Review
Feature Review
Colloidal systems for drug delivery:
from design to therapy
Mariana Beija1, Robert Salvayre2, Nancy Lauth-de Viguerie3 and Jean-Daniel Marty3
1
Australian Centre For NanoMedicine (ACN), School of Chemical Engineering, The University of New South Wales, Sydney,
NSW 2052, Australia
2
INSERM UMR 1048, Laboratoire de Biochimie IV, Hôpital de Rangueil 1, Avenue du Professeur Jean Poulhès,
TSA 50032–31059, Toulouse Cedex 9, France
3
Laboratoire des IMRCP, UMR CNRS 5623, Université de Toulouse, 118 Route de Narbonne, 31062 Toulouse Cedex 9, France
Nanomedicine, or medicine using nanometric devices,
has emerged in the past decade as an exhilarating domain
that can help to solve a number of problems linked to
unsatisfactory therapeutic responses of so-called ‘old
drugs’. This dissatisfaction stems from inadequate bio-
distribution after a drug’s application, which leads to a
limited therapeutic response but also to numerous side
effects to healthy organs. The biodistribution of drugs
encapsulated in a nanoobject that will act as a vector can
be modified to tune its therapeutic efficacy. This review
provides a general overview of existing colloidal nano-
vectors: liposomes, polymeric micelles, polymeric vesi-
cles, polymeric nanoparticles (NPs), and dendrimers. We
describe their characteristics, advantages and drawbacks,
and discuss their use in the treatment of various diseases.
Nanocarriers: general considerations
During the last century, progress in medicine has been
associated with the development of new drugs, which has
led to improved therapeutics. However, in some instances
such as cancer, the results are not proportionally linked to
the amount of research that has been performed. This is
often due to impaired pharmacokinetics or pharmacody-
namics leading to elimination of the drug or severe side
effects [1–4]. To overcome this problem, several approaches
have been tried aiming to protect the drug, to slow down its
degradation, to optimize its targeting, to limit its accumu-
lation in healthy organs, to reduce its potential toxicity,
and/or to control its release either through natural pro-
cesses or by external stimuli.
Thanks to the tremendous progress in organic synthesis
and physical chemistry, it is now possible to design and
elaborate colloidal systems made of small molecules, poly-
mers, or coated NPs. Their size, typically between 10 nm
and 1 mm, renders their biodistribution completely different
from that of small molecules [5]. Therefore, by encapsulating
a drug within a colloidal system (that will act as nanovector
or nanocarrier), the biodistribution of the drug will be
determined by that of the nanocarrier, improving its thera-
peutic effect. Owing to the difficulties encountered in their
administration, several generations of nanovectors have
Corresponding authors: Beija, M. (m.beija@unsw.edu.au);
Marty, J-D. (marty@chimie.ups-tlse.fr).
Keywords: drug delivery; soft matter; oncology; nanovectors; central nervous system.
0167-7799/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tibtech.2012.04.008 Trends in Biotechnology, September 2012, Vol. 30, No. 9
been developed [3]. The early ones, called first generation,
are constituted of simple colloids, such as regular liposomes
or polymeric NPs and lead to passive delivery. Their sur-
faces can be modified in order to avoid their recognition and
clearance by the mononuclear phagocyte system. According
to another classification, this first generation can be divided
in two classes: one of carriers without surface modification
and another of ‘stealth’ carriers with surfaces with antifoul-
ing properties that enable longer blood circulation times [6].
The second generation nanocarriers allow active targeting
using specific ligand–receptor interactions. Finally, the
third generation group aims at passing all biological
barriers before targeting (metabolic clearance, osmotic pres-
sure gradients, hemodynamics, etc.) and at organizing time
sequences of different functions on the vector.
After 30 years of development of colloidal drug nano-
vectors [1,3,7,8], a few systems are reaching the market
and many are currently in preclinical or clinical trials,
creating the new field of nanopharmaceutics that will
complement nanomedicine. The number of scientific
papers dealing with drug delivery by nanovectors and
the number of reviews on this subject continues to grow,
showing the importance of this new field. The aim of this
review is to present the different existing systems, includ-
ing their advantages and drawbacks, and to link them with
the different diseases that can benefit from such colloidal
drug formulation. This review is primarily focused on soft
materials, meaning that drug delivery from hard NPs such
as silica NPs or carbon nanotubes are not presented here,
due to the vastness of this subject. However, a glance on the
therapeutic applications of organic–inorganic nanohybrids
is included (Box 1) to offer the readership with a broader
view of the recent nanopharmaceutics field. In this context,
the NP combines a structural role with a therapeutic one,
whereas the organic coating interferes with the biodistri-
bution. Furthermore, colloidal formulation has been used
for a very long time for topical application and will not be
described here. Finally, gene therapy is also omitted, owing
to the very large domain linked to this. Therefore, the
reader is oriented to recent reviews for further information
on these subjects [9–12]. We present the existing developed
systems that are already in or are coming close to clinical
application. We also point out several issues that need to be
addressed for optimizing existing nanocarriers.
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Box 1. Organic–inorganic nanohybrids for therapy
Another appealing class of colloids to be used in nanopharmaceutics
is organic–inorganic NPs. Recently, their great potential for not only
imaging and diagnosis but also for clinical therapeutics has started to
flourish. Inorganic NPs of different chemical natures can not only be
used as nanocarriers [84,85] (in a similar way as soft NPs), but they
can also play the role of active therapeutic agent [86].
Cancer therapy via hyperthermia relies on the fact that cell death is
induced when the temperature rises above 428C. The use of metallic
NPs provides a noninvasive and more controlled way to specifically
heat the cancer cells using non-ionizing electromagnetic radiation
that is converted into heat [87]. Gold NPs with an appropriate shape
can be excited by a laser in the near infrared (NIR) region to induce
this light-to-heat conversion. For example, poly(styrenesulfonate)-
coated Au nanorods conjugated to monoclonal antibody were
efficient in the photothermal treatment of oral epithelial malignancies
(Figure I) [88]. Also, AuroShell, a PEGylated NP consisting of a silica
