selenide (Se–Se) and carbon-selenium (C–Se)

bonds, can be broadly applied to develop reduction-responsive nano-vehicles,

which are prone to rapid cleavage by GSH through a dithiol-disulfide exchange

process

Peptide-polysaccharide inter-polyelectrolyte nanocomplexes through self-

assembly of polysaccharide of carboxymethyl dextran (CMD) and disulfide-

linked oligoamine, in which microRNA-34a (miR-34a) and indocyanine green

(ICG) are simultaneously embedded

Reactive oxygen species (ROS)-responsive poly(amino thioketal) (PATK) for

efficient and safe intracellular gene delivery in prostate cancer cells.

5. Enzyme-responsive

materials

Protease-

responsive

nanomaterials

Optimized protease- sensitive liposome;

Extracellular matrix metallo-proteinase (MMP); MMP-2

and MMP-9

Nanovesicles, which are responsive to overexpression of

glutathione (GSH) and MMP-9 in the tumour

microenvironment to deliver the anticancer drug

gemcitabine (Gem) efficiently and selectively.

PEG-SS-Ce6-MMP2 nanoparticles

Lipase-responsive

nanomaterial

Liposomes composed of lipid prodrugs by using the up-

regulated phospholipase A2 type IIA (sPLA2) activity



1326

PLA2-sensitive amphiphilic prodrug, 1-O-octadecyl-2-(5-

fluorouracil)-N-acetyl-3- zidovudine-phosphoryl glycerol

(OFZG).

Glycosidase-

responsive

nanomaterials

Gate-like functional hybrid systems consisting of

nanoscopic MCM-41-based materials functionalized on the

pore outlets with different ‗saccharide‘ derivatives and a

dye contained in the mesopores; The saccharide-

functionalized nanoparticles.

Oxidoreductase-

responsive

nanomaterials

Oxidoreductase-responsive nanomaterials from synthetic

amphiphilic block copolymers (‗polymersomes‘) of

ethylene glycol and propylene sulfide and the resulting

nanocarrier encapsulated glucose oxidase.

3.2.4.Temperature controlled drug release

Most tumours have a slightly higher temperature than normal body temperature and this

differential is used for triggered release of molecules from MSNPs.[21]

Temperature-

responsive polymers Poly(N-iso-propylacrylamide) (PNIPAM) is the most commonly used as

pores‘ plugs.[22]

Low critical solution temperature (LCST) or lower consolute temperature „is

the critical temperature below which the components of a mixture are miscible for all

compositions and is the temperature at which volume of the said polymer can change in

water‟. Pure PNIPAM has a LCST of about 32°C that keeps the pores open at all times and is

not used in drug delivery. Below this temperature, PNIPAM chains are hydrated, extended

and MSNPs prevent the drug release from the pores. At temperatures above LCST, PNIPAM

chains are dehydrated, become contracted, and release the drug held within them. Co-

polymerization with other monomers like acrylamide, or N-isopropyl-methacrylamide release

temperature and LCST is raised to above 37°C.[23]

Light or magnetic field act as external

stimuli that interact with the inorganic NPs included in or bound to MSNPs. A combination

of iron oxide nanoparticles and PNIPAM when exposed to an outer electromagnetic field,

rises local temperature around the nanoparticles and leads to a phase transformation of

PNIPAM and the drug is released.[24]

3.2.5.Redox Potential Control

Redox potential(Reduction/Oxidation potential, 'ROP') ‗is a measure of the tendency of a

chemical species to acquire electrons from or lose electrons to an electrode and thereby be

reduced or oxidised respectively‘.[25]

Intracellular and extracellular environments of living

tissues exhibit different redox potentials. The intracellular concentration of Glutathione

(GSH) can reach 10 μM, while the extracellular concentration ranges from 2 to 20 μM.[26]

GSH is the most abundant low molecular weight thiol compound synthesized in cells. It



1327

maintains redox homeostasis, protects cells from oxidative damage and toxicity of xenobiotic

electrophiles. GSH concentration of tumour tissues is at least 4-fold higher than that in

normal tissues, and especially high in some multi-drug resistant tumours.[27]

The natural

redox potential acts as an ―inside trigger‖ and initiates drug release from NPs within cancer

cells. Gold NPs, CdS, Fe3O4, and MSNPs biomolecules are covalently bound to pH system.

Disulphide is a typical redox responsive plug-MSNP bond. When disulphide bridge

dissolves, release of two thiol groups occur on the targeted tumour site due to high

intracellular concentration of GSH that acts as a reducing agent. A low blood level of GSH

reducing agent allows the disulphide connections to remain intact.

3.2.6.Biomechanical Triggering

Biocompatible and bioactive molecule are responsive to bodily stimuli. Biomolecules are bio-

enzymes e.g., β-D- galactosidase glucose, antigens, and aptamer targets are frequently used

for controlled drug release. Enzyme responsive nano-gates are ideal for MSNP pore closure

technique due to gross elevation of enzymatic activity in unhealthy tissues.[28]

Aptamers are

short, single-stranded DNA, RNA, or synthetic XNA molecules with high affinity and

specificity to interact with any desired targets. Newer generation of aptamers are more

reliable and efficient in targeting, achieved by methods that include the systematic evolution

of ligands by exponential Enrichment(SELEX) approach and its variations, such as immuno-

precipitation-coupled SELEX(IP-SELEX), capture-SELEX, cell-SELEX, capillary

electrophoresis-SELEX(CE-SELEX), atomic force microscopy-SELEX(AFM-SELEX), and

artificially expanded genetic information system-SELEX(AEGIS-SELEX).

3.2.7.Ultrasound-activated drug delivery

Sound wave with frequencies above 20 kHz are known as ultrasound and focused ultrasonic

(FUS) waves cause localized hyperthermia at focused tissues. A low intensity ultrasound can

alter cell membrane, result in increase of Ara-C cell uptake, that is responsible for ultrasonic-

enhanced cell killing. Ultrasound also cause acoustic cavitation, and/or acoustic radiation

forces to promote drug release from carriers and are capable of mapping location for targeted

drug delivery. Micro-bubbles, liposomes, NPs, micro-capsules, micro/nanomotors, and

injectable depots are the common NPs systems used for ultrasound-activated drug

delivery.[29]

Advantages of ultrasonic power as a drug release mechanism include non-

invasive technique, and can penetrate deep into the interior of the body, which optical visible

wave-length techniques cannot penetrate. Ultrasonic waves can be focused, reflected and



1328

refracted through optical medium methods, can be focused and controlled at tumour site.

Ultrasound consists of pressure waves with frequencies of 20 kHz or greater, generated by

piezo-electric transducers that change an applied voltage into mechanical movement.

3.2.8.Optic Tuning

Light acts as a trigger for release of encapsulated molecules from micro-and nano-systems

that incorporate light sensitive molecules within mesoporous silica nanoparticles (MSNPs) as

"nanocarriers".[30]

Chromophore bonding to MSNPs decide the reversible or irreversible

property of light-responsive MSNP modulation properties in a light-responsive drug delivery

system. Chemical structure of macromolecules is changed by isomerisation, but does not alter

molecular weight. Photochromic NP component isomerisation is usually followed by heat or

visible re-isomerisation. Light has a wavelength of 300–400 nm and a visible light ( λ > 400

nm) is used to achieve re-isomerisation.[31]

Complex drug releasing mechanisms are

developed based on reversible pore plugging and unplugging.

3.2.9.Magnetic Activation

Multimodal drug delivery systems respond to magnetic field based on superparamagnetic

properties of magnetic NPs of size10 nm to 100 nm scale.[32]

The most commonly used iron

oxide nanoparticles (IONP) are magnetite(Fe3O4) and its oxidised metabolite, maghemite (γ-

Fe2O3)[100101102]. Hydrophobic polymers coated IONPs are less susceptible to

opsonization, their circulation time is prolonged and secures binding surface for drug

molecules or specific target ligands. MSNPs in combination with magnetic NPs have high

capacity, target specificity and are promising in drug delivery methods. Magnetic field

focussed on IONP-drug systems create strong neodymium permanent magnets to release the

drug at target tissue. The magnetic field gradient depends on local resistance caused by blood

flow and depth of the targeted site.[33]

Nanoparticles are more efficient in areas with less

blood flow, and in regions closer to surface. NPs accumulation in tissues can be modified by

the power and location of the magnetic field; and hence has the least unwanted cytotoxic

effects on healthy tissues.

3.2.10. Margination

Margination, adhesion and uptake are crucial properties for efficiency of nanocarrier

vasculature-bound NPs design that flow through tumoral vasculature.[34]

Intravascular drug

delivery technologies use spherical NPs as vehicles with targets aimed at blood vessel wall or

in tissues beyond the wall. Small-sized (300 nm) eccentric NPs are associated with stronger



1329

margination tendency and rate of margination increases with its size (2000, 5000 nm). The

basis for drug delivery function depends on nano-vehicle localization towards vessel wall and

microparticles ‗marginate‘ to the wall, higher than NPs. Non- spherical particles such as

spherical, oblate, rod and prolate have higher area of surface-adhesive interactions than

spherical particles. An enhanced „margination + adhesion‟ property is the basic factor for

improved design of vascular targeted drug delivery systems and presence of RBCs result in

higher binding of microscale non-spherical particles.[35]

Efficacy of carriers in drug delivery

is based on variable shape, functioning size, and loading capacity of NP systems. NPs

achieve beneficial new pharmacological properties such as segmentation, slow release and

special route internalisation, and selectivity to improve the drug delivery systems.

4.Nanoparticle drug delivery systems

Protection of proteins or nucleic acids from degradation, precise drug delivery and enhanced

efficacy are the advantages of novel nanoparticle drug delivery carrier systems, that have an

improved bioavailability and also achieve a targeted delivery of drugs.[36]

Controlled release

of medication from a single dose and prevention of drug degradation by endogenous enzymes

are the added advantages.[37]

Reduction in drug dosage, frequency of dosing and lesser

complications are achieved by natural and synthetic polymer (bio-degradable and non-

biodegradable) nanoparticles. NPs motivate for design of new formulations, help identify

more effective delivery methods and create powerful market force for benefit of patients.[38]

Fig. 2: Representation of a smart multifunctional drug loaded nanoparticle, decorated

with various moieties for targeting, imaging and stealth properties. [Rizvi, Syed &

Saleh, Ayman. (2018). Saudi Pharmaceutical Journal. 26. 64-70.

10.1016/j.jsps.2017.10.012].



1330

Smart multifunctional NPs

Nanomaterials are most promising for clinical translation with nanoparticles act as ―nano-

transducers‖. A ―smart‖ interface between biological and non-biological environments is by

remote manipulation of biological activities.[39]

Polymeric nanostructures are the most used

Multifunctional Drug Delivery Systems (MDDS) due to the advantages that include high

versatility of fabrication process, controllable size and shape, high encapsulation efficiency,

and possible easy surface functionalization by numerous targeting groups, including peptides,

proteins, and antibodies[Figure:2]. Coating of the nanostructures with stealth materials like

poly(ethylene glycol) (PEG) increases the circulation time inside the body, combined with

targeting ability, are ideal for specific delivery of drugs, enzymes, proteins, RNA, and DNA

to specific diseased tissues.[40]

Most used polymeric nanostructures are polymeric NPs, nano-

capsules, dendrimers, spherical, nanospheres, worm-like micelles, nanotubes, and hydrogels

[Table:4].

