organic nanocarriers for cancer drug delivery

COPHAR-1028; NO. OF PAGES 6

Organic nanocarriers for cancer drug deliveryVıctor Lopez-Davila, Alexander M Seifalian and Marilena Loizidou

Available online at www.sciencedirect.com

A major focus in translational cancer research is the study of

nanocarriers as novel delivery systems for chemotherapeutics.

Organic vesicular nanocarriers, such as liposomes and

micelles, have the advantage of low toxicity and the versatility

to carry diverse drugs and conjugate to targeting agents. This

offers the potential for combining treatment and diagnosis

(theranostics). Successful incorporation into these

nanoformulations has been demonstrated for classical

chemotherapeutic drugs that are mostly hydrophobic, small

interfering RNA, biological therapeutics and specific

nanoparticles, such as superparamagnetic nanoparticles.

Liposomes and micelles appear to take advantage of the

enhanced permeability and retention (EPR) effect in solid

tumours to increase accumulation at the target site (passive

targeting). This translates to the clinic, where liposomal drug

formulations are reported to exhibit higher efficacy and less

side effects. Multidrug formulations and combinations with

other treatments, for example, radiation or radiofrequency

ablation, to trigger drug release from the nanocarrier at the

target site, are mostly at the pre-clinical stage. More

complex formulations that incorporate treatment agents

together with targeting (active targeting) and imaging

molecules have also been investigated in in vivo models with

encouraging results.

Address

UCL Centre for Nanotechnolology and Regenerative Medicine, Division

of Surgery and Interventional Science, University College London,

London, UK

Corresponding author: Loizidou, Marilena ([email protected])

Current Opinion in Pharmacology 2012, 12:1–6

This review comes from a themed issue on

Cancer

Edited by Marilena Loizidou

1471-4892/$ – see front matter

Published by Elsevier Ltd.

DOI 10.1016/j.coph.2012.02.011

IntroductionChemotherapy, either alone or in combination with other

modalities, currently remains the commonest cancer treat-

ment. However, its efficacy is unacceptably low, owing to

two major limitations: Firstly the inaccessibility of cancer

tissue that presents a number of barriers to molecule

penetration, ranging from high tissue density to modified

characteristics of the cancer cell membrane [1��]; secondly

Please cite this article in press as: Lopez-Davila V, et al.. Organic nanocarriers for cancer drug de

www.sciencedirect.com

the limitations of the molecule itself in terms of chemical

characteristics, for example, solubility and stability. These

determine pharmacodynamics and kinetics and underlie

efficacy at the site of action but also the severity of side

effects resulting from toxicity at non-target tissues. Simply

put, for a lot of drugs the dose cannot be raised enough to

eradicate disease because of the side effects [2]. Therefore

chemotherapy is often aggressive, but unfortunately

results remain suboptimal.

Novel nanosized drug carriers have been developed in an

attempt to overcome limitations of chemotherapy. As

opposed to the classical definition of the ‘nanoscale’ that

considers systems below 100 nm in size, nanocarriers are

small particles that may reach a few hundred nanometres.

Furthermore, nanocarriers can be broadly divided into

organic and inorganic. The latter are normally much

smaller, contain elements such as gold, cadmium or

selenium, and exhibit specific nanoscale physical proper-

ties. The organic carriers are carbon based (with the

striking exception of fullerenes that are considered inor-

ganic) and are generally characterised by their biocom-

patibility and improved drug loading capacity. In these

nanocarriers, drugs are often trapped or bound within the

matrix. There are four main groups of organic nanocar-

riers; liposomes, micelles, protein-based or peptide-based

nanocarriers, and dendrimers. Dendrimers, tree-like

structures formed by the ramification of subunits around

a core, while promising, are at a much earlier stage of

development than the others. Protein/peptide-based

nanocarriers rely mainly on the conjugation of the thera-

peutic agent to an amorphous structure that is never-

theless amenable to further functionalisation. A number

have shown promising outcomes and reached the clinical

approval stage. Both micelles and liposomes are vesicles

formed by the interaction of amphiphilic molecules,

forming monolayers and bilayers respectively. Owing to

their vesicular structure and amphiphilic components,

micelles and liposomes offer special protection against

degradation and a wide range of possibilities for targeted

functionalisation/combined therapy. This article focuses

on these engineered nanostructures and presents evi-

dence on their efficacy in the clinical and preclinical

settings.