core (80–150 nm) and a gold shell (10–20 nm), was developed by
HaCat
nonmalignant cells
160 mW
120 mW
80 mW
40 mW
Figure I. Selective photothermal therapy of cancer cells with Au nanorods conjugated to monoclonal antibody. Whereas the malignant cells were injured by laser
impact (shown as a circle), normal cells were only injured above 120 mW (15 W/cm2). Adapted from [88].
486
Trends in Biotechnology September 2012, Vol. 30, No. 9
Nanospectra Biosciences (http://www.nanospectra.com) for the treat-
ment of head and neck tumors and is currently under clinical trial.
Alternatively, iron oxide NPs can generate heat when exposed to
alternating magnetic field. Commercially-available dextran-coated
IONPs produced hyperthermia when sufficiently concentrated [89],
and aminosilanized IONPS (NanoTherm1) are now in the final phase
of clinical trials. In radiotherapy, hafnium oxide NPs were used as
radiosensitizers by the generation of free radicals by X-ray
excitation [90], and radioactive gum arabic glycoprotein-modified
198
AuNPs could accumulate in tumoral tissue, leading to 80%
reduction of tumor when compared with a control [91]. Various
others NPs also demonstrated efficiency in cancer treatment via
different mechanisms [92].
In preventive medicine, CeO2 NPs can act as radical scavengers,
protecting tissues from radiation-induced damage [93]. CaP NPs are
efficient vaccine adjuvants, enhancing vaccine immune responses to
viral antigens [93].
HSC HOC
malignant cells malignant cells
100 µm
TRENDS in Biotechnology
Review
Soft materials for drug delivery
General considerations
When designing a vector for a specific application, several
characteristics and functionalities will be conferred not
only from the nature of the molecules that compose the
vector but also from its size and morphology. In addition,
for each administration method, different biological bar-
riers have to be crossed, each having their own character-
istics, which must be considered [13,14].
A first requirement is that the materials that compose
the vector should be biocompatible and ideally biodegrad-
able (or at least easily cleared off the organism after drug
delivery). Thus, mainly two families of molecules have
been used for the formation of vectors: (i) lipid-based
compounds like dipalmitoyl-phosphatidylcholine (DPPC),
and (ii) polymers including natural polymers such as
proteins and polysaccharides to biocompatible synthetic
polymers such as poly(e-caprolactone), poly(ethylene
oxide), poly(alkyl cyanoacrylate), among others. Starting
from those building blocks, appropriate vectors can be
obtained.
Particle size is also a key factor in the biological out-
comes and in the internalization process of particles. The
upper limit strongly depends on the target. Whereas there
seems to be no size limit up to 5 mm to gain cellular
internalization, sizes below 400 nm are more suitable for
accumulation in most tumors depending on cut-off size of
vascular pores. The lower limit is determined by the siev-
ing coefficients for the glomerular capillary wall in the
kidney to avoid a rapid renal filtration (that clears particles
Branched polymers
Micelles
Layer-by-layer assemblies
1 nm 10 nm
Figure 1. The different families of colloidal systems for drug delivery.
Trends in Biotechnology September 2012, Vol. 30, No. 9
below 10 nm). Finally, small particles, ranging between 10
and 100 nm in size, avoid being cleared by the reticulo-
endothelial system or being mechanically filtered through
the spleen and liver (that captures particles over 200 nm)
and are small enough to efficiently accumulate in tumors
through the enhanced permeability and retention effect
(EPR effect) [15]. This effect is based on a pathophysiologi-
cal vascular feature of solid tumor tissues, which often
exhibit increased vascular permeability, associated with
impaired lymphatic drainage that impedes the efficient
clearance of macromolecules accumulated in solid tumor
tissues.
Surface charge and surface chemistry are other key
parameters. Positively-charged NPs may interact electro-
statically with negatively-charged components of the outer
leaflet of the plasma membrane (e.g., proteoglycans) and
are subsequently internalized by cells, possibly through
clathrin-mediated endocytosis [16]. Negatively-charged
NPs and liposomes may be internalized through the caveo-
lae-mediated endocytotic pathway and could be useful to
target monocyte/macrophages [17]. By contrast, neutral
poly(ethylene glycol) (PEG)-ylated particles are ideal to
avoid macrophage uptake [18]. Introducing targeting
ligands can also potentially enhance uptake by cancer cells.
Methods of preparation and resulting morphology
Keeping these considerations in mind, different families of
objects can be obtained whose size and morphology
depends strongly on the preparation method used (Table
1 and Figure 1) [1].
Polymersomes, nanoparticles
Nanocapsules
Liposomes
100 nm 1μm
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Table 1. Families of vectors from soft materials: method of preparation, main advantages, and drawbacks
Nanocarrier Preparation methods Advantages Drawbacks
Liposomes Film casting and rehydration of this film Can encapsulate both hydrophobic Fair stability
+ extrusion and hydrophilic drugs Poor batch-to-batch reproducibility
Lower toxicity Difficulties in sterilization
Functionalization of the surface Low drug loading
is possible
Polymersomes Solvent switch method Can encapsulate both hydrophobic
Film casting and rehydration of the film and hydrophilic drugs
Lower toxicity
Possibly stimuli-responsive
May help in MDR
Polymeric micelles Direct organization or controlled Prolonged blood circulation time Not good for hydrophilic drugs
aggregation in a solvent Adequate size for EPR Obtained by self-assembly,
Efficient for hydrophobic drugs mostly spherical shape
Lower toxicity
Possibly stimuli-responsive
May help for MDR
Simple preparation
Functionalization of the surface
is possible
Layer-by-Layer systems LbL Can be applied to a huge variety Ionic nature of the vector
of surfaces (tissue engineering)
Solid lipid NPs Freezing of an emulsion of lipids Most established Poor stability
heated above melting point of lipids Biocompatible, biodegradable Poor batch to batch reproducibility
Flexibility of size and surface Sterilization difficulties
manipulation Low drug loading
Higher efficacy, lower toxicity vs Release of drug not always
non-liposomal formulation well controlled
Possibly stimuli-responsive Presence of possibly toxic
co-solvents
Polymer NPs/capsules NPs: Simplicity Colloidal stability not always good
polymerization of monomers by May help for MDR Possible residual chemicals
emulsion process H/E Shape, size, and mechanical from process
or starting from existing polymers, properties can be tuned
nanoprecipitation, gelification Controlled release is possible
or emulsion process