Table 4: Physiochemical properties of smart systems.

1 Composition Organic, inorganic, or hybrid

2 Dimensions Small or large sizes

3 Shapes Sphere, rod, hyper- branched, multilamellar, or multi-layered

structures

4 Surface properties Functional groups, surface charge, PEGylation, coating

processes, or attachment of targeting moieties

4.1. Characteristics of nanoparticle drug formulations

4.1.1. Size of particles: The efficiency of most drug delivery systems is directly related to

size and shape of particles (excluding intravenous and solutions), NPs modify the way cells

in the body „„see” them. Drug NPs show increased solubility and enhanced bioavailability

that determine their distribution, toxicity, and targeting abilities. They acquire new abilities to

be absorbed through tight junctions of endothelial cells of skin, to cross the blood brain

barrier (BBB), and enter the pulmonary system.[41]

Nanoparticles cross the BBB and provide

sustained delivery of medication for diseases that were previously considered difficult to

treat.[42]

Manipulation of techniques help drugs reach intended targets and in a controlled

manner of drug distribution. NPs in size range of 100 nm have a 2.5-fold greater uptake

compared to 1 lm diameter particles and a 6-fold great uptake than a 10 lm particles. In NP

systems more drug is closer to the surface of particle compared to a larger molecule and a

faster drug release is achieved as the drug is at or near surface and effective drug release is



1331

the advantage of NP drug delivery systems.[43]

Toxicity of NPs must always be monitored as

smaller particles size and an increased surface area to volume ratio of NPs pose toxicity

issues.

4.1.2. Surface properties

Manipulation of surface characteristics of NPs develop an ideal drug delivery system.

Changes in surface curvature, modification of reactivity to prevent aggregation and addition

of targeting ligands are some of the techniques used commonly.[44]

These modifications

enhance the stability of drug, receptor binding and help achieve an optimal pharmacological

effect. The size of the particle must be large enough to avoid leakage into blood capillaries,

but not too large to become susceptible to macrophage clearance. The extent of aggregation

and clearance can be controlled by manipulating the surface of NPs.[45]

Surface modification

technologies include coating the NPs with polymers or surfactants or creating copolymers

like polyethylene glycol and polyethylene oxide that has reduced opsonization. Polyethylene

glycol prevents hepatic and splenic localization; polyoxamer, poloxamine, and polysorbate

80, a non-ionic surfactant and emulsifier are also used for surface modification.[46]

NPs made

hydrophilic by surface modification have an enhanced circulation time. Polyethylene glycol

is relatively an inert polymer with hydrophilic nature, when incorporated on to NP surface,

blocks binding of plasma proteins. PEGylation is a widely used technology for improving the

pharmacokinetics (PK) of a variety of NPs. PEGylated NPs are often referred as “stealth”

nanoparticles. They escape reticuloendothelial system (RES) surveillance better than control

nanoparticles. Without opsonization PEGylated nanoparticles remain undetected by the RES

as stealth nanoparticles.[47]

Opsonization is coating of particles with proteins that facilitate

phagocytosis of the particle by tissue macrophages and activated follicular dendritic

cells(FDCs) as well as binding by receptors on peripheral blood cells, this prevents

substantial loss of the dose administered.

4.1.3. Targeted drug delivery

Targeted drug delivery is the ultimate aim of nanoparticle-based drug delivery systems.

Nanoparticle penetration, passive or active into inflamed or damaged tissues happen at larger

epithelial junctions. Active targeting happens when the drug carrier system is conjugated to a

tissue or cell-specific ligand. The NPs reaching target organ due to leaky junctions is known

as passive targeting.[48]

Targeting agents are small organic molecules that have relative ease

of preparation, good stability and control of conjugation chemistry. Targeting ligands



1332

commonly employed include small molecules, peptides, antibodies, designed proteins and

nucleic acid aptamers.[49]

Biotin (vitamin H) has very high affinity for streptavidin and is

widely used for conjugation with nanoparticles.[50]

Folic acid (vitamin B9) has excessive

affinity for endogenous folate receptor. They are used for targeting cancer types where folate

receptors are highly expressed. Task specific carbohydrates, short peptides, antibodies and

small molecules are also designed for drug targeting. Their only disadvantage is that they

may not have the desired specificity and affinity.

4.2. Fate of exogenous particulate matter in the body

Nanoparticles enter into human body by three main routes namely, direct injection, inhalation

and oral intake. As they enter systemic circulation, particle-protein interaction occurs first

before distribution to various organs.[51]

Absorption from blood capillaries occur and allows

the lymphatic system to distribute and eliminate the particles. Two main functions pertaining

to drug delivery are filtering and recovery of fluids by lymphatic system from blood

capillaries and the second function that involve immunity. Cells and chemicals identified as

‗foreign‘ in recovered fluid are detected by lymph nodes. Macrophages engulf them, clear

―foreign particles‖ from the body and fluid is filtered back into blood.[52]

In NP-based drug

delivery system, the size and surface characteristics of particles influence its clearance.

Biological fate of nanoparticles is determined by its size, and surface area to volume ratio.

Vascular and lymphatic systems filter and clear them similar to the fate of foreign matter and

chemicals. NPs recognized as foreign matter by lymphatic system are dealt with by body‘s

natural immune responses. Hydrophobic NPs are cleared fast due to higher binding of blood

components[53]. Particles of 200 nm or more activate the lymphatic system and are removed

from circulation quicker. Nanoparticles at an optimum size of 100 nm, pass through BBB,

achieve a targeted delivery of sufficient amount of drug and to avoid immediate clearance by

lymphatic system.

5. Drug delivery nanoparticle systems in skin care products and treatment of

Dermatological conditions

The skin is the largest organ of human body, presents a total area of approximately 2 m2

.

Nanotechnology interacts at sub-atomic level with skin tissue and help in diagnosis and

treatment of dermatological conditions. Skin acts as a good vehicle for study of drug delivery,

active ingredient delivery and therapeutic efficacy of the drugs. Three potential pathways for

drug delivery routes across human skin when drug molecules come in contact with the skin



1333

surface are through the sweat ducts, via hair follicles and sebaceous glands (collectively

called the shunt or appendageal route), or directly across the stratum corneum.

Table 5: Skin permeation enhancement/optimization techniques [Drug/vehicle based and

stratum corneum modifications]

1.Drug/vehicle based

Drug selection: Optimal permeability is

related to low molecular size (ideally less than

500 Da) as this affects diffusion coefficient,

and low melting point which is related to

solubility.

Drug selection based on the ideal characteristics help

enhance transdermal delivery.

Prodrug and ions-pairs: The prodrug design

strategy involves addition of a promoiety to

increase partition coefficient and hence

solubility and transport of the parent drug in

the stratum corneum

5-fluorouracil, a polar drug with reasonable skin

permeability was increased up to 25 times by

forming N-acyl derivatives.

Steroid esters (e.g. betamethasone-17-valerate)-

provide greater topical anti-inflammatory activity

than the parent steroids.

Drug-vehicle interactions: Chemical potential

of drug in vehicle (Saturated and

Supersaturated Solutions)

The maximum skin penetration rate is obtained when

a drug is at its highest thermodynamic activity and in

supersaturated solution.

Eutectic systems: Melting point of a drug

influences solubility and hence skin

penetration. Lower the melting point, the

greater the solubility of a material in a given

solvent, including skin lipids. The melting

point of a drug delivery system can be lowered

by formation of a eutectic mixture.

EMLA cream, a eutectic mixture of lignocaine and

prilocaine applied under an occlusive film, provides

effective local anaesthesia for pain-free venepuncture

and other procedures. The 1:1 eutectic mixture (m.p.

18°C) is an oil which is formulated as an oil-in-water

emulsion thereby maximizing the thermodynamic

activity of the local anaesthetics.

Mixture of two components (at a certain ratio) inhibit

crysta-lline process of each other, such that m.p of

the two compo-nents in mixture is less than that of

each component alone.

Complexes

Complexation of drugs with cyclodextrins has been

used to enhance aqueous solubility and drug

stability.

Liposomes: Transfersomes are vesicles

composed of phospholipids as their main

ingredient with 10-25% surfactant (such as

sodium cholate) and 3-10% ethanol.

Surfactant molecules act as ―edge activators‖,

conferring ultra-deformability on the transfersomes,

that allows them to squeeze through channels in the

stratum corneum that are less than one-tenth the

diameter of the transfersome.

Vesicles and particles: Enhanced skin

penetration is primarily due to an increase in

skin hydration caused by the occlusive film

formed on the skin surface by SLN.

Solid lipid nanoparticles (SLN) are being used as

carriers for enhanced skin delivery of sunscreens,

vitamins A and E, triptolide and glucocorticoids.

A 31% increase in skin hydration has been reported

following 4 weeks application of SLN-enriched

cream.

2. stratum corneum modifications: Lipid-protein partitioning (LPP) theory describes the mechanisms

by which enhancers effect skin permeability by 1) Disruption of the intercellular bilayer lipid structure



1334

2) Interaction with the intracellular proteins of the stratum corneum and 3) Improvement of

partitioning of a drug, co-enhancer, or co-solvent into the stratum corneum.

A). Hydration : Water is the most widely used

and safest method to increase skin penetration

of both hydrophilic and lipophilic permeants.

Hydration can be increased by occlusion with plastic

films; paraffins, oils, waxes as components of

ointments and water-in-oil emulsions that prevent

trans-epidermal water loss; and oil-in-water

emulsions that donate water. Occlusive films of

plastic or oily vehicle have the most profound effect

on hydration and penetration rate

b). Lipid fluidisation: Lipid Disruption

/Fluidisation by chemical penetration

enhancers.

Enhancers, such as Azone, DMSO, alcohols, fatty

acids and terpenes, increase permeability by

disordering or ‗fluidising‘ the lipid structure of the

stratum corneum.

c). Interaction with Keratin: Penetration of a

surfactant into the intracellular matrix of the

stratum corneum, followed by interaction and

binding with the keratin filaments, result in a

disruption of order within the corneocyte. This

causes an increase in diffusion coefficient, and

hence increases permeability

Chemicals such as DMSO, decylmethylsulphoxide,

urea and surfactants interact with keratin in the

corneocytes, in addition to their effect on stratum

corneum lipids.

d). Increased Partitioning and Solubility in

Stratum Corneum.

Solvents such as ethanol, propylene glycol,

Transcutol and N-methyl pyrrolidone, increase

permeant partitioning into and solubility within the

stratum corneum, hence increasing P in Fick‘s

equation (Eqn. 1). Ethanol was the first penetration

enhancer-cosolvent incorporated into transdermal

systems.

e). Combined Mechanisms: Fick‘s law (Eqn.

1) - A combination of enhancement effects on

diffusivity (D) and partitioning (K) will result

in a multiplicative effect.