Drug delivery challenges – why use organicvesicular nanocarriers?Vesicular nanocarriers can easily entrap nucleic acids,

hydrophilic and hydrophobic drugs, or even smaller nano-

particles within their aqueous and lipid cores; also their

surface can be readily functionalised to improve pharma-

cokinetic profiles or for cancer targeting (Figure 1).

livery, Curr Opin Pharmacol (2012), doi:10.1016/j.coph.2012.02.011


http://dx.doi.org/10.1016/j.coph.2012.02.011

mailto:[email protected]


http://www.sciencedirect.com/science/journal/14714892

2 Cancer


Figure 1

hydrophobic tails

polar heads

PEG

targeting molecule

hydrophobic drug

RNA/DNA

hydrophilic drug

cholesterol

Current Opinion in Pharmacology

Schematic structures of liposomes (left) and micelles (right). Simple

structures shown above and potential loadings/conjugations below.

PEG, polyethylene glycol; siRNA, short interfering RNA.

For liposomes specifically, the major advantage is that

they can encapsulate both hydrophilic and hydrophobic

molecules, in their core and membrane respectively.

However, liposomes loaded with hydrophobic molecules,

for example, rhodamine, tend to be more unstable than

those loaded with hydrophilic molecules, for example,

fluorescein [3]. Nevertheless, Moribe et al. reported

increased stability of liposomes encapsulating the hydro-

phobic amphotericin B as a result of interactions with poly

ethylene glycol (PEG) and phosphate groups of the

liposome components: suggesting stability can be

improved by choosing the correct constituent molecules

and fabrication parameters [4].

Micelles tend to have a smaller loading capacity than

liposomes. They are natural nanocarriers of hydrophobic

molecules, since they provide a relatively large water-free

environment in their core, while their outer surface is

hydrophilic. Further surface attachment of other mol-

ecules, such as N-methylpyrrolidone that is a powerful

amphiphilic solvent, can help stabilise the system [5].

Micelle formulations of chemotherapeutics, which are

mostly hydrophobic in nature, increase solubility of the

overall product and would circumvent the danger of

emboli resulting from free drug aggregation in vivo [6].

Although micelles of certain size are likely to trigger a

blood clearance mechanism, most of them are small

enough to avoid the accelerated blood clearance

(ABC), which is size-dependent [7]. This however has

been reported on occasion for injected liposomes, either

PEGylated or non-PEGylated, owing to their larger size.



Innovative micellar constructions can increase encapsula-

tion capacity and particle size, and enhance the ability to

cross biological barriers in vivo [8]. Here, quaternary

ammonium palmitoyl glycol chitosan (GCPQ) micelles

encapsulating topical anti-inflammatory prednisolone or

the anaesthetic propofol present a novel conformation in

which micelles combine to form larger aggregates – these

reach sizes up to 200 nm with a large hydrophobic centre

that increases amounts of encapsulated drug by an order

of magnitude. The nanoformulation released the same

levels of prednisolone in the aqueous humour as those

detected when administering a ten-fold concentration of

the free drug. Furthermore, in the case of propofol,

administration of the micellar construct achieved up to

ten-fold ‘sleeping time’ in mice compared to commercial

propofol formulations.

The inherent advantage of organic nanocarriers (and their

degradation products) is their lack of intrinsic toxicity

compared to other carriers, for example, carbon nanotubes

(CNT), which were reported to cause inflammation

coupled with general pulmonary toxicity, regardless of

functionalisation, after intratracheal administration in a

rat model [9].

The ultimate goal is selective accumulation inside the

target cell or tissue. Here the enhanced permeability and

retention (EPR) effect plays a fundamental role. This

property promotes the accumulation of macromolecules

and nanocarriers in solid cancer tumours rather than normal

tissues: owing to the disorganised tumour vasculature that

impedes flow; the abnormally large fenestrations in the

endothelium; and the decreased lymphatic clearance

associated with the majority of tumours [10]. EPR is vari-

able, partlyowing to the wide range in the diameterofvessel

fenestrations [1��]. Resultant preferential accumulation of

nanocarriers inside the tumour mass (also described as

passive targeting) increases concentration of locally available

drug and therefore improves delivery, even when further

drug penetration through the tissue layers (smooth muscle,

stroma) to the cancer parenchyma is difficult. One emerging

experimental approach that facilitates drug penetration is

the combination of nanoparticle-conjugated chemotherapy

with radiotherapy. In an in vivo study of rats inoculated with

various syngeneic prostate carcinomas, animals were trea-

ted with radiation and then injected with different sized

N-(2-hydroxypropyl)-methacrylamide (HPMA) copoly-

mers to determine effect on tissue accumulation. This

resulted in higher amounts detected in cancer tissues in

the radiation treated group [11]. Possible explanations

include the increase in vascular permeability owing to

the secretion of permeabilizing factors (e.g. vascular endo-

thelial growth factor) or endothelial cell apoptosis resulting

from radiation-induced free radical formation.