Nanocapsules:
Interfacial polymerization of monomers
or phase inversion process with
emulsions of polymers
Dendrimers Convergent or divergent synthesis Carrier solidity Tedious preparation
Highly functionalized surface Some are toxic
Prolonged pharmacodynamic profile

The first family involves the self-assembly of lipids or
polymers to obtain organized or aggregated systems: lipo-
somes are obtained from lipid-based compounds [19],
whereas polymer micelles [20] and polymersomes [20]
are obtained from the use of block copolymers, where each
block has a specific role that can be structural (to ensure
vector formation) or functional (drug encapsulation, spe-
cific interaction with outside medium, stimulus responsive,
etc.). Polymersomes and liposomes present some strong
similarities in their overall architecture. Both are nano- to
micrometer-sized capsules with a bilayered membrane
enclosing an aqueous compartment and able to encapsu-
late hydrophilic and hydrophobic drugs. Nevertheless,
because polymersomes are composed of block copolymers
instead of small molecules, they present a less permeable
and less fluid membrane, higher chemical stability, and
their architecture is more tunable than that of liposomes
(Figure 2). Amphiphilic block copolymers spontaneously
aggregate into polymeric micelles with sizes that can be
easily controlled within the diameter range of 20–100 nm,
which provides obvious benefits over liposomes. Their
488
hydrophobic inner core allows encapsulation of hydropho-
bic drugs by chemical conjugation or physical entrapment,
whereas the hydrophilic shell acts as a stabilizing/inter-
acting corona and can be designed to be biocompatible.
Compared with previous systems, they have a simple
preparation and efficient drug loading [8].
Another system is based on thin film deposition around
templates of different shapes and sizes by a Layer-by-
Layer (LbL) technique, i.e., by depositing alternating
layers of oppositely charged materials with wash steps
in between [21]. Interestingly, a chosen drug can be solu-
bilized in one of the layers during thin film formation. Drug
delivery kinetics can be controlled either by adjusting the
number or nature of layers [22].
The third family of vectors consists of spherical solid
NPs made of lipids (solid lipid NPs, SLN) or polymers
(nanospheres) [23]. They are mainly prepared through
the use of emulsions or precipitation processes. With some
synthetic procedures, the formation of hollow structures,
named nanocapsules, is achievable. Their size is generally
between 10 and 1000 nm and depends greatly on the
 Review Trends in Biotechnology September 2012, Vol. 30, No. 9

(a)
Drug-loaded
PEG-PLA
polymersome
10 nm

DOX ppt. 20 nm
(c)
Saline or empty
polymersome
(b) 100 1.0
Porated polymersomes in vitro (%)

Tumor area (cm2)

37ºC 1.0
80

Relative tumor size

pH 5.5 Free drug
37ºC 0.8

60 pH 7.4
0.5

0 1 2 3 4 5
40 0.6
Time (days)

20 4ºC Polymersome-loaded
pH 7.4 0.4

0
0 20 40 60 80 1 month 0 1 2 3 4 5
Polymersome incubation time in vitro (h) Days after tail vein injection
TRENDS in Biotechnology

Figure 2. Drug loading, release, and antitumor activity of degradable polymersomes. (a) Cryo-transmission electron microscopy (TEM) image of doxorubicin (DOX)- and
taxoter (TAX)-loaded nanopolymersomes. DOX permeates and precipitates as an aggregate (ppt., circumscribed) within the poly(ethylene glycol)-poly(lactic acid)
(PEG-PLA)-based vesicles, whereas TAX intercalates into the 10-nm thick hydrophobic core visible with fluorescent-TAX. (b) Degradable giant vesicles visibly porate and
release encapsulants in isotonic phosphate-buffered saline (PBS), pH 7.4 at 378C and even faster in isotonic 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH
5.5 at 378C; but the vesicles are stable in PBS pH 7.4 at 48C. (c) Solid tumors shrink after a single injection in the tail vein of (DOX + TAX)-loaded polymersomes (red), free
drug (blue), or empty polymersome or saline control (adapted from [37]).