Synergistic effects of combinations: Azone and

propylene glycol, Azone and Transcutol, oleic acid

and propylene glycol, terpenes and propylene glycol,

in various combinations and alcohols eg. N-methyl

pyrrolidone and propylene glycol, urea analogues

and propylene glycol, supersaturation and oleic acid.

f). Skin irritancy and toxicity due to chemical

penetration enhancers

Chemical penetration enhancers increase skin

permeability by reversibly damaging or altering the

physicochemical nature of the stratum corneum to

reduce its diffusional resistance.

g). Other Physical and electrical methods: A

number of electrical methods of penetration

enhancement are available, cause a possible

transient permeabilisation of the stratum

corneum.

Iontophoresis (driving charged molecules into the

skin by a small direct current – approximately 0.5

mA/cm2 ); Phonophoresis (cavitation caused by low

frequency ultrasound energy increases lipid fluidity),

Electroporation (application of short micro- to milli-

second electrical pulses of approximately 100-1000

V/cm to create transient aqueous pores in lipid

bilayers) and Photomechanical waves (laser-

generated stress waves)

h). Skin Penetration Retarders were first

reported by Hadgraft and coworkers

Skin penetration retarders e.g. some Azone

analogues stabilise rather than disordered bilayer

lipids thereby reducing permeability.



1335

5.1.Physical methods for topical drug delivery; The Stratum Corneum acts as a barrier to

penetration by drugs and different strategies are used for drug penetration enhancement

[Table:5]. Formulation optimization, occlusion, and physical methods are used alone or in

combination. Physical methods increase transport of macromolecules to the SC, enabling

higher concentrations of drugs into deep skin layers by transdermal drug delivery.[54]

The

most utilized strategies are iontophoresis, sonophoresis and micro-needles [Figure:2].

Transdermal drug delivery (TDD) is an alternate to oral or parenteral injection for delivery of

bioactive molecules through the skin, prevents the first-pass effect as it bypasses the

gastrointestinal tract, is painless and allows self-administration. Topical delivery is useful in

the treatment of skin inflammations, photoaging, microbial and fungal infections and also in

skin cancer. Skin is the main route of choice for treatment of dermatological disorders and

local anaesthetics. Topical drug delivery eliminates the need of systemic administration of

drugs, reduce the total drug dose required and thus reduce off-target adverse effects.

Figure 3: Physical enhancement approaches for transdermal drug delivery.

5.2. Polymer as a drug delivery carriers

Polymer-based NPs (nanospheres and nanocapsules) permit diffusion of active ingredients

through the polymeric matrix to permeate the skin and have a controlled release of the

encapsulated drugs[Table:6]. The rigid matrix is structurally stable, maintain their structure

for prolonged period of time of time and hence are used for topical administration through

skin.[55]

Hydrogel with dexamethasone has an active ingredient with potential for controlled



1336

drug delivery for treatment of psoriasis. Localized psoriasis involving nails and scalp can be

treated using methotrexate encapsulated in a thermosensitive polymer.[56]

Table 6: Prepared polymeric nanoparticles (nanocapsules and nanospheres) drug

release mechanisms.

Nanospheres Nanocapsules

Homogeneous system Heterogeneous system

Polymer chains arrange in a similar

fashion to surfactants in micelle

formation

Drug is inside a reservoir

composed of the polymer

Phase-separated from the bulk solution Like vesicle

Drug is released by erosion of the

matrix

Drug diffusion through

polymeric layer

Rapid burst of drug release related to

weakly bound drug to the large surface

area of NP followed by a sustained

release

Drug diffusibility through

polymer is a determining factor

of its deliverability

Polymeric nano-capsules are vesicular particles, smaller than 1 μm composed of an oily core

surrounded by an ultrathin polymeric wall stabilized by steric agents and/or surfactants.

Diffusion of active ingredient from the oily core depends on the characteristics of the

polymeric wall. Thermosensitive polymers encapsulate drugs below a critical temperature

and prevent drug release. At temperature above critical levels they dissolve to release the

drug, this drug delivery system is beneficial when used at sites of inflammation or wherever

external heat is applied. Polymeric NPs encapsulating small inhibitor ribonucleic acids

(siRNAs) selectively inactivate gene expression. Nano-encapsulated siRNAs have successful

targeted delivery and are used for management of pachyonychia congenital and for inhibition

of a test gene expressed in melanoma in human trials.[57]

Polymers are the structural

backbones for controlled release drug delivery systems due to the basic and flexible

properties that they may be swollen, non-swollen, poriferous, non-porous, bio-adhesive,

erodible etc. Polymers utilized in controlled release of drug delivery systems must fulfil

following requirements.[58]

1) Biocompatibility: Harmful impurities must be removed and

should be bio-compatible for inclusion in controlled release drug delivery. Chemicals used in

polymerisation process requirements viz additives, stabilizers, plasticizers and catalyst must

be chosen carefully to meet regulatory guidelines. 2). Physical and mechanical properties

required for controlled release drug delivery system design are the polymers should have

properties like elasticity, compactibility, resistant to tensile forces, swelling and shear stress

as well as resistance to fatigue. 3). Pharmacokinetic properties: Polymer should not be



1337

chemically degradable; and if the polymer has a tendency to chemical degradation, the by-

products of degradation must be non-toxic, non-immunogenic and non-carcinogenic.[59]

Biocompatible NPs and nano-robots are used in prevention and cure of various diseases by

nanotechnology. Nanomedicine utilize nanoscale materials for various applications including,

diagnosis, delivery, sensor, or actuation purposes in living organisms. Nanostructures deliver

drugs through passive and self-delivery methods. In passive method, drugs are incorporated

by hydrophobic effect into the inner cavity of the structure. At targeted sites the intended

amount of drug is released from the nanostructure materials due to low content of drugs

encapsulated in a hydrophobic environment. In self-delivery method, drugs intended for

release are directly conjugated to the carrier nanostructured material for easy delivery and the

challenges faced are the timing of drug release, drug may not reach target site, and drug may

dissociate from carrier very quickly. Hence, bioactivity and efficacy will be decreased if drug

is not released from its nanocarrier system at the right time.

Active or passive methods of targeting of drug are used. In active targeting, moieties such as

antibodies and peptides, coupled with a delivery system anchor them to receptor structures

expressed at the target site. In passive targeting, the prepared drug carrier complex circulates

through the bloodstream and the affinity or binding of the drug is influenced by factors like

pH, temperature, molecular site and shape. The carrier complex passively reaches main

targets including receptors on cell membranes, lipid components of the cell membrane and

antigens or proteins on cell surfaces. Nanotechnology-mediated drug delivery system are

targeted towards cancer and its treatment. Cellular microenvironment of tumour tissues have

different acidic, enzyme and reducing environments. Nanocarriers respond to unique

physiological microenvironments immediately after entering cells and release the drug. An

ideal NP drug delivery system should reach its specific target, be recognized, bind and deliver

drugs to specific pathologic tissues without any drug induced damage to adjacent healthy

normal tissues. Coating specific targeting ligand(s) on the surface of nanoparticles is the most

common strategy to achieve this goal. Disadvantages of biomolecular therapy like short

plasma life, poor stability and potential immunogenicity must be addressed to maximize

therapeutic efficacy with minimal toxicity and to avoid damage to normal healthy tissues.

Creating polymer complexes

Nanoparticles of small size like dendrimers, quantum dots, and micelles are characterized by

formation of aggregation, because of large surface area. Prevention of aggregation surface



1338

charges is done by coating of NPs with capping agents and by altering the zeta potential.[60]

Drug loading and release: Drug release from nanoparticle matrix to the tissues is the next

critical step, that can be released from carrier by changes in drug solubility, pH, and

temperature. Nanoparticles incorporated with drugs have enhanced bioavailability, enhanced

stability properties, and decreased clearance. Other mechanisms involved in drug release are

desorption of the surface-bound or adsorbed drug; drug diffusion through the NP matrix;

nanoparticle matrix swelling and erosion; or a combination of erosion and diffusion

processes.[61]

Nano-spheres are matrix systems where the drug is physically and uniformly

dispersed.[62]

In nano-capsule systems drug release is controlled by ionic interactions between

the drug and the polymer; and formation of complexes inhibit release of drug from the

capsule. Polyethylene oxide-propylene oxide (PEO-PPO) decreases interactions between the

drug and capsule matrix and allows release of drug to target tissues.

Polymeric micelles (PMs) are multifunctional nanotechnology-based delivery system for

poorly water-soluble drugs.[63]

The application of PMs as drug delivery system was described

by H. Ringsdorf in 1984. Kataoka in early 1990s developed doxorubicin-conjugated block

copolymer micelles. PMs are self-assembled core-shell nanostructures formed in an aqueous

solution consists of amphiphilic block copolymers, that increases above a certain

concentration called the critical micelle concentration(CMC).[64]

Micelles prepared from poly

(ethylene glycol)/ phos-phatidyl ethanolamine (PEG-PE) conjugates are highly stable. They

are of 10 to 40 nm size, easily soluble and firmly retain various poorly soluble anti-cancer

drugs (m-porphyrin, taxol, tamoxifen,). The stable drug-loaded polymeric micelles are

efficient drug delivery systems for tumours by utilizing enhanced permeability and retention

(EPR) effect.[65]

5.3. Liposomes

Liposome has an aqueous solution core surrounded by a hydrophobic membrane, in the form

of a lipid bilayer; hydrophilic solutes dissolved in the core cannot readily pass through the

bilayer. Hydrophobic chemicals also associate with the bilayer and liposomes can be loaded

with hydrophobic and/or hydrophilic molecules. Liposome is a spherical vesicle having at

least one lipid layer, prepared by disrupting biological membranes by sonication process.

Liposome design is composed of phospholipids, mainly phosphatidylcholine; or egg

phosphatidylethanolamine.



1339

They are compatible with lipid bilayer structure, that employ surface ligands for attaching to

unhealthy tissues and are used as vehicles for nutrients and pharmaceutical drugs.[66]

The

major types of liposomes are the multilamellar vesicle (MLV, several lamellar phase lipid

bilayers), the small unilammellar liposome vesicle (SUV, with one lipid bilayer), the large

unilamellar vesicle (LUV), and the cochleate vesicle. Multi-vesicular liposomes have one

vesicle that contain one or more smaller vesicles and are the less desirable forms[Table:7].

Table 7: Classification of Liposomes based on structure, method of preparation,

composition, conventional use and special purpose liposomes.

Basis Categories

Based on structure

Uni-lamellar, small unilamellar, medium unilamellar, large

unilamellar, giant unilamellar, oligolamellar, multilamellar,

and multivesicular vesicles.

Based on method of

preparation

Single or oligolamellar vesicle made by reverse phase

evaporation method (REV); multilamellar vesicle made by

reverse phase evaporation method (MLV-REV); stable

pluri-lamellar vesicle (SPLV), frozen and thawed multi-

lamellar vesicle (FATMLV); vesicle prepared by extrusion

technique (VET), and dehydration-rehydration method

(DRV).

Based on composition and

applications.

Conventional, fusogenic, pH-sensitive, cationic, long

circulatory, and immuno- liposomes.