By carrying the therapeutic agent in their core, vehicular

nanocarriers limit interactions between drugs with the




Organic drug nanocarriers Lopez-Davila, Seifalian and Loizidou 3


hostile environment and minimise toxic effects of drug

action on healthy tissue. Contrary to this, the acidic

conditions within the tumour environment have been

used to disrupt the nanocarriers at the action site. While

blood pH is 7.4, the average pH in tumours is 7.0, with

80% reported at below 7.2. Disruption has been demon-

strated in vitro, where pH-sensitive particles were pre-

pared by adding poly(L-lactide) (PLLA) and PEG to the

formulation; the most pH-sensitive micelles (with higher

concentrations of PLLA/PEG) were the most cytotoxic to

MCF-7 breast cancer cells. Furthermore, conjugation

with folate and a fusogenic peptide increased internalis-

ation and enhanced efficacy [12].

The main drawback of nanocarriers is size-induced anti-

genicity that leads to increased reticuloendothelial sys-

tem clearance. However, surface functionalisation, for

example, addition of hydrophilic molecules like PEG,

can minimise interactions with serum proteins that med-

iate opsonisation (cloud effect) and subsequent targeting

of the drug for elimination. Poly(lactic-co-glycolic acid)

(PLGA) nanocarriers injected into mice demonstrated

significant differences between PEGylated and non-

PEGylated particle clearance: 66% of the non-PEGylated

nanocarriers were cleared two hours after administration

while PEGylated nanocarriers underwent <30% clear-

ance even after five hours [13].

Current clinical applications of liposomes andmicellesLiposomal formulations form the largest group of clinically

approved anticancer drug nanocarriers (Table 1). The best

known example is Doxil (Caelyx), which is the PEG-

coated liposomal formulation of the classical anthracycline

chemotherapeutic doxorubicin. Doxil proved successful in

clinical trials for several cancer types and showed through-

out significant improvements in pharmacokinetic profiles,

tumour accumulation and reduction of toxicity when com-

pared to free doxorubicin. This has been demonstrated in a

phase III trial of patients with breast cancer, where Doxil

had equivalent efficacy to free drug. Furthermore, it

exhibited significant reduction of the more serious toxi-

cities, that is, cardiotoxicity and neutropenia, but had more

skin and mucosal-related side effects [14]. Similar results

were reported from a phase III study in taxane-refractory


Table 1

Approved vesicular nanoformulations: *Non-PEGylated; **In phase II c***Only approved in Korea

Name Nanoformulation

Doxil Liposomal

Myocet Liposomal*

DaunoXome Liposomal

Depocyt Liposomal

Genexol-PM Micellar


breast cancer that compared efficacy and toxicity of PEG-

liposomal doxorubicin versus vinorelbine or mitomycin C

plus vinblastine. PEG-liposomal doxorubicin showed 24%

and 10% less decrease in leucocyte numbers than the other

two treatments, respectively [15]. In addition to clinical

trials, a number of other reports have highlighted the

potential efficacy of Doxil in combination with several

drugs like taxane, vinorelbine or cisplatin for various can-

cers including ovarian and breast [16].

Amongst micelle formulations, only Genexol-PM that

incorporates paclitaxel and is designed for the treatment

of breast, lung and ovarian cancers has been approved and

only in Korea [1��]. A phase II clinical trial of Genexol-

PM with a total of 41 women with metastatic breast

cancer showed five complete and 19 partial responses

and 13 patients with stable disease, for >6 months [17].

Late phase clinical trials are ongoing in western countries

for further evaluation.

Various micelle constructs are in clinical trials: NC-6004, a

cisplatin-containing micelle, was evaluated in a phase I

clinical trial of patients with a variety of cancers. Of 17

patients, only two presented haematological toxicity. The

most common side effects were nausea, vomiting, anorexia

and fatigue, reported by �40% of patients. However,

except for one case, no cisplatin-related toxicity was

observed; this is very encouraging especially considering

the renal toxicity associated with other cisplatin-formu-

lations and that necessitates extra protective hydration

treatment [18�].