preparation method. Concerning their use as vectors, their women (Reuters, http://www.reuters.com/article/health-
solid nature confers great stability and provides controlled News/idUSN1633064920071217). Since the discovery of
drug release. Drug delivery generally occurs either via a chemotherapy, a massive research effort has been devel-
diffusion process through the solid NPs or by matrix oped, but the impact on patient survival remains modest
degradation. Kinetics can be adjusted by the careful choice [25]. This is mainly due to (i) the lack of selectivity of
of polymer or polymer blends used to form the vector. anticancer drugs that are often toxic to non-cancer cells,
Surface functionalization of those nanospheres can be and (ii) the high ratio of cancer cell mutation, which protects
easily made and is often necessary to improve their phar- them against anticancer drugs.
macokinetics properties. This poor therapeutic index implies the use of high
Lastly, dendrimers or hyperbranched polymers are doses, leading in turn to severe side effects including bone
macromolecules characterized by repeated branching marrow suppression, cardiac and kidney toxicity, hair loss,
around a central core and synthesized via divergent or mucositis, due to a nonspecific biodistribution of the drug
convergent synthesis. The level of repetition defines in the body. In this context, the challenge of nanopharma-
the so-called generation of the dendrimers. High gener- ceutics is to decrease the side effects by specifically
ation dendrimers resemble spheres with many cavities delivering the drug into tumoral cells. Several reviews
that may contain pharmacological agents [1]. They on this particular subject have recently been published
present multiple functional groups on their surface, [2,4,6,9,26,27], thus our goal herein is to strictly focus on
which can be easily tuned to control their delivery the latest progress and remaining challenges.
properties [24]. In current chemotherapeutic treatments, a large num-
ber of anticancer drugs are employed. However, a few are
Application to oncology more particularly studied for their formulation in nanoas-
General point on chemotherapy semblies [2]. The most common ones are (i) paclitaxel used
Cancer affects a large part of the world population and is one in ovarian, breast, and lung cancers and Kaposi sarcoma;
of the first causes of mortality in developed countries. (ii) cisplatin indicated for sarcomas, carcinomas, lympho-
According to the estimations of the World Health Organiza- mas, and germ cell tumors; (iii) doxorubicin prescribed for
tion, approximately 12.3 million persons developed some the treatment of ovarian, bladder, and lung cancers; and
type of cancer during 2007 and 7.6 million persons died, (iv) camptothecin for advanced colorectal carcinoma and
primarily of lung cancer in men, and of breast cancer in ovarian cancers.
489
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Review
Table 2. Colloidal systems in development or on the market for oncology
Drug Product Company Formulation Administration Application Status Refs
mode a
Paclitaxel Abraxane Abraxis Bioscience NPs i.v. Head and neck, lung, ovarian, On the market [74,75]
prostate, colon, and metastatic
breast cancer
Genexol-PM Samyang Pharmaceuticals Polymeric micelles i.v. Breast and lung cancer On the market, [76]
USA phase II
NK105 Kataoka’s team Polymeric micelles i.v. Pancreatic, bile duct, gastric, Phase I [20,27,77,78]
colon cancer
Doxorubicin Doxil/Caelyx Janssen Products Liposomes i.v. Metastatic breast cancer, ovarian, On the market [1,20,76,79]
Kaposi’s sarcoma
Myocet Cephalon Liposomes i.v. Metastatic breast cancer On the market
Livatag Bioalliance NPs i.v. Hepatocellular carcinoma Phase II
NK911 Kataoka’s team Polymeric micelles i.v. Solid tumors Phase I [20]
SP1049C Supratek pharma Polymersomes i.v. Upper GI cancer Phase II [80]
Thermodox Celsion Liposomes i.v. Carcinoma, hepatocellular, and Phase I to market [81] b
recurrent chest wall breast cancer depending on
application
Cisplatin NC-6004 Kataoka’s team Polymeric micelles i.v. Colorectal, NSCLC, esophageal, Phase I [20,27,78,82,83]
pancreatic, melanoma,
mesothelioma, renal cell, and
hepatocellular cancer