Based on conventional

purposes

Stabilize natural lecithin (PC) mixtures, synthetic identical

chain phospholipids, and glycolipids containing liposomes.

Based upon speciality

liposome

Bipolar fatty acid, antibody directed liposome,

methyl/methylene x-linked liposome, lipoprotein coated

liposome, carbohydrate coated liposome, and multiple

encapsulated liposome.

Composition of liposome is similar to targeted cell membrane, and there is an enhanced lipid-

lipid exchange. Specific lipid monomer with physicochemical properties such as size and

charge can be incorporated to surface targeting ligands.[67]

This enhances convective flux of

lipophilic drugs from the liposomal lipid layer into the targeted cell membrane.[68]

Pharmaceutical and cosmetic applications

Peptides and proteins are used for treatment of cancer, infectious disease, autoimmune

disease, acquired immunodeficiency syndrome, and in anti-aging treatments. Most polymeric

systems are retained in the stratum corneum and skin absorption characteristics of the drug as

well as drug releasing properties are crucial for improved drug release through the skin.

Encapsulated nano-botox causes relaxation of muscles of facial expression by transcutaneous

administration of α-aminobutyric acid, a topical paralytic agent. Tiny dosages of nano-botox



1340

(botulinum toxin) injection under skin produces disappearance of facial creases and the effect

lasts as long as 6 months.[69]

Nitric oxide, a short-lived, diatomic, lipophilic gas defends

against pathogens. Nitric oxide volatile antimicrobial gas trapped in nanoparticulate chitosan

is beneficial in the treatment of skin infections and in penetrating abscesses.

5.4. Inorganic nanoparticles

Inorganic nanoparticles are non-toxic, hydrophilic, biocompatible and highly stable compared

to organic materials. The inorganic nanocarriers are composed of a core and a shell region.

The core region contains inorganic component such as gold, quantum dots, silica, or iron

oxide and the shell region is composed mainly of organic polymers or metals. They provide a

suitable substrate for the conjugation of biomacromolecules, protect the core region from

unwanted physicochemical interactions with external biological microenvironment. Inorganic

NPs are stable for longer periods for specific targeting, high functionality, and control of their

cellular actions. They have good biocompatibility, wide availability, and has potential

capability for targeted delivery. They are ideal for targeted cellular delivery, controlled

release of drugs and selective destruction of cancer cells with tissue-sparing effect on normal

tissues. They are also effective as anti-aging and anti-acne agents and used in the treatment of

vitiligo, skin cancers and for transdermal delivery of substances. They are used extensively in

hydration and skin care products in cosmetic industry. Inorganic nanosized particles of ZnO

and titanium dioxide(TiO2) are used in sunscreen formulations. They are transparent,

cosmetically desirable and have a broad-band UV protection. Nano-particles of TiO2 are

more effective in UVB and ZnO in the UVA range and are used increasingly for UV

protection. Combination of TiO2 and ZnO NPs of <100 nm size provide the required balance

between UVA and UVB protection to prevent undesired opaqueness.[70]

Silver metallic NPs

are effective anti-septic agents against Methicillin Resistant Staphylococcus aureus,

onchomycosis, trichophyton and dermal leishmaniasis.

Gold NPs are excellent intracellular targeting vector capable of long wave-length light

directed tumour photo-thermolysis. They allow deeper targeting of cutaneous tumours, can be

easily tailored to a desirable size from 0.8 nm to 200 nm, and their surface can be modified to

impart various functionalities to achieve good biocompatibility. Visible light extinction

behaviour make it possible to track trajectories of nanoparticles in the cells.[71]

Carbon

nanotubes are stable carbon nanoparticles (<100 nm) with antioxidant and cytoprotective

effects. Small biomolecules are loaded in their large inner volume and outer surface is



1341

chemically modified to load proteins and genes for effective drug delivery. Conductivity

properties of carbon nanotubes yield highly sensitive sub-organellar biomarker sensor for

early diagnosis of chronic skin infections and skin cancers. Fullerenes are 1nm sized

hydrophobic carbon spheres of 60 carbon atoms that are organically functionalized by

attaching a hydrophilic moiety. They are water-soluble and capable of carrying genes,

proteins and other biomolecules for targeted delivery. Topical therapeutics and rejuvenating

cosmetic products like sun-screens, moisturizers, long lasting make-up, and perfumes are the

common applications. Transport characteristics of nanocarriers, irrespective of transdermal or

topical application are related to its hydro-dynamic diameter, shape (spherical, elliptical, nail-

shaped) and their pathway via the inter-cellular route or the hair follicle. They are small sized

spherical shaped NPs with a hollow interior.

5.5. Reversal of MDR in cancers by inorganic nanocarriers

Inorganic nanocarriers are associated with stimuli‐responsive release function. They release

drugs in tumour microenvironments in response to external triggers like hyperthermia, light,

and magnetic field. The most encountered drug resistance is caused by increased drug efflux

from cancer cells, mediated by the ATP Binding Cassette (ABC) family of membrane

transporters. More than 48 types of ABC transporters have been identified in humans, and

over 12 of them cause drug resistance.[72]

The Trojan horse drug delivery avoids drug efflux

transporters recognizing anti-cancer drugs, is a common method to avoid MDR. "A large

molecule pharmaceutical, that normally has no activity in the brain because of lack of

BBB transport, is transformed into a powerful neuro-pharmaceutical following attachment

to a BBB molecular Trojan horse." A variety of recombinant proteins, peptides, antisense

agents, and even non- viral gene therapy are the molecular Trojan horses in vivo CNS

pharmacologic practice. Peptides and recombinant proteins such as vasoactive intestinal

peptide (VIP), brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF)-2,

and lysosomal enzymes, such as βgalactosidase molecules are all potential therapeutics for

brain disorders, when enabled to cross BBB. Synergistic therapeutic effects of anti-cancer

agents as well as therapeutic genes (e.g., DNA or siRNA) are loaded in inorganic nano-

carriers due to ease of surface modifications. Inorganic nanocarriers provide multifunctional

platforms for cancer treatment (hyperthermia therapy), with potential to reverse MDR in

cancers by combination with chemotherapy. They also have molecular imaging function, that

monitor drug delivery processes and therapeutic outcomes, leading to improved treatment

efficacy, especially for treating MDR cancers.



1342

Drug delivery nanoparticles for chemotherapeutic agents

Conventional drug delivery systems of chemotherapeutic agents have limitations of sensitive

toxicity, poor specificity and induction of drug resistance, that decrease their therapeutic

efficiency. Nanocarrier-based systems to transport chemotherapeutic active drugs are

composed of colloidal NPs of submicron size, typically <500 nm with a high surface area to

volume ratio. These nanostructured prototypes enable effective delivery of active anti-cancer

drugs into affected tissues. Therapeutics results are improved by manipulating micro-

environment of the diseased tissues and treatment is effective with minimum side-effects.

Modern smart nanostructured materials are broadly divided into organic and inorganic

nanocarriers.

Table 8: Advantages and disadvantages of Liposomes.

Advantages Disadvantages

Increased stability High production cost

Biocompatible and

biodegradable Low solubility

Increased efficacy Leakage of drug

Site avoidance effect Occasionally oxidation and hydrolysis

reaction

Reduced toxicity Osmotically sensitive

Ease of penetration in

dermal layer Inadequate stability

5.6. Solid lipid nanoparticles

SLN are less stable due to interaction between particle components and skin lipids. They lose

their shape and melt after a period of 2 hours following topical application, result in a

reduced skin barrier function, occlude the skin surface, favours skin penetration process and

increase permeation to receptor medium. Drugs encapsulated in either matrical or vesicular

lipid-based NPs enhance active substance penetration into skin layer [Table:8]. Permeation of

drug is enhanced by lipid components, by interaction with skin surfactant components of

NPs, by lipid nanoparticles added to ethanol and magnetic nanoparticles.[73]

Topically

delivered nanosized hyaluronic acid penetrate the skin easily. Active ingredients in the centre

of solid lipid NPs and nanostructured lipid carriers have properties of delayed release.

Submicron colloidal carriers (40 nm to 1000 nm) have a solid lipid core and penetrate

through several anatomical barriers. They form an occlusive film over the epidermis and

enhance skin hydration by minimizing water loss. They also act as a physical UV blocker and

are combined with organic sunscreen formulations. Nanoemulsions (NE) are oil-in-water



1343

emulsions. Macro-emulsions have disadvantages of creaming, flocculation, coalescence and

sedimentation. Nanoemulsions contain high energy nanometer-sized droplets stabilized by

surfactants and have better stability of the formulation. They are designed for topical

treatment of skin infections by their inherent antimicrobial activity, lyse pathogens upon

contact and overcome existing resistance mechanisms.[74]

Nano-emulsion formulations with

antimicrobial, antifungal, and anti-acne agents have enhanced delivery of drugs into the

epidermis and dermis.

Lipid-based nanoparticles: Modifications of solid lipid nanoparticles(SLN), nanostructured

lipid carriers (NLC) and lipid drug conjugate (LDC)-nanoparticles were introduced in

addition to liquid crystal DDS. SLN and NLC formulations maintain the enhanced solubility

benefits of traditional liquid colloidal carrier DDS and are innovative lipid-based NP drug

delivery technologies. Additional benefits of increased chemical stability for the Active

Pharmaceutical Ingredient (API), potential for sustained release, targeted delivery, and

lymphatic delivery, which allows for the avoidance of first-pass metabolism as well as

lymphatic targeting are achieved.

Nanostructured lipid carriers (NLCS) is a mixture of a solid lipid with chemically different

liquid lipids, a formulation extension of SLNs in which the NLC lipid particle carrier matrix

is composed of multiple lipids. Solid lipid and liquid lipid(s) combination has advantages for

higher active loading than SLNs, due to the presence of liquid carrier materials, which have a

higher solvent capacity in the finished NLC. Areas of carrier matrix inconsistency provides

for a series of for NLCs over typical single matrix material SLNs. Lipid-based nanoparticle

(LBNP) systems are colloidal carriers for bioactive organic molecules. Liposomes, solid lipid

nanoparticles (SLN) and nanostructured lipid carriers (NLC) are the most commonly used in

topical application formulations and also in cancer therapy.[75]

Lipid particles, micro-and

nanoparticles, micro-and nano-spheres, polymeric micelles, and vesicular systems like

liposomes, sphingosomes, niosomes, transfersomes, aquasomes, and ufasomes are the various

particulate/ colloidal type carriers systems available. [Figure: 4].



1344

Figure 4: Lipid particulate drug delivery systems.

Vesicle is a structure within or outside a cell, that consists of liquid or cytoplasm enclosed by

a lipid bilayer. Vesicles form naturally during the processes of secretion (exocytosis), uptake

(endocytosis) and transport of materials within the plasma membrane, they are called

liposomes when prepared artificially. „Vesicular Drug Delivery System‟(VDDS) utilize

vesicles as vehicle of choice in drug delivery systems. Liposomes, niosomes and

pharmacosomes are the most commonly used that have advantages over conventional

dosages forms with prolonged release dosage forms.[76]

They improve bio-availability of

drugs, have an effective permeation of drugs into cells and overcome problems related to

drug insolubility and instability. They also prolong duration of drugs in systemic circulation,

sustained-release system function, and facilitates incorporation of hydrophilic and lipophilic

drugs. Effectiveness of therapy is improved by enhanced selective uptake of drugs, reduced

toxicity and lower cost of therapy. Also delayed elimination of rapidly metabolized drugs,

and rapid degradation ensure better treatment outcomes.