Complex approaches to micelle and liposomeapplicationsAdditional to their capacity for incorporating diverse

agents (e.g. drugs, biologics, siRNA, vaccines [19] or

nanoparticles), liposomes and micelles have the ability

to conjugate cancer targeting molecules (active targeting).

Therefore, these nanocarriers have the potential to deli-

ver simultaneously therapy and diagnostics (theranostics).Below we highlight illustrative examples.

Combining drugs within nanoformulations is one of the

fastest growing areas in the field and some have shown

promise in clinical trials. This is the case for CPX-1, a


linical trials for leukemia and phase I–II for glioblastoma [1��,26];

Drug Cancer

Doxorubicin Breast and ovarian cancer,

Kaposi’s sarcoma

Doxorubicin Breast

Daunorubicin Kaposi’s sarcoma

Citarabine Lymphomatus meningitis**

Paclitaxel Breast, lung and ovarian***



4 Cancer


liposome containing irinotecan and floxuridine, which is

formulated to maintain a synergistic ratio between the

two molecules. CPX-1 had encouraging results in a phase

I clinical trial of advanced colorectal cancer, with 11 out of

15 patients achieving stable disease and two patients

attaining a partial response [20]. Furthermore, an HPMA

polymeric nanocarrier containing both gemcitabine and

doxorubicin achieved greater growth inhibition than the

combination of the two drugs – either free or individually

encapsulated in the polymer – in an in vivo prostate cancer

model [21]. In this case, the system was loaded with

traditional therapeutic agents that share physicochemical

characteristics (two hydrophilic drugs). However, mol-

ecules with different solubility patterns may also be co-

encapsulated. A cationic liposome containing PD0325901

(an inhibitor of the mitogen activated protein kinase MEK)

and siRNA against Mcl1 (whose silencing has been

suggested to sensitise cancer cells to chemotherapeutics)

resulted in inhibition of expression of target proteins in KB

nasopharyngeal carcinoma cells; and significant apoptosis

enhancement and growth inhibition in KB mice xenografts

[22�]. Liposomal formulations have also been combined

with free drugs. Especially interesting are neutral

liposomes that evade the characteristic lung toxicity of

cationic liposomes. A neutral 1,2-dioleoyl-sn-glycero-3-

phosphatidylcholine (DOPC)-based liposome encapsulat-

ing EphA2-directed siRNA in combination with free pacli-

taxel treatment showed superior tumour growth inhibition

in vivo, than the control liposome (with non-specific RNA)

combined with paclitaxel [23].

As described previously, chemotherapeutic-containing

nanocarriers in combination with radiotherapy are

specially promising, since the latter improves per-

meability of the tumour tissue. Davies et al. [24] demon-

strated the effectiveness of liposomal doxorubicin in

human tumour-bearing mice after exposing the tumour

to radiation. Other approaches involving the addition of

permeabilising agents have also been explored, as

reported in [25], where the use of TNFa increased the

accumulation of liposomes in murine melanoma tissues.

Another novel approach is triggered drug delivery, where

drug is released when specific stimuli are applied to the

target site. Despite the difficulties encountered in design-

ing a nanocarrier whose triggered release is realistic and

effective enough, some examples are already in clinical

trials. Thermodox, a temperature-sensitive doxorubicin-

liposome was designed for the treatment of breast and

liver cancers and is currently in Phase III clinical trials

[1��]. The principle relies on breaking apart the liposomes

at the target site by applying radiofrequency that heats

the specific region to �40 8C.

The usefulness of passively or actively targeted nanocar-

riers remains controversial. Only passively targeted nano-

carriers have been clinically approved to date; partly



because the targeting molecules conjugated to nanocar-

riers tend to alter pharmacokinetic characteristics. How-

ever, it has been demonstrated widely in vitro that

actively targeted nanocarriers are better internalised at

the cell surface, with subsequent increased cytotoxicity of

cancer cells [26,27]. Furthermore, increase in specificity

for cancer tissues avoids the need for higher drug con-

centrations and is associated with reduced toxicity in

normal tissue [1��]. As proof of principle, non-nanocar-

rier-based targeted therapies, for example, Zevalin (B-cell

Non-Hodgkins lymphoma), Bexxar (follicular lymphoma)

or Ontak (cutaneous T-cell lymphoma), which target

overexpressed membrane receptors, have clinical

approval [1��,28]. An example of a targeted nanotreat-

ment in the early phases of clinical trials, is the doxor-

ubicin-containing liposome MCC465 conjugated to the

F(ab0)2 fragment of the human antibody GAH directed

against stomach cancer cells. Treatment resulted in the

disease stabilising in 10 out of the 18 patients and the

pharmacokinetic profile was similar to Doxil [29].