Trends in Biotechnology September 2012, Vol. 30, No. 9

SLIT cisplatin Transave, Inc. Liposome Aerosol Lung cancer, pulmonary metastases Phase I/II [2] c
Camptothecin NK-012 (encapsulation Kataoka’s team Polymeric micelles i.v. Colon cancer, resistant tumors Phase I [27,78]
of a camptothecin
derivative)
Daunorubicin Daunoxome NeXstar Pharmaceutica Liposome i.v. Kaposi sarcoma On the market [1]
Annamycin L-Annamycin Callisto Pharmaceuticals Liposomes i.v. Leukemia Phase I/II [2]
Docetaxel Docetaxel-PNP Samyang NPs i.v. Advanced solid malignancies Phase I [2]
Irinotecan NL CPT-11 University of California Liposomes i.v. Recurrent high-grade gliomas Phase I [2]
a
Abbreviations: i.v., intravenous; NSCLC, non-small cell lung cancer.
b
See also: http://www.celsion.com/products.cfm.
c
See also: http://www.prnewswire.com/news-releases/transave-inc-reports-promising-data-from-a-phase-iii-trial-of-slittm-cisplatin-in-patients-with-osteosarcoma-metastatic-to-the-lung-57764302.html.
Review
Development of nanopharmaceuticals for oncology
A powerful approach for changing the biodistribution of
anticancer drugs through the use of nano-objects takes
advantage of the EPR effect. Indeed, blood vessels close to
solid tumors are known to exhibit leaky junctions, which
can lead to extravasation of NPs from blood flow. Owing to
a poor lymphatic drainage in tumors, NPs are preferably
concentrated on neoplastic tissues rather than in normal
tissues, increasing the chance of a specific delivery. How-
ever, this requires a long blood circulation of the NPs
without detection by the mononuclear phagocyte system,
which is achievable by an adequate choice of antifouling
carrier.
In addition, when designing nanocarriers, it is essential
to ensure that the drug is not released too early. Therefore,
the affinity between the drug and the carrier must be
enhanced [20]. For instance, the same carrier will not
release hydrophobic paclitaxel and the more hydrophilic
doxorubicin in the same manner, owing to different affini-
ties. Table 2 presents the colloidal formulations that are
currently either on the market or under development. Most
applications are linked to recurrent or metastatic cancers
for which regular chemotherapy has been found to be
ineffective. For all cases, the anticancer efficiency of the
drug is either equal or higher compared to the free drug.
However, their advantages lie on the lesser side effects. For
example, Doxil exhibits lesser cardiotoxicity, alopecia, and
vesicant effect. Nevertheless, a new toxicity profile can
appear. In the case of Doxil, mucositis and palmar-plantar
erythema were observed, which were absent with the free
drug. In the same manner, NC-6004 led to minimal neph-
rotoxicity and no significant myelosuppression, but a
higher rate of hypersensitivity was observed.
All these formulations use passive targeting but
improve the balance between therapeutic efficiency and
side effects. To further enhance the treatments, some
points need to be addressed. For example, on these sys-
tems, the mechanism of action at the cellular level is not
always well understood and can be different between the
nanocarriers, the target cancers, and the drugs. Some
drugs, such as Doxil, are reported to be delivered in the
extracellular matrix of the tumors, whereas others seem to
be delivered within the cancer cells after endocytosis [28].
Improvement of anticancer drug nanocarriers
Therefore, to improve the therapeutic effect of these new
formulations, a more precise control of the delivery must be
attained. For this, three strategies are being developed:
active targeting, stimuli-responsive systems, and multi-
stage nanovectors.
Active targeting requires the design of nanocarriers
exhibiting a special ligand at their surface that is supposed
to be specifically recognized by a receptor on the cancer cell
membranes. However, this elegant strategy is very difficult
to fulfill, owing to the lack of specific receptors for cancer
cells. Indeed, several systems have been already studied,
such as folic acid receptor, epidermal growth factor, or
metal receptors [26,29]. Even if these are overexpressed
on cancer cells, they also exist on healthy cells. Moreover,
the synthesis of such a nanocarrier is far from obvious. This
complexity explains the discrepancy between the number
Trends in Biotechnology September 2012, Vol. 30, No. 9
of fundamental studies on active targeting and the number
of systems in preclinical or clinical stages. In fact, only a
few preclinical trials exist using so-called immunolipo-
somes (Mebiopharm, http://www.mebiopharm.com/en-
glish/pro.html; [30]). However, active targeting is crucial
in some cases, such as transport across specific barriers
like the blood–brain barrier (BBB) [31] or to reach tissues
not subjected to the EPR effect [13]. In another interesting
case, a drug that partitioned in erythrocytes was protected
and its therapeutic index improved by an active targeting
using transferrin-PEG-liposomes [32]. Another attractive
strategy is to develop a nanocarrier with a shell that acts by
itself as an active ligand towards cancer cells. This is the
case for hyaluronan, which can bind to CD44 glycoproteins
[33].
The development of nanocarriers that would deliver
their cargo on demand has also been explored in order
to improve their specificity. Chemical (pH, concentrations
of electrolytes, metabolites, or redox reactants) or physical
(temperature, magnetic field, ultrasound, or light) [34,35]
stimuli have been investigated. For chemical stimuli, the
principle is that the stimulus should change the nature of
the nanocarrier from an amphiphilic molecule to a hydro-
philic one, disrupting the vector and releasing the drug.
Very often, pH-responsive systems are used, exploiting the
fact that tumors exhibit a slightly lower pH compared with
regular tissues. Therefore, if the nanocarrier consists of a
polymer with basic groups, these can become protonated in
tumor tissues, leading to the breakdown of the nanocarrier
and release of its payload uniquely in diseased cells [36].
Acidic hydrolysis of a degradable block is an alternative
approach for the pH-induced release of drugs [37]
(Figure 2). For physical stimuli, the aim is either to release
the drug under the stimulus or to add a stress to the cancer
cell to improve the treatment efficacy. This is typically the
case for temperature-sensitive systems. Thermodox is the
only commercial example of such a system. This consists of