5.6.1.Pharmacosomes are defined as ―the colloidal dispersion of drugs covalently bound to

lipids, and may exist as an ultrafine vesicular, micellae or hexagonal aggregates depending

upon the chemical structure of drug-lipid complex.‖ Pharmacosome is derived from

pharmacon (active principle) and soma (the carrier). The principle of vesicular

pharmacosome is based on surface and bulk interaction of lipids with water.[77]

Drugs with

active hydrogen atoms (-COOH, -OH, -NH2), esterified to lipid with or without spacer chain,

result in a strongly amphiphilic compound that facilitate tissue or cell wall or membrane

transfer. Advantages of Pharmacosomes: Since vesicles are formed with conjugation of drug

itself with lipids, entrapment efficiency is very high and predetermined. Unlike with

liposomes the following features of Pharmacosomes are crucial for its function: Encaptured

volume and drug-bilayer interactions do not influence entrapment efficiency; There is no



1345

need of tedious, time-consuming step for removing the free, unentrapped drug from the

formulation and there is no problem of drug incorporation and drug is released by hydrolysis

(including enzymatic); The drug is covalently linked, and loss due to leakage of drug does not

occur. However, loss may occur by hydrolysis. Membrane fluidity in Pharmacosomes depend

upon the phase transition temperature of the drug lipid complex, but it does not affect release

rate since the drug is covalently bound. They can be given orally, topically, extra-or

intravascularly. Multiple transfer through lipophilic membrane system or tissue, through

cellular walls, piggyback endocytosis and exocytosis is possible in this system after

medication due to their amphiphilic behavior. Disadvantages of Pharmacosomes are they

can only encapsulate the water insoluble drugs in relatively small hydrobic regions within

membrane bilayer rather than relatively large surface and on storage pharmacosomes undergo

fusion and aggregation as well as chemical hydrolysis.

5.6.2. Niosomes are novel drug delivery system vesicles in nano-metric scale, composed of

bilayer of non-ionic surface active agents. Niosomes are non-ionic surfactant vesicles

(nisomes or NSVs) structurally similar and mimic liposomes. Components of Niosomes

include surfactant, cholesterol and solvents [Figure:5].

Figure 5: The structural composition of liposomes, niosomes, nano-emulsions, solid-lipid

nanoparticles, nanostructured lipid carriers. [Image: Poonia et al. 2016].

Niosomes as carriers of amphiphilic and lipophilic drugs, have more penetrating capability

than their previous preparations of emulsion. They have lamellar (bilayer) structures

composed of amphiphilic molecules (surfactants) surrounded by an aqueous compartment.

Non-ionic surfactants are preferred because they cause less irritation (decreases in order of

cationic > anionic > non-ionic).[78]

The surfactants contain both hydrophobic groups (tails)

and hydrophilic groups (heads) and show self-assembling properties, aggregating into a

variety of shapes like micelles or into a planar lamellar bilayer. Sorbitan esters and analogs,

poly-oxyethylene-based, sugar-based, polyglycerol, or crown ether-based surfactants are



1346

commonly used as drug delivery systems. They may be used in addition to membrane

additives, such as cholesterol or its derivatives.

Advantages over liposomes include greatly increased transdermal drug delivery and targeted

drug delivery. Further research has potential for development of newer structures that can

provide new methods of drug delivery. Advantages of niosomes compared to other nano-

carriers: Surfactants used in preparation of niosomes are biodegradable, biocompatible, and

not immunogenic. Routine and large-scale production of niosomes does not involve use of

unacceptable solvents. Structural composition has chemical stability; handling and storage of

niosomes is easy. Shape, fluidity, and size (physicochemical properties of niosomes) can be

easily controlled/ modified by changes in structural composition and method of production.

They are capable of encapsulating a large amount of material in a small vesicular volume.

Niosomes are used for delivery of labile and sensitive drugs, as their structure protect drug

ingredients from various factors present both inside and outside the body [Table :9].

Table 9: Advantages and Disadvantages of niosomes.

Advantages Disadvantages

Controlled and targeted drug delivery

May exhibit fusion, leaching, or

hydrolysis of entrapped drug which limits

the shelf life

Stable and osmotically active Insufficient drug loading capacity

Increased dermal penetration and oral

bioavailability

Specialized equipment required for

manufacture

Niosomes are nonimmunogenic, nontoxic,

biocompatible, and biodegradable Leakage of entrapped drug

Used for parenteral and oral as well as topical

routes Physically instable

No special conditions required for handling

and storage of surfactants

Time consuming techniques required for

formulation

Improved therapeutic performance of drug Aggregation

Niosomes have water base, thus having great

patent compliance over oily dosage forms Expensive

Niosomes can be administered via different routes (oral, parenteral, and topical) and a

delayed clearance from the circulation and restricting effects to target cells improve the

therapeutic performance of drug molecules. Different dosage forms (powders, suspensions,

and semisolids) are available with improved oral bioavailability of poorly soluble drugs and

also an enhanced permeability of drugs through skin on topical application. Aqueous vehicle-

based suspension formulation results in better patient compliance, compared with oily dosage

forms; Niosomal dispersion(being aqueous) can be emulsified in a non-aqueous phase to



1347

regulate drug release rate. Niosomes have been reported to achieve better patient adherence

and satisfaction and also better effectiveness than conventional oily formulations.

Disadvantages of niosomes include, a decrease their shelf life, physical and chemical

instability, fusion of vesicles, aggregation, and leaking or hydrolysis of the encapsulated

drug. The methods required for preparation of multilamellar vesicles (such as extrusion or

sonication) are time-consuming.

Recent advances in niosomal formulations for transdermal drug targeting are focused on

optimization of procedures, new compositions, and final formulations e.g. elastic vesicles,

new highly flexible niosomes that are effective at delivering molecules through the skin.

Edge activators (i.e. ethanol) provide vesicles with elastic characteristics, which allow them

to penetrate more easily into the deeper layers of the skin. The major limitation of niosomes

is liquid nature of the preparation, when applied they leak from the application site. This

can be overcome by incorporation of an adequate, gelling vehicle agents to niosomal

dispersions, that form a niosomal gel. Niosomal gels enhance retention of therapeutics by the

skin and provide high and sustained drug concentrations in the skin. Proniosomes or “dry

niosomes”, are niosomal formulations hydrated before use, and hydration results in formation

of an aqueous niosomal dispersion.[79]

Proniosomes decrease aggregation, leakage, and fusion

problems associated with traditional niosomes and offer a versatile transdermal drug delivery

system, they become hydrated on application to the skin with water from the skin under

occlusion. Trans-dermal drug delivery has great importance as it overcomes the main

problems associated with oral drug delivery systems. Techniques for enhancing TDD include

electrophoresis, microneedles, iontophoresis, nanoneedles, sonophoresis and vesicles like

liposome, ethosome, transfersome and cetosomes.

5.6.3. Transfersomes carrier system is composed of phospholipids, surfactants and water,

ideal for delivery of active constituents. Tranfersomes described by Gregor Cevc (1991) is a

stress responsive, elastic and an extremely adaptable aggregate, exists as an ultra-deformable

complex with a hydrated core surrounded by a complex layer of lipid[80]. Self-optimizing

and self-regulatory properties help the vesicle traverse different transport barriers effectively

and help the carrier in targeted and sustained delivery of active constituents in a non-invasive

manner. Applications of Transfersomes include

1. As carrier for protein and peptides like insulin, bovine serum albumin, vaccines, etc.

2. Successful non-invasive therapeutic use of large molecular weight drugs on the skin.



1348

3. Improves site specificity, overall drug safety, and lower the doses.

4. Enhanced passive oestradiol penetration is achieved

5. Improves therapeutic efficacy of cyclosporine; and site specificity and safety of cortico-

steroids.

Limitations of Transfersomes include they are chemically unstable because of their

predisposition to oxidative degradation, lack of purity of natural phospholipids and a higher

cost factor.

5.6.4.Aquasomes first developed by NirKossovsky (1995) are spherical in shape with 60–

300 nm particle size. They are three layered self-assembled structures, comprised of a solid

phase nanocrystalline core coated with oligomeric film to which biochemically active

molecules are adsorbed with or without modification. Their water like properties (bodies of

water) protect and preserve fragile biological molecules. These properties help maintain

conformational integrity and has high degree of surface exposure, that are used for targeting

of bio-active molecules like peptide and protein hormones, antigens and genes to specific

sites. Applications of aquasomes include insulin delivery, oral delivery of acid labile

enzyme, oxygen carrier, antigen delivery, delivery of drug, for delivery of genes and for

delivery of enzymes.[81]

Selective recognition of NPs is achieved by nanoparticle-imprinted matrices (NAIMs). The

NPs are imprinted in a matrix followed by their removal that form voids/spaces that have the

capability to reuptake the original NPs. NAIMs are extension of the well-known concept of

molecularly imprinted polymers (MIPs) to nano-analytes. Nanoparticle-imprinted matrices

enable size or shell differentiation of AuNPs from aqueous solutions. AuNPs as nano-objects

are used extensively in medical diagnostics and drug delivery. In MIPs the molecular analyte-

template is imprinted in a polymeric matrix, a cavity with the dimensions of analyte molecule

and functional groups is left behind in the walls of the matrix following their release.

Interaction of analyte molecule and specific voids help in selective reuptake of the analyte.

MIPs are used as sensing layers, catalysts and as chromato-graphic phases. Solid lipid NPs,

nano emulsions and nanostructured lipid carriers are the main types of matrix NPs.

Liposomes are the main type of vesicular particles, and Niosomes, cubosomes, bicellar

systems, vesicles, and nano-dispersions are other types of particles. Unique advantageous

‗occlusive properties‘ increase skin hydration, modify release profile, increase skin

penetration associated with a targeting effect and avoid systemic uptake.[82]

‗Elastic



1349

liposomes‘ are capable of deformation to flow through capillaries and the narrow pores of

skin and help enhance skin permeation and carry the active compound into deeper skin

layers. Anti-inflammatory agent ―1dipotassium glycyrrhizinate‖ as a liposomal preparation

has good skin delivery and is used for treating acute and chronic dermatitis.