Increasingly complex nanocarriers that are potentially

suitable for theranostics are being reported. For example,

the co-encapsulation of superparamagnetic iron oxide

(SPIO) nanoparticles and doxorubicin within a micellar

nanocarrier functionalised with cyclo-Arg-Gly-Asp

(cRGD)-conjugated PEG aims at: active targeting of

the cancer cells by RGD, treatment by doxorubicin;

and magnetic resonance imaging based on SPIOs. SLK

cells (Kaposi’s sarcoma) exposed to micelles with higher

quantities of cRGD exhibited larger growth inhibition,

consistent with successful cRGD targeting of surface

integrins. In addition, owing to the SPIO nanoparticles

contained in the micelles, an increase in the magnetic

resonance signal inside the cells was observed when

increasing the micelle doses [30]. This approach also

allows monitoring drug delivery efficiency and delinea-

tion of pharmacokinetic profiles [31��]. HER-2 targeted

immunoliposomes loaded with doxorubicin and attached

to quantum dots (QD) were tested both in vitro and invivo. Toxicity was demonstrated in HER-2 overexpres-

sing breast cancer cells and this was not affected by QD

conjugation. Furthermore, experiments in mice showed

increased fluorescence accumulation of these liposomes

inside xenografts, compared to free QD accumulation.

Clearance was also faster for free QDs, suggesting suc-

cessful active targeting by the functionalised liposomes.

ConclusionLiposomes and micelles are especially attractive drug

nanocarriers, since their structure and relatively large size

offer protection to the incorporated drugs and allow

considerable loading. Their organic nature minimises

intrinsic toxicity, unlike other metal-containing nanocar-

riers; and also makes them suitable for exploiting the EPR

tumour effect, thus increasing passive targeting. Issues

related to the lack of stability and systemic clearance are




Organic drug nanocarriers Lopez-Davila, Seifalian and Loizidou 5


being addressed through several surface modification and

fabrication methods. A number are now in clinical trials,

with the more conservative formulations (such as liposo-

mal doxorubicin) used routinely in the clinical treatment

of various solid tumours.

Combinations with other therapies, particularly radiother-

apy, are promising. Pre-clinical reports demonstrate an

increase in passive targeting that is probably facilitated

via the radiation-induced production of endothelial per-

meabilising factors.

These vehicular organic nanocarriers are also suitable for

active targeting. They offer the potential for surface

functionalisation with targeting molecules and incorpora-

tion of both therapeutic agents and imaging agents of very

different physicochemical characteristics in a single

carrier, for theranostics.

References and recommended readingPapers of particular interest, published within the period of review,have been highlighted as:

� of special interest�� of outstanding interest

1.��

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An outstanding review that not only effectively summarises the currentstate of nanocarriers in clinical studies, but also offers an excellent criticalviewpoint on important limitations in the field.

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18.�

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An exciting translational application of micellar cisplatin that demon-strates significant lower toxicity to patients in a phase I trial.

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A ground-breaking application of complex liposomes delivering siRNAtogether with a ‘small molecule’ for therapeutics, in an in vivo cancermodel.

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http://dx.doi.org/10.1016/j.jconrel.2011.09.063


6 Cancer


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30. Nasongkla N, Bey E, Ren J, Ai H, Khemtong C, Guthi JS, Chin SF,Sherry AD, Boothman DA, Gao J: Multifunctional polymericmicelles as cancer-targeted, MRI-ultrasensitive drug deliverysystems. Nano Lett 2006, 6:2427-2430.

31.��

Weng KC, Noble CO, Papahadjopoulos-Sternberg B,Chen FF, Drummond DC, Kirpotin DB, Wang D, Hom YK,Hann B, Park JW: Targeted tumor cell internalization andimaging of multifunctional quantum dot-conjugatedimmunoliposomes in vitro and in vivo. Nanoletters 2008,8:2851-2857.

A comprehensive study that demonstrates the great potential of lipo-somes for multifunctionality, by designing a liposome carrying a thera-peutic agent, quantum dots, and a targeting molecule with encouragingresults both in vitro and in vivo.




organic nanocarriers for cancer drug delivery

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