temperature-responsive liposomes that first accumulate in
the tumor tissues owing to the EPR effect; then, after
inducing a temperature increase, permeability of the en-
dothelial cells is enhanced, intensifying the EPR effect and
triggering drug release. Some systems benefit from the
change of hydrophilicity of polymers as a function of tem-
perature. This is typically the case of poly(N-isopropyla-
crylamide), which becomes hydrophobic when the
temperature increases. This property can be used either
for the synthesis of the nano-objects or to release the drug.
Interestingly, the cytotoxicity of the vectorized drug may
depend on the temperature [35]. The drug release can also
be triggered by light as long as the tissues to be treated are
accessible. This is the case in epithelial neoplasias, mela-
nomas, carcinomas, head and neck, lung, and even prostate
cancers [34]. Alternatively, light can be used to activate the
drug itself in photodynamic therapy. For this purpose,
liposomes or polymeric micelles [38–42] carrying photo-
sensitizers were developed to improve their solubility and
their therapeutic efficiency.
Further progress in the development of nanovectors
involved the combination of several responsive groups:
temperature/pH [43], pH/light [41], or pH/active targeting
[44]. However, the synthesis of such delivery systems can
491
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be quite difficult, which prompted the development of an
innovative two-component nanosystem that can communi-
cate in vivo [45]. The principle is to have a first nanoparti-
culate component that accumulates in the tumor and can
also be activated by heat producing a local coagulation in
the proximity of the tumor. The second nanoparticulate
component has no particular affinity towards tumors but
exhibits a peptidic ligand on their surface recognizing
transglutaminase Factor XIII, an enzyme involved in
the coagulation cascade. Therefore, the second particles
circulate in the bloodstream until they receive the signal
from the coagulation cascade in the tumor area, enabling
them to deliver their cargo at the desired location.
The preceding examples have highlighted the benefits of
using nanopharmaceuticals for oncology, mainly based on
improved biodistribution. Another essential advantage of
nanopharmaceuticals in this domain involves multidrug
resistance (MDR).
Multiple resistance of cancer to chemotherapeutic drugs
and MDR
Several mechanisms are implicated in the resistance of
cancer to chemotherapeutic drugs. Two main mechanisms
are responsible for reduction of the efficacy of several anti-
cancer drugs: (1) by limiting or impeding the access of drugs
to the tumor, and (2) by rejecting the drugs outside the
cancer cell. In the case of solid tumors, poor vascularization
of the tumor (or of some part of the tumor) can occur; physical
factors impede blood circulation or fluid diffusion in the
tumor, for example, as a result of higher tumor interstitial
pressure (Ptumor>Pblood) and/or physico-chemical properties
of the tumor interstitium (e.g., structure or charge, leading
to low diffusion). In all cases (i.e., solid tumors and leuke-
mias), decreased drug influx, increased drug efflux, altered
apoptotic mechanism, and genetic instability leading to high
mutation rate and selection of resistant clones of cancer cells
may be responsible for drug resistance. MDR is generally
due to increased drug efflux due to overexpression of ATP-
dependent pumps for xenobiotic compounds with broad
substrate specificity and is responsible for decreased drug
accumulation in multidrug-resistant cells. P-glycoprotein
(P-gp, MDR-1, ABCB1 transporter) was the first MDR
protein identified, but other ATP-binding cassette (ABC)
transporters of the MDR/transporter associated with anti-
gen processing (TAP) and multidrug resistant protein
(MRP) subfamilies can induce the MDR phenotype.
Nanomedicine can improve treatment of resistant cells
by evading the efflux. Doxorubicin encapsulated in poly-
cyanoacrylate NPs renders the drug invisible to the drug
efflux system [46]. Another strategy uses NPs made of
squalenoyl drugs. The principle is to transform the drug
into a squalene-bearing molecule, which self-assembles
spontaneously into NPs in aqueous solutions.
An elegant strategy using nonspecific cell penetrating
peptides incorporates TAT peptide in the shell of a poly-
meric micelle [47]. The originality of this system was that
the TAT peptide became exposed only when the pH became
acidic (as in tumor tissues). This enabled the delivery of the
nanopharmaceutical into cancer cells, and the study
showed that adriamycin was efficient in such a context
even in resistant cell lines.
492
Trends in Biotechnology September 2012, Vol. 30, No. 9
In addition to avoiding recognition during cell penetra-
tion, nanopharmaceuticals can also deliver P-glycoprotein
inhibitors together with the regular anticancer drug in a
multi-stage NP system. For example, this was used where
both doxorubicin and a P-glycoprotein inhibitor were en-
capsulated in an NP [48]. Additionally, this system was
light-sensitive, enabling the programmed delivery of the
drugs. This was shown to be active on doxorubicin-resis-
tant MCF7 breast cancer cells by permitting the correct
delivery of the drug up to the nucleus without being
eliminated by the cell.
Drug delivery to the central nervous system (CNS)
Drug delivery to the CNS is a key point in the treatment of
brain disorders such as migraine, epilepsy, psychiatric
disorders, and neurodegenerative diseases including Alz-
heimer’s disease (AD), Parkinson’s disease, and multiple
sclerosis. Nevertheless, similar to treatment of brain
tumors, this remains a challenge because of the existence
of the BBB. The BBB endothelial cells limit the paracel-
lular flux of hydrophilic molecules across the BBB and only
nonionic, lipophilic, and low molecular weight molecules
may passively cross the BBB. In addition, passive diffusion
that generally occurs in other body compartments is hin-
dered in the CNS by effective efflux pump systems. These
efflux pump systems include multiple organic anion car-
riers and especially P-glycoprotein (P-gp), which is some-
times referred to as the MRP. Other essential compounds
such as nutrients, dioxygen, amino acids, hexoses, neuro-
peptides, and proteins need specific carriers or transporter
systems to permeate the brain. Consequently, these mech-
anisms hinder the accumulation of most active compounds