5.7. Nano-emulsion-based topical therapies

Nano-emulsions are nano-sized emulsions that have oil, emulsifying agents, and aqueous

phases as main components, that are used for improving delivery of active pharmaceutical

ingredients.[83]

These are the thermodynamically stable isotropic system in which two

immiscible liquids are mixed to form a single phase by means of an emulsifying agent, i.e.,

surfactant and co-surfactant. Droplet size of nano-emulsion falls typically in the range 20–

200 nm. The main difference between emulsion and nano-emulsion lies in the size and shape

of particles dispersed in the continuous phase. Advantages of nano-emulsion are they are

used as substitute for liposomes and vesicles, help improve bioavailability of drug, non-toxic

and non-irritant in nature, has improved physical stability.[84]

Nano-emulsions have small-

sized droplets with greater surface area that provide greater absorption. It can be formulated

in variety of formulations such as foams, creams, liquids, and sprays, provides better uptake

of oil-soluble supplements in cell culture technology. It helps to solubilize lipophilic drug, in

taste masking and less amount of energy is required.

Nano-emulsion-based topical therapies have antimicrobial, anti-inflammatory effects and

enhanced drug delivery properties. Nanoemulsions are extensively used for delivery of poor

soluble drugs and active pharmaceutical compounds to a specific site through various routes

of administration. They are used in cancer therapy as carriers for photosensitizer agents, for

hyperthermia effect, targeted delivery of anti-cancer drugs, and in gene delivery as non-viral

vectors. Nano-emulsions have lipophilic interior and are efficient at transporting hydrophobic

substances in aqueous environments. Nanoemulsions have higher capacity to penetrate,

flexibility, lack of polymer and affinity with stratum corneum. They are useful as cutaneous

delivery vehicle for anti-aging products due to effective concentrations in target tissues. They

also allow permeation of skin for water immiscible active ingredients such as retinol,

antioxidants and lipid. Hence nano-emulsions are used as drug delivery vehicles for

ingestion, parenteral use, intranasal, intratracheal uses and in topical applications.

Gamma-amino-butyric acid is an inhibitory neurotransmitter with muscle relaxing

properties, used in topical nano-emulsions delivery system for wrinkle reduction.[85]

They are



1350

stable for transport of lipophilic compounds into the skin and are used in treatment of acne

vulgaris. Quantum dots attached to tags such as antibodies are useful in animal models for

visualization of skin tumours without use of radioactive materials. Nano-punch is an origami

claw shaped small biopsy tool comprising of nickel, chromium, silicon and copper layers, the

opening and closure can be controlled by mere change of temperature as the metals have

variable coefficients of expansion. It is a latest biopsy tool for collecting samples from

challenging sites like nail matrix or fascia. It can be administered into the bloodstream and its

movement can be governed by a magnetic field as it is also paramagnetic. Using this

technique, biopsy can be obtained from the most difficult sites like nail matrix, fascia etc.

6. Future of nanomedicine and drug delivery systems

Nanomedicine Research is currently making great advances in health care sector.

Nanomedical technologies have improved diagnosis and treatment of dermatological

conditions and skin cancer. NPs deliver drugs in accurate amount in a cell-specific manner in

tumour cells, without disturbing the physiology of normal cells. Materials with consistent

uniformity, drug loading and release capacity are the need for future. Research on metal-

based NPs like gold and silver for both diagnosis and therapy has wider applications of

nanomedicines in future. Gold NPs are well absorbed in soft tissue tumours, make tumours

susceptible to radiation in the near infrared region and radiation-based heat therapy for

selective tumour elimination will be improved for future therapies. Fundamental markers of

diseased tissues including key biological markers identification is a main area of research for

future; that will allow absolute targeting without altering normal cellular process. Study of

diseases at molecular level and/or nanomaterial-subcellular size comparable marker

identification, will help avenues for newer diagnosis and therapy methods in nanomedicine.

Molecular signatures of diseases in future will lead to advances in nanomedicine

applications. Further research on nanoprobes and Nanotheranostic products will have wider

applications in future. Further assessment of drug effect in tissues or at cellular level by

controlled release of specific drugs at difficult sites is required. Biomaterials and formulation

studies in biomedicine applications in nanomedicine are future areas of research. More

intelligent and multicentred approach of nanomedicine and nano-drug delivery technology

will be put to use in future. Nanorobots and nanodevices for tissue diagnosis and repair

mechanism with full external control mechanism will be a reality soon. Affordability of

nanomedicines in future, long term impact analysis of risk of nanomaterials, acute or chronic

toxicity effects to both human and environment are other areas of research. Proper analysis of



1351

new nanomaterials on its effect in humans and on environment must be analysed, and the

regulation of nanomaterials must continue to evolve alongside the advances in nanomedicine

applications.

6.1.Nano-diagnosis

Nanotechnology-based devices for diagnosis in future will be fast, highly sensitive, specific

and require miniscule quantities of analytical material. Two promising methods currently in

the development stage are Optical fabric and quantum dots. Fibre optic fabric cloths could

have dermatological applications, characterised by nevus mapping or tracking psoriasis or

atopic dermatitis on body surface areas, as well as providing the dimensions of skin lesions.

Inflammatory diseases such as psoriasis, atopic dermatitis, or mycosis fungoides can be

monitored by detecting changes in skin temperature. Highly fluorescent QDs has

fluorescence that is stable, intensely bright and durable and the emission absorption spectrum

can be tuned over a wide range of frequencies from infrared to ultraviolet and this method is

applied for tumour localization without using radioactive substances. Topical application of

quantum dots allow sentinel lymph node evaluation without disturbing the skin or tumour

evolution. Formulations of biocompatible quantum dots are being developed to make the

procedure less toxic.

6.2.Nanotheranostic platforms

Nanotheranostic platform based on carbon quantum dots (CQDs) doped with S, N and Gd

(GdNS@CQDs), and functionalized with FA through ECD/Sulfo-NHS reaction has been

developed for a targeted dual mode fluorescence or MRI.[86]

The targeting capability of nano-

platform was evaluated on two cancerous cell lines, HeLa and HepG2, and confirmed good

stability, biocompatibility and low toxicity. Drug-loading capacity for FA-GdNS@CQDs

with anticancer drug DOX was ~80% and drug release is pH-sensitive.[87]

Nanotheranostic

platforms have bimodal contrast imaging functionality (fluorescence/magnetic resonance),

cancer cell targeting and pH-sensitive drug release capabilities.[88]

CQDs developed in a one-

step green process from sodium alginate has low toxicity, good biocompatibility and broad

excitation spectra and has been used for gene delivery applications.

6.3.SPIONs in drug delivery

Thermally crosslinked SPIONs (TCL-SPIONs) system consists of a copolymer having

thermally cross-linkable Si–OH groups in its structure (poly(3-(trimethoxysilyl)propyl

methacrylate-r-PEG methyl ether methacrylate-r-N-acryloxysuccinimide)) as a stabilizing



1352

coating for SPIONs and are used in drug delivery. Folic acid is integrated to receptors on

surface of cells for successful treatment of tumours overexpressing FA receptors. SPIONs

with a polymeric shell made of PEG and PEI (poly (ethyl-enimine)), which was modified

with folic acid (FA) using the EDC (1-ethyl-3-(3-dimethyl-aminopropyl)-carbodiimide)/NHS

(N-hydr-oxysuccinimide) chemistry has been designed. Other uses of SPIONs include

Alzheimer‘s disease, photodynamic therapy, cytotoxicity in osteosarcoma cells, delivery of

Linoleic acid in breast cancer therapy, SPIONs interfering with Electron Transport Chain in

Hepatic Carcinoma. Remote Control in SPIONs is another way of inducing apoptosis of the

tumour cells, detection of aflatoxin, Prevention of bleeding after application of heparin-based

drugs in haemodialysis. SPIONs against bacterial diseases: SPIONs have antibacterial

properties. Gold-coated SPIONs penetrate and have strong toxic effects on bacterial biofilms.

Both SPIONs‘ cores and gold shells induce heat with a laser and alternative magnetic fields

and high temperature has a deadly effect on bacteria. Magnetic Particle Imaging: SPIONs

are used to improve the contrast of obtained images in MRI, whereas in magnetic particle

imaging (MPI), they serve as the only source of signal and the only visualized element.[89]

Side effects of SPIONs include toxic effects induced by iron oxide nanoparticles is their

ability to cause oxidative stress. Another limitation of SPIONs is their uptake by

Reticuloendothelial system, that can be avoided by selecting proper coating and chitosan-

coated SPIONs are alternative solutions for the side effects.[90]

CONCLUSION

Nanotechnology covers diverse fields of medicine, engineering, oncology, infective

medicine, chemistry, dermatology, and other disciplines. Many researches are promising for

treatment of serious diseases such as cancer due to its specificity, half-life, penetration

capacity in tissues, and possibility of early diagnosis and better localization. In dermatology,

nanotechnology has gained prominence mainly in cosmetic industry, in the treatment and

monitoring of inflammatory and immuno-mediated dermatoses. Biological activity of certain

nanomaterials, micro and nanoparticles are being widely investigated as carriers or drug

delivery systems for development of special route internalisation, selectivity, slow release

and segmentation. Specific toxicological studies are needed for each product prior to

commercial use and establish safety standard for human use. Long term limitations on the use

of nanotechnology include toxicity, tissue deposition, long-term oncological potential and

environmental concerns. There is a greater tendency towards a wider association between

machines and nanotechnologies with advanced technology. is the ultimate aim of the future.



1353

The ultimate aim for future is need for the probability of a deeper in vitro and in vivo

understanding and new perspectives for an important reduction in morbidity and mortality for

different diseases.

Funding

―This review/research received no external funding‖

ACKNOWLEDGMENTS

I would like to thank Mrs. Geetha Mariappan for her valuable technical and clerical support

during the preparation of this manuscript.

Conflicts of Interest

―The author Dr. Mariappan Natarajan declares no conflict of interest.‖

REFERENCES

1. Lee DY, Li KC. Molecular theranostics: a primer for the imaging professional. AJR Am J

Roentgenol, 2011; 197(2): 318-324. doi: 10.2214/AJR.11.6797.

2. Schurer NY, Elias PM. The biochemistry and function of stratum corneum lipids. Adv

Lipid Res, 1991; 24: 27–56.

3. Sahle F.F; et al. [Skin Diseases Associated with the Depletion of Stratum Corneum Lipids

and Stratum Corneum Lipid Substitution Therapy]. Skin Pharmacol Physiol, 2015; 28:

42-55. Available: < https: //www.karger.com/Article/FullText/360009.

4. Schoellhammer C.M., Blankschtein D., Langer R. Skin Permeabilization for Transdermal

Drug Delivery: Recent Advances and Future Prospects. Expert Opin. Drug Deliv, 2014;

11: 393–407. doi: 10.1517/17425247.2014.8 Zhao, X., Li, H., et al., 2008. Targeted drug

delivery via folate receptors. Expert Opin. Drug Deliv, 5(3): 309–319. 75528.

5. Caspers, P.J. et al. Semiquantitative in vivo concentration profiles of NMF and sweat

constituents in the stratum corneum of the thenar as determined by Raman spectroscopy,

J. Invest. Dermatol., 2001; 116: 434.

6. Jain, Kewal. Drug Delivery Systems - An Overview. Methods in molecular biology

(Clifton, N.J.), 2008; 437. 1-50. 10.1007/978-1-59745-210-6_1.