that present low lipophilicity in the CNS, thus decreasing
therapeutic effectiveness [49–51].
Several strategies have been described for brain drug
delivery. Drugs that do not readily penetrate the CNS can be
injected directly into the ventricular or lumbar cerebrospi-
nal fluid (CSF) or can be administered by neurosurgical
disruption of the BBB. However, most of these procedures
are invasive, not easily implemented, and can induce brain
tissue damage. Modification of the lipophilicity of the drug
may lead to a modification of its affinity for a chosen receptor
as well as its biodistribution. In this context, non-invasive
strategies using supramolecular devices to enhance the
solubility and transport of drugs across the BBB are of
special interest to bypass active efflux transporters. Pep-
tides can pass through the BBB with poly(butyl cyanoacry-
late) NPs modified with polysorbate 80 [52]. Here, NP
translocation to the brain is related to affinity for apolipo-
proteins E and A-I and subsequent NP internalization
through lipoprotein receptors. More recently, such a vector
has been investigated for the delivery of rivastigmine and
tacrine, two A-ChE inhibitors approved by the FDA that are
used in AD treatment to maintain cognitive function and
global behavior of the patient. Brain uptake of rivastigmine
[53] and tacrine [54] was significantly increased by a factor of
3.8 and 4.0, respectively, when compared to free drug ad-
ministration after intravenous injection in rats. Rivastig-
mine encapsulated in poly(lactide-co-glycolide) (PLGA) has
also demonstrated a positive effect in amnesic mice [55]. As
described earlier, PEG modification of vectors may enhance
Review
the residence time of those vectors in the blood. PEGylated
nanospheres bioaccumulate three times more than non-
PEGylated ones in the brain, probably through a diffu-
sion/convection process [56]. In the case of AD, PEGylated
phospholipidic micelles interact with Ab peptides [57]. In
order to improve the uptake of these particles in the brain,
they can be attached to specific transporters such as mono-
clonal antibodies and transferrin or other small peptides
[58–60]. Numerous delivery systems for the CNS have taken
advantage of soft materials to design vectors for passive or
active delivery of drugs. Nevertheless, commercially-avail-
able products are scarce to date.
Pulmonary drug delivery
Pulmonary drug delivery is carried out in a variety of
ways – via aerosols, pressurized metered dose inhaler
systems, powders (dry powder inhalers), and solutions
(nebulizers), which may contain nanostructures such as
liposomes, micelles, NPs, and dendrimers [61]. Nanocarrier
systems in pulmonary drug delivery are an attractive con-
cept because particles retained in the lungs provide pro-
longed drug release (reduced dosing frequency), drug
protection, and improved bioavailability over the conven-
tional pulmonary drug delivery systems [62,63]. The de-
crease in particle size leads to an increase in distribution of
drug dose among the alveoli. However, the use of controlled
drug releasing systems in the lung is a controversial issue.
Beyond academic attempts, not many commercial solutions
have emerged to date. The major reason is that the highly
efficient physiological defense system for particulates in
the lung is difficult to overcome. Therapeutically-used
polymeric NPs are composed of biodegradable or biocompat-
ible materials such as alginate, chitosan, gelatin, poly(lactic-
co-glycolic acid), poly(e-caprolactone), or poly(butyl cyano-
acrylate). These structures are intensively studied using
various pulmonary drugs such as antiasthmatic drugs
(budesonide), antituberculosis drugs (isoniazid, pyrazina-
mide, rifampicin, ethionamide, and streptomycin), pulmo-
nary hypertension drugs (sildenafil), chemotherapeutic
antibiotics (ciprofloxacin), and anticancer drugs (doxorubi-
cin). Liposomes are one of the most extensively investigated
nanocarriers for pulmonary drug delivery. The first lipo-
somal product in the market at the end of the 1980s was the
synthetic lung surfactant Alveofact1 (Dr Karl Thomae
GmbH, Biberach, Germany) for pulmonary instillation in
the treatment of respiratory distress syndrome [64].
Table 3. Other colloid systems in development or on the market
Drug Application Name
Amphotericin B Fungal and parasite infections Abelcet
Ambisome
Amphocil
Corticosteroids Anti-inflammatory Nanocort
Estradiol Post-menopausal hot flashes Estrasorb
Insulin Diabetes Basulin
Lysine-based dendrimer Herpes and HIV infections Vivagel
Nystatin Fungal infections Nyotran
Porphyrins Photodynamic therapy Foslip
Visudyne
Propofol Anesthesia Diprivan
Trends in Biotechnology September 2012, Vol. 30, No. 9
Liposomal formulations were delivered in liquid state, or
more recently, in dry powder form. Liposomal drug dry
powder formulations have shown many promising features
for pulmonary drug administration, such as selective locali-
zation of drug within the lung, controlled drug release,
reduced local and systemic toxicities, propellant-free na-
ture, patient compliance, high dose carrying capacity, sta-
bility, and patent protection. The most commonly used
liposomes are composed of lung surfactants and synthetic
lipids. Examples include delivery of anticancer agents for
lung cancer, corticosteroids for asthma, immunosuppres-
sants for avoiding lung transplantation rejection, antifungal
drugs for lung fungal infections, antibiotics for local pulmo-
nary infections and cystic fibrosis, and opioid analgesics for
pain management using liposome technology. Many lipo-
somal formulations have reached the stage of clinical trials
for the treatment of pulmonary distress, cystic fibrosis, lung
fungal infection, and lung cancer.
Other diseases
Although nanopharmaceuticals have been mainly devel-
oped for cancer treatment, they tend to be used for an
increasing number of diseases. This is evident from the
number of formulations based on nanoobjects that are
currently on the market or in clinical trials (Table 3)
corresponding to diseases not yet discussed in this article.
Among other specialties, ophthalmology has benefitted
from nanoformulations [65]. A major reason comes from
the ability of the eye to rapidly eliminate all drugs that are
introduced on its surface. Chitosan/polylactide NPs are
beneficial for delivering rapamycin for immunosuppres-
sion after corneal transplantation [66]. The new formula-
tion enabled the drug to remain on the eye surface for a
long time, therefore enabling a good sustained delivery.
Polyion complex micelles also successfully accumulated in
the damaged areas of the eye in age-related macular
degeneration [20,67]. Photodynamic therapy could then
be used to treat the eye, and a single irradiation led to
60–78% occlusion of the lesions.
Delivery of proteins remains a very difficult task, owing
to their sensitivity to enzymes and physicochemical
parameters such as pH. Nanopharmaceuticals can thus
be useful in such a context because they can provide
protection to the protein. This is the reason why diabetes
has also benefitted from nanoformulations. Although peo-
ple suffering from diabetes learn to treat themselves with
Company Website
Enzon www.enzon.com
Pharmaceuticals
Gilead www.gilead.com
Samaritan Pharmaceuticals www.samaritanpharma.com
Enceladus Pharmaceuticals www.enceladus.nl
Novavax www.novavax.com
Flamel Technologies www.flamel.com
Starpharma www.starpharma.com
Aronex Pharmaceuticals www.aronex-pharm.com
Biolitec www.biolitec.de
Novartis www.novartis.fr
Zeneca Pharmaceuticals www.astrazeneca.fr
493
Review
insulin injections, this is far from ideal because of low
patient compliance and poor mimicry of natural insulin
delivery. Indeed, subcutaneous injection of insulin leads to
its aggregation and its delivery to the peripheral circula-
tion instead of the portal circulation to the liver, which is
the physiological route for healthy people. Therefore, sev-
eral teams have proposed nanoformulations for the oral
delivery of insulin [68–70]. The nanocarrier is designed in
order to protect insulin from degradation in the stomach
but to enable its delivery in the more basic pH of the
intestine. These formulations are active in lowering glu-
cose levels over long periods of several hours, and they
have the advantage of lowering the risk of hyperinsuline-
mia. Inhalation has also been proposed using double emul-
sion and a bioavailability of 44% was reported [71].
Concerning diabetes, a very elegant study was described
by Stupp’s team, the aim of which was to deliver a nanos-
caffold bearing growth factors to help pancreatic islet
transplantation [72]. The scaffold was constituted of self-
assembled peptidic molecules having strong affinities to
vascular endothelial and fibroblast growth factors. This
was implanted on the omentum of diabetic rats and showed
that 80% of the grafts resulted in normal glycemia. This
result is comparable to that obtained with intrahepatic
implantation, but it prevents liver damage.
Finally, two very different studies need to be highlight-
ed. NPs have also been synthesized by a process called
particle replication in nonwetting templates (PRINT)
based on microelectronics techniques [17]. This process
can be used to create NPs of any size and shape, which
cannot be done by self-assembly. Different polymers have
been used, either synthetic (polyesters, hydrogels) or nat-
ural (proteins, dextran). This system is being developed by
Liquidia, and clinical trials are under way for the influenza
virus vaccine.
Another study tackles detoxification after a bee sting.
The system uses molecular imprinted polymers (MIP) that
are able to specifically recognize the molecule for which
they have been synthesized. In this study, MIP NPs could
recognize melittin, the principal component of bee venom
[73]. In vivo tests were carried out on mice. They were first
injected with melittin, followed by MIP injection 20 s later.
The MIPs were able to circulate in the bloodstream suffi-
ciently enough to trap melittin before they were detected
by the mononuclear phagocyte system and led to the liver.
This led to the survival of 50% of the animals, whereas they
all died without MIP injection.
Concluding remarks
Despite its infancy, the nanopharmaceutics field has rap-
idly progressed during the past few decades. At present, it
is possible to find several formulations based on soft col-
loids for the treatment of various diseases on the market,
from fungal infections to cancers.
A plethora of colloidal nanovectors have been reported,
including liposomes, polymersomes, solid NPs, nanocap-
sules, dendrimers, among others. They are primarily made
of phospholipids and/or polymers and, as desired, their
sizes are in the range of 10–1000 nm. Whereas most of
them are successful in changing the biodistribution of the
drug and delivering it into cells, many challenges still
494
Trends in Biotechnology September 2012, Vol. 30, No. 9
remain. Most of the current nanovectors deliver the drug
by simple passive targeting via the EPR effect. However,
active targeting of exclusively diseased cells is still far from
desirable. Indeed, although some markers are overex-
pressed in tumor cells, they also exist in healthy cells.
In addition, it is still difficult to control when and how
the drug is released. The optimization of affinity between
the carrier and the drug with a precise balance is a very
challenging task, which was certainly not fulfilled entirely
until now. In addition, for some diseases, it would be
desirable to deliver more of one type of drug or therapeutic
agent. For instance, the combined delivery of RNA and
organic drugs is still not well developed. In this context,
there is a need for compartmentalization inside of the
nanocarrier, featuring different zones with affinity for each
of the therapeutic agents. This would be particularly im-
portant for cancer therapy because many of today’s che-
motherapeutic regimens involve the use of more than one
drug, even up to five or six drugs.
Finally, the real objective of nanomedicine is to create
multimodal vectors that would act as ‘smart nanodoctors’,
i.e., a single NP gathering the abilities of diagnosis and
therapy. Some multimodal NPs for ‘theragnostics’ have
been reported in the literature. Many of them consist of
inorganic NPs [e.g., iron oxide NPs (IONPs)] that will
ensure the diagnosis (by MRI, in this particular case)
and an organic shell that carries the therapeutic agent.
However, they have not yet reached the clinical trial stage.
In addition, it would be desirable to develop a ‘theragnostic’
NP, in which the therapeutics would be triggered only by a
positive diagnosis of a disease. This is also far from being
accomplished and is definitely the main goal of current
nanomedicine research.
Acknowledgments
The authors thank A.F. Mingotaud, IMRCP, Toulouse for fruitful
discussions.
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