7. 4. Sokolova E.A., Vodeneev V.A., Deyev S.M., Balalaeva I.V. 3D in vitro models of

tumors expressing EGFR family receptors: A potent tool for studying receptor biology

and targeted drug development. Drug Discov. Today. 2018 doi:

10.1016/j.drudis.2018.09.003.



1354

8. Swetha T*, Mrs.Tanush Ree Chakraborty. (2019). Nanosponges: New Colloidal Drug

Delivery System For Topical Drug Delivery. Indo American Journal Of Pharmaceutical

Sciences, O6(02): 4263–4276. Http: //Doi.Org/10.5281/Zenodo.2574445

9. Xiuxiu Wang, Ru Cheng, Liang Cheng, Zhiyuan Zhong. Lipoyl Ester Terminated Star

PLGA as a Simple and Smart Material for Controlled Drug Delivery

Application. Biomacromolecules, 2018; 19 (4): 1368-1373. https:

//doi.org/10.1021/acs.biomac.8b00130

10. V. Dias, A. Gothoskar, K. Fegely, and A. Rajabi-Siahboomi, ―Modulation of drug release

from hypromellose (HPMC) matrices: suppression of the initial burst effect. paper

presented at The American association of pharmaceutical scientists annual meeting and

exposition; San Antonio, TX, USA, 2006‖.

11. Siegel RA, Rathbone MJ (2012) Overview of controlled release mechanisms. In:

Siepmann J et al (eds) Fundamentals and applications of controlled release drug delivery.

Advances in delivery science and technology. Springer, New York, 21–22.

12. Shader, Richard I, Dose Dumping and the Dumping of Dose, Journal of Clinical

Psychopharmacology, August 2007; 27(4): 327-328.

13. Ghosh T.K., Jasti B.R. Theory and Practice of Contemporary Pharmaceutics. CRC press;

Boca Raton, FL, USA, 2004.

14. Van Agthoven JF, Xiong JP, Alonso JL, Rui X, Adair BD, Goodman SL, Arnaout MA

(April 2014). "Structural basis for pure antagonism of integrin αVβ3 by a high-affinity

form of fibronectin". Nature Structural & Molecular Biology, 21(4): 383-8. doi:

10.1038/nsmb.2797. PMC 4012256. PMID 24658351.

15. Hu, H.; Wan, J.; Huang, X.; Tang, Y.; Xiao, C.; Xu, H.; Yang, X.; Li, Z. iRGD-decorated

reduction-responsive nanoclusters for targeted drug delivery. Nanoscale, 2018; 10:

10514–10527.

16. M. P. Turunen, H. L. Puhakka, J. K. Koponen et al., ―Peptide-retargeted adenovirus

encoding a tissue inhibitor of metalloproteinase-1 decreases restenosis after intravascular

gene transfer, ‖ Molecular Therapy, 2002; 6(3): 306–312.

17. Vera AM, Ca rcamo JJ, Aliaga AE, Go mez-Jeria JS, Kogan MJ, Campos-Vallette MM

(2015) Interaction of the CLPFFD peptide with gold nanospheres. A Raman, surface

enhanced Raman scattering and theoretical study. Spec- trochimica Acta Part A: Mol

Biomol Spectrosc, 134: 251–256. doi: 10.1016/j.saa.2014.06.116

18. Lertkiatmongkol, P. et al. The Role of Sialylated Glycans in Human Platelet Endothelial

Cell Adhesion Molecule 1 (PECAM-1)-mediated Trans Homophilic Interactions and

http://doi.org/10.5281/zenodo.2574445

https://doi.org/10.1021/acs.biomac.8b00130

https://doi.org/10.1021/acs.biomac.8b00130

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012256


https://en.wikipedia.org/wiki/Digital_object_identifier

https://doi.org/10.1038%2Fnsmb.2797

https://en.wikipedia.org/wiki/PubMed_Central


https://en.wikipedia.org/wiki/PubMed_Identifier

https://pubmed.ncbi.nlm.nih.gov/24658351



1355

Endothelial Cell Barrier Function. J Biol Chem, 291: 26216-26225, https:

//doi.org/10.1074/jbc.M116.756502 (2016). CAS Article PubMed PubMed

Central Google Scholar

19. Z. Yuan, Z. Que, S. Cheng, R. Zhuo, and F. Li, ―PH-triggered blooming of ‗nano-

flowers‘ for tumor intracellular drug delivery, ‖ Chemical Communications, 2012;

48(65): 8129–8131. View at: Publisher Site | Google Scholar

20. A. Guha, N. Biswas, K. Bhattacharjee, P. Das, and K. Kuotsu, ―In vitro evaluation of pH

responsive Doxazosin loaded mesoporous silica nanoparticles: a smart approach in drug

delivery, ‖ Current Drug Delivery, 2016; 13(4): 574–581.

21. C. de la Torre, A. Agostini, L. Mondragón et al., ―Temperature-controlled release by

changes in the secondary structure of peptides anchored onto mesoporous silica supports,

‖ Chemical Communications, 2014; 50(24): 3184–3186.

22. J. Dong and J. I. Zink, ―Simultaneous spectroscopic measurements of the interior

temperature and induced cargo release from pore-restricted mesoporous silica

nanoparticles, ‖ Nanoscale, 2016; 8(20): 10558–10563.

23. A. Zintchenko, M. Ogris, and E. Wagner, ―Temperature dependent gene expression

induced by PNIPAM-based copolymers: potential of hyperthermia in gene transfer,

‖ Bioconjugate Chemistry, 2006; 17(3): 766–772.

24. T. K. Jain, M. A. Morales, S. K. Sahoo, D. L. Leslie-Pelecky, and V. Labhasetwar, ―Iron

oxide nanoparticles for sustained delivery of anticancer agents, ‖ Molecular

Pharmaceutics, 2005; 2(3): 194–205.

25. Y. Jiao, Y. Sun, B. Chang, D. Lu, and W. Yang, ―Redox- and temperature-controlled drug

release from hollow mesoporous silica nanoparticles, ‖ Chemistry, 2013; 19(45): 15410–

15420.

26. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat

Mater, 2013; 12: 991–1003.

27. Traverso, N., R.Ricciarelli, M.Nitti, B.Marengo, A.L.Furfaro, M.A.Pronzato, U.M.

Marinari, and C.Domenicotti. 2013. Role of glutathione in cancer progression and

chemoresistance. Oxid. Med. Cell. Longev, 2013: 972913. https:

//doi.org/10.1155/2013/972913

28. A. Bernardos, E. Aznar, M. D. Marcos et al., ―Enzyme-responsive controlled release

using mesoporous silica supports capped with lactose, ‖ Angewandte Chemie—

International Edition, 2009; 48(32): 5884–5887.

https://doi.org/10.1074/jbc.M116.756502

https://doi.org/10.1074/jbc.M116.756502

https://www.nature.com/articles/cas-redirect/1%3ACAS%3A528%3ADC%252BC28XitVOjsr%252FP

https://doi.org/10.1074%2Fjbc.M116.756502

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27793989

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207088

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207088

http://scholar.google.com/scholar_lookup?&title=The%20Role%20of%20Sialylated%20Glycans%20in%20Human%20Platelet%20Endothelial%20Cell%20Adhesion%20Molecule%201%20%28PECAM-1%29-mediated%20Trans%20Homophilic%20Interactions%20and%20Endothelial%20Cell%20Barrier%20Function&journal=J%20Biol%20Chem&doi=10.1074%2Fjbc.M116.756502&volume=291&pages=26216-26225&publication_year=2016&author=Lertkiatmongkol%2CP

https://doi.org/10.1039/c2cc34225a

https://scholar.google.com/scholar_lookup?title=PH-triggered%20blooming%20of%20‘nano-flowers’%20for%20tumor%20intracellular%20drug%20delivery&author=Z.%20Yuan&author=Z.%20Que&author=S.%20Cheng&author=R.%20Zhuo&author=&author=F.%20Li&publication_year=2012

https://doi.org/10.1155/2013/972913

https://doi.org/10.1155/2013/972913



1356

29. Sennoga, C. A., Kanbar, E., Auboire, L., Dujardin, P. A., Fouan, D., Escoffre, J. M., et al.

(2017). Microbubble-mediated ultrasound drug-delivery and therapeutic

monitoring. Expert Opin. Drug Deliv, 14: 1031–1043. doi:

10.1080/17425247.2017.1266328

30. M. Colilla, B. González, and M. Vallet-Regí, ―Mesoporous silica nanoparticles for the

design of smart delivery nanodevices, ‖ Biomaterials Science, 2013; 1(2): 114–134

31. Y. Qin, J. Chen, Y. Bi et al., ―Near-infrared light remote-controlled intracellular anti-

cancer drug delivery using thermo/pH sensitive nanovehicle, ‖ Acta Biomaterialia, 2015;

17: 201–209.

32. A. R. K. Sasikala, A. GhavamiNejad, A. R. Unnithan et al., ―A smart magnetic

nanoplatform for synergistic anticancer therapy: manoeuvring mussel-inspired functional

magnetic nanoparticles for pH responsive anticancer drug delivery and hyperthermia,

‖ Nanoscale, 2015; 7(43): 18119–18128.

33. H. Kakwere, M. P. Leal, M. E. Materia et al., ―Functionalization of strongly interacting

magnetic nanocubes with (thermo)responsive coating and their application in

hyperthermia and heat-triggered drug delivery, ‖ ACS Applied Materials and Interfaces,

2015; 7(19): 10132–10145.

34. Chow B.W., Nunez V., Kaplan L., Granger A.J., Bistrong K., Zucker H.L., Kumar P.,

Sabatini B.L., Gu C. Caveolae in CNS arterioles mediate neurovascular

coupling. Nature, 2020; 579: 106–110.

35. McIntosh D.P., Tan X.Y., Oh P., Schnitzer J.E. Targeting endothelium and its dynamic

caveolae for tissue-specific transcytosis in vivo: a pathway to overcome cell barriers to

drug and gene delivery. Proc. Natl. Acad. Sci. U. S. A, 2002; 99: 1996–2001.

36. Vo, T.N., Kasper, F.K., et al., 2012. Strategies for controlled delivery of growth factors

and cells for bone regeneration. Adv. Drug Deliv. Rev, 2012; 64(12): 1292–1309.

37. Zhang, J., Saltzman, M. Engineering biodegradable nanoparticles for drug and gene

delivery. Chem. Eng. Prog, 2013; 109(3): 25–30.

38. Emerich, D.F., Thanos, C.G. Targeted nanoparticle-based drug delivery and diagnosis. J.

Drug Target, 2007; 15(3): 163–183.

39. D. E. Owens III and N. A. Peppas, ―Opsonization, biodistribution, and pharmacokinetics

of polymeric nanoparticles,‖ International Journal of Pharmaceutics, 2006; 307(1): 93-

102.

40. Jain A, Jain SK (2016) Stimuli-responsive smart liposomes in cancer targeting. Curr Drug

Targets. doi: 10.2174/1389450117666160208144143

https://doi.org/10.2174/1389450117666160208144143



1357

41. Kohane, D.S. Microparticles and nanoparticles for drug delivery. Biotechnol. Bioeng,

2007; 96(2): 203–209.

42. McMillan, J., Batrakova, E., et al. Cell delivery of therapeutic nanoparticles. Prog. Mol.

Biol. Transl. Sci, 2011; 104: 563–601.

43. Buzea, C., Pacheco, I.I., et al. Nanomaterials and nanoparticles: sources and toxicity.

Biointerphases, 2007; 2(4): MR17-71.

44. Bantz, C., Koshkina, O., et al. The surface properties of nanoparticles determine the

agglomeration state and the size of the particles under physiological conditions. Zellner,

R., ed. Beilstein J. Nanotechnol, 2014; 5: 1774–1786.

45. Sykes, E.A., Dai, Q., et al. Tailoring nanoparticle designs to target cancer based on tumor

pathophysiology. Proc. Natl. Acad. Sci. USA, 2016; 113: E1142–E1151.

46. 11. Win K.Y., Feng S.S. Effects of particle size and surface coating on cellular uptake of

polymeric nanoparticles for oral delivery of anticancer drugs. Biomaterials, 2005; 26:

2713–2722. doi: 10.1016/j.biomaterials.2004.07.050.

47. Zhu S., Qian F., Zhang Y., Tang C., Yin C. Synthesis and characterization of PEG

modified N-trimethylaminoethylmethacrylate chitosan nanoparticles. Eur. Polym.

J, 2007; 43: 2244–2253. doi: 10.1016/j.eurpolymj.2007.03.042.

48. Varshosaz, J., Farzan, M. Nanoparticles for targeted delivery of therapeutics and small

interfering RNAs in hepatocellular carcinoma. World J. Gastroenterol, 2015; 21(42),

12022–12041.

49. Friedman, A.D., Claypool, S.E., et al. The smart targeting of nanoparticles. Curr. Pharm.

Des, 2013; 19(35): 6315–6329.

50. Pramanik, A.K., Siddikuzzaman, et al. Biotin decorated gold nanoparticles for targeted

delivery of a smart-linked anticancer active copper complex: in vitro and in vivo studies.

Bioconjug. Chem, 2016; 27(12): 2874–2885.

51. Mu, Q., Jiang, G., et al., 2014. Chemical basis of interactions between engineered

nanoparticles and biological systems. Chem. Rev, 2014; 114(15): 7740–7781.

52. Park, H.S., Nam, S.H., et al., 2016. Clear-cut observation of clearance of sustainable

upconverting nanoparticles from lymphatic system of small living mice. Sci. Rep, 6:

27407.

53. Kou, L., Sun, J., et al., 2013. The endocytosis and intracellular fate of nanomedicines:

implication for rational design. Asian J. Pharm. Sci, 8: 1–10.



1358

54. Uche LE, Gooris GS, Beddoes CM, Bouwstra JA. New insight into phase behavior and

permeability of skin lipid models based on sphingosine and phytosphingosine

ceramides. Biochim Biophys Acta Biomembr, 2019 Jul 01; 1861(7): 1317-1328.

55. Zheng L, Qiulin L, Duanguang Y, Yong G, Xujun L. Well-defined poly(N-

isopropylacrylamide) with a bifunctional end-group: synthesis, characterization, and

thermoresponsive properties, Designed. Monomers Polymers, 2013; 16: 465–74. https:

//doi.org/10.1080/15685551.2012.747165.

56. Ma Y, Hou S, Ji B, Yao Y, Feng X. A novel temperature-responsive polymer as a gene

vector. Macromol Biosci, 2010; 10: 202–10.

57. 4. Zhang X, Li X, You Q, Zhang X. Prodrug strategy for cancer cell-specific targeting: a

recent overview. Eur J Med Chem, 2017; 139: 542–563. doi:

10.1016/j.ejmech.2017.08.010.

58. Wu QX, Lin DQ, Yao SJ. Design of chitosan and its water soluble derivatives-based drug

carriers with polyelectrolyte complexes. Marine Drugs, 2014; 12: 6236–53.

59. Hamman JH. Chitosan based polyelectrolyte complexes as potential carrier materials in

drug delivery systems. Marine Drugs, 2010; 8: 1305–22.

60. Li, D., Kaner, R.B., 2006. Shape and aggregation control of nanoparticles: not shaken.

Not Stirred. J. Am. Chem. Soc, 128(3): 968–975.

61. Son, G.H., Lee, B.J., et al., 2017. Mechanisms of drug release from advanced drug

formulations such as polymeric-based drug-delivery systems and lipid nanoparticles. J.

Pharmaceut. Invest. https: //doi.org/10.1007/s40005-017- 0320-1.

62. Lee JH, Yeo Y. Controlled drug release from pharmaceutical nanocarriers. Chem Eng

Sci, 2015; 125: 75–84.

63. Polymeric Micelles: Nanocarriers for Cancer-Targeted Drug Delivery Y Zhang, Y Huang,

S Li, AAPS PharmSciTech, 2014; 15: 862-871.

64. Polymeric nano-micelles: a versatile platform for targeted delivery in cancer S Mohamed,

N N Parayath, S Taurin, K Greish, Therapeutic delivery, 2014; 5: 1101-1121.

65. Advances in nanomicelles for sustained drug delivery N Amirmahani, N O Mahmoodi, M

Mohammadi Galangash, A Ghavidast, Journal of Industrial and Engineering Chemistry,

2017; 55: 21-34.

66. Allena MT, Cullis PR. Liposomal drug delivery systems: from concept to clinical

applications. Adv Drug Deliv Rev 2013; 65: 36–48.

67. Kelly, C., Jefferies, C., et al., 2011. Targeted liposomal drug delivery to monocytes and

macrophages. J Drug Deliv, 727241.

https://doi.org/10.1080/15685551.2012.747165

https://doi.org/10.1080/15685551.2012.747165



1359

68. Pattni, B.S., Chupin, V.V., et al., 2015. New developments in liposomal drug delivery.

Chem. Rev, 115(19): 10938–10966.

69. Gart MS, Gutowski KA. Overview of botulinum toxins for aesthetic uses. Clin Plast Surg,

2016; 43(3): 459–471. doi: 10.1016/j.cps.2016.03.003

70. Newman MD, Stotland M, Ellis JI. The safety of nanosized particles in titanium dioxide-

and zinc oxide-based sunscreens. J Am Acad Dermatol, 2009; 61: 685–692. 14.

71. Dykman L.A., Khlebtsov N.G. Immunological properties of gold nanoparticles. Chem.

Sci, 2017; 8: 1719–1735. doi: 10.1039/C6SC03631G.

72. Locher, K. P. (2016). Mechanistic diversity in ATP-binding cassette (ABC)

transporters. Nat. Struct. Mol. Biol, 23: 487. doi: 10.1038/nsmb.3216

73. Geszke-Moritz M., Moritz M. Solid lipid nanoparticles as attractive drug vehicles:

Composition, properties and therapeutic strategies. Mater. Sci. Eng. C Mater. Biol.

Appl, 2016; 68: 982–994. doi: 10.1016/j.msec.2016.05.119.

74. Ganesan P., Narayanasamy D. Lipid nanoparticles: Different preparation techniques,

characterization, hurdles, and strategies for the production of solid lipid nanoparticles and

nanostructured lipid carriers for oral drug delivery. Sustain. Chem. Pharm, 2017; 6: 37–

56. doi: 10.1016/j.scp.2017.07.002.

75. Khosa, A.; Reddi, S.; Saha, R.N. Nanostructured lipid carriers for site-specific drug

delivery. Biomed. Pharmacother, 2018; 103: 598–613. [CrossRef]

76. S. M. Jadhav, P. Morey, M. M. Karpe, and V. Kadam, ―Novel vesicular system: an

overview,‖ Journal of Applied Pharmaceutical Science, 2012; 2(1): 193–202.

77. Rewar S, Mirdha D, Rewar P. A vital role of pharmacosome‘s on controlled and novel

drug delivery, Asi J of Res in Biol and Pharm Scienc, 2014; 2(4): 163-170.

78. O. Thanaketpaisarn, ―Niosome delivery systems in pharmaceutical applications, ‖ Isan

Journal of Pharmaceutical Sciences, 2012; 8(2): 12–26.

79. El Maghraby GM, Ahmed AA, Osman MA. Penetration enhancers in proniosomes as a

new strategy for enhanced transdermal drug delivery. Saudi Pharm J, 2015; 23: 67–74.

80. Bragagni M, Mennini N, Maestrelli F, et al. Comparative study of liposomes,

transfersomes and ethosomes as carriers for improving topical delivery of celecoxib. Drug

Deliv, 2012; 19: 354–61.

81. J. K. Patel, K. N. Patel, H. K. Patel, B. A. Patel, and P. A. Patel, ―Aquasomes: a self-

assembling nanobiopharmaceutical carrier system for bio-active molecules: a review,

‖ International Journal for Pharmaceutical Research Scholars, 2012; 1(1): 11–21.



1360

82. Pashirova, T.N.; Sapunova, A.S.; Lukashenko, S.S.; Burilova, E.A.; Lubina, A.P.;

Shaihutdinova, Z.M.; Gerasimova, T.P.; Kovalenko, V.I.; Voloshina, A.D.; Souto, E.B.;

et al. Synthesis, structure-activity relationship and biological evaluation of tetracationic

gemini Dabco-surfactants for transdermal liposomal formulations. Int. J. Pharm, 2020;

575: 118953.

83. Nastiti, C.M.R.R.; Ponto, T.; Abd, E.; Grice, J.E.; Benson, H.A.E.; Roberts, M.S. Topical

nano and microemulsions for skin delivery. Pharmaceutics, 2017; 9: 37.

84. Gupta, A.; Eral, H.B.; Hatton, T.A.; Doyle, P.S. Nanoemulsions: Formation, properties

and applications. Soft Matter, 2016; 12: 2826–2841.

85. Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine

antinoci-ception: Pharmacological and genetic approaches. Pharmacol. Biochem. Behav,

2019 May; 180: 11-21.

86. S. S. Kelkar and T. M. Reineke, ―Theranostics: combining imaging and therapy,

‖ Bioconjugate Chemistry, 2011; 22(10): 1879–1903.

87. H. Ding and F. Wu, ―Image guided biodistribution and pharmacokinetic studies of

theranostics, ‖ Theranostics, 2012; 2(11): 1040–1053.

88. Chiu SH, Gedda G, Girma WM, et al. Rapid fabrication of carbon quantum dots as

multifunctional nanovehicles for dual-modal targeted imaging and chemotherapy. Acta

Biomater, 2016; 46: 151–164.

89. Ma, X. H.; Gong, A.; Chen, B.; Zheng, J. J.; Chen, T. X.; Shen, Z. Y.; Wu, A. G.

Exploring a new SPION-based MRI contrast agent with excellent water-dispersibility,

high specificity to cancer cells and strong MRimaging efficacy. Colloids Surf. B

Biointerfaces, 2015; 126: 44–49.

90. Zhao, X., Li, H., et al. Targeted drug delivery via folate receptors. Expert Opin. Drug

Deliv, 2008; 5(3): 309–319.

nano-drug delivery systems and applications in … · 2020. 8. 31. · (cdds) are particulate or...

Documents