Progress in Solid State Chemistry 34 (2006) 231e235

www.elsevier.com/locate/pssc

Nanotechnologies for drug delivery: Application

to cancer and autoimmune diseases
P. Couvreur*, R. Gref, K. Andrieux, C. Malvy
UMR CNRS 8612, Centre d’Études Pharmaceutiques, University of Paris South,
92296 Chatenay-Malabry, France

Abstract

Polymer-based nanotechnologies are now proposed as an alternative to classical formulations for drug
administration, delivery and targeting. Therapeutic applications of the first generation of nanotechnologies
include the treatment of cancer liver diseases. Avoiding the recognition by the liver is also possible by
developing long circulating polymeric colloidal carriers (‘‘stealth’’ systems) able to avoid the opsonization
process and the recognition by the macrophages. The design of such carriers of second generation is based
on the physico-chemical concept of the ‘‘steric repulsion’’: by grafting polyethyleneglycol chains at the
surface of nanoparticles, the adsorption of steric proteins may be dramatically reduced due to steric hin-
drance. Such an approach allows maintaining the drug carrier for a longer time into the circulation and the
resulting extravasation towards non reticuloendothelial-located cancers may become possible. Now, new
applications and exciting perspectives are proposed for the delivery of drugs to previously non accessible
diseased sanctuaries, like the brain (treatment of glioma and autoimmune diseases of the brain) or the oc-
ular tissues (treatment of the autoimmune uveitis). Finally, the use of nanotechnologies for the delivery of
nucleic acids (oligonucleotides) is also discussed in this review.
Ó 2005 Elsevier Ltd. All rights reserved.

Particulate colloidal carriers (i.e. liposomes or nanospheres or nanocapsules) (Fig. 1) were de-
veloped and are now proposed as a new approach for drug administration and vaccines [1e3].
A better fundamental knowledge of their in vivo interaction with the biological fluids has led to
the tailoring of systems efficient, after intravenous administration, in targeting the macrophages
of the reticuloendothelial system (the Kupffer cells of the liver or the macrophages of the spleen
and of the bone marrow). This specific tissue and cell distribution is due to the opsonization

* Corresponding author. Fax: þ33 1 0146619334.

E-mail address: patrick.couvreur@cep.u-psud.fr (P. Couvreur).

0079-6786/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.progsolidstchem.2005.11.009
232 P. Couvreur et al. / Progress in Solid State Chemistry 34 (2006) 231e235

A
100 nm

B
500 nm

Fig. 1. Electron microscopy after freeze-fracture of (A) nanospheres and (B) nanocapsules.

processes which occur at the surface of these carriers. Therapeutic applications of these systems
include the treatment of liver cancer or the targeting of antibiotics for the treatment of intrama-
crophagic opportunistic infections [4].
On the contrary, avoiding recognition by the liver and the spleen is also possible by devel-
oping long circulating colloidal carriers (‘‘stealth’’ systems) able to avoid the opsonization
process and recognition by the macrophages. The design of such carriers is based on the
 P. Couvreur et al. / Progress in Solid State Chemistry 34 (2006) 231e235 233

Plasmatic
proteins

Fig. 2. Schematic representation showing the steric repulsion of plasma proteins when nanoparticles are decorated with
hydrophilic and flexible polymers (i.e. polyethyleneglycol).

physico-chemical concept of steric repulsion: by grafting polyethyleneglycol or polysaccharidic

[5] chains at the surface of nanoparticles or liposomes, the adsorption of steric proteins may be
dramatically reduced due to steric hindrance (Fig. 2). Such an approach allows the drug carrier
to be maintained for a longer period of time into the blood circulation and the resulting extrav-
asation to non-reticuloendothelial system located cancers may become possible. Tumour blood
vessels present, indeed, several abnormalities in comparison with normal physiological vessels,
often including a relatively high proportion of proliferating endothelial cells, an increased tor-
tuosity, a deficiency in pericytes and an aberrant basement membrane formation. The resulting
enhanced permeability of the tumour vasculature may allow the long circulating carriers to dif-
fuse into the tumoral tissue. This has been shown on an experimental rat model of 9L glioma in
which the long circulating polyethyleneglycol decorated nanoparticles were found to be able to
concentrate [6] (Fig. 3). During neurological diseases, the blood brain barrier (BBB) permeabil-
ity increases dramatically, and it has been hypothesized that drug carrier systems such as poly-
meric nanoparticles could cross the BBB and penetrate into the central nervous system.
PEGylated polyalkylcyanocrylate nanoparticles are one such system and have been shown to
dramatically penetrate the brain during experimental allergic encephalomyelitis (EAE) [7].
In the same way, tamoxifen-loaded onto nanoparticles were found to be able to reduce exper-
imental autoimmune uveitis (EAU) by entering into the ocular tissues and delivering the drug
specifically to the inflammatory cells [8].
If the physico-chemical characteristics of colloidal carriers allow certain tissues or cells to
be targeted, it is also possible using those systems to improve the intracellular penetration of
non-intracellularly diffusible and/or unstable compounds. This is illustrated by the delivery,
with the aid of nanotechnologies, of antisense oligonucleotides against junction oncogenes
which are found in cancers such as certain leukemias, Ewing sarcoma and thyroid papillary car-
cinomas. These tumours are particularly interesting targets since they originate from a chromo-
somal translocation and are therefore only found in the tumour cells. However, successful
234 P. Couvreur et al. / Progress in Solid State Chemistry 34 (2006) 231e235

Fig. 3. Brain biodistribution of the 14C-nanospheres, after intravenous injection of 40 mg/kg to rats. (A) 9L tumour
bearing rats receiving PHDCA nanospheres; (B) 9L tumour bearing rats receiving PEG-PHDCA nanospheres;
(C) control rats receiving PHDCA nanospheres; and (D) control rats receiving PEG-PHDCA nanospheres (for
the tumour bearing group: n ¼ 1 at 3 min and n ¼ 4 at 5, 30 and 240 min; for the control group: n ¼ 4 at 30 and
240 min). Statistical differences between PEG-PHDCA and PHDCA nanospheres are expressed by *p < 0.05, and
statistical differences between the tumour and control group are expressed by
p < 0.05 (non-parametric Manne
Whitney test) (from Ref. [6]).

results have never been obtained with antisense oligonucleotides directed against junction
genes on solid tumours in vivo, probably because of their short biological life and limited cel-
lular uptake. We have shown recently that antisense oligonucleotides against EWS-Fli-1 onco-
gene may inhibit with high specificity the growth of an EWS-Fli-1 dependent tumour grafted to
nude mice provided they are delivered by nanocapsules (Fig. 4) or nanospheres [9]. In this ex-
perience, the antisense effect was confirmed by the specific downregulation of EWS-Fli-1
mRNA.
Thus, without question, nanotechnologies now open new and exciting perspectives for
the discovery of new medicines, more efficient because they are delivered at the right place
in the body. However, the preparation methods are often complex and need the use of or-
ganic solvents and surfactants which clearly represent a limitation for further medical ap-
plications. To overcome these inconveniences, we recently developed a new concept to
obtain self-assembling nanoparticles in water without requiring any organic solvent or sur-
factant [10]. These nanoparticles are made in a simple way, by mixing two aqueous
 P. Couvreur et al. / Progress in Solid State Chemistry 34 (2006) 231e235 235

10000

9000
NC SE
8000

7000 NaCl
SE
6000
AS
5000

4000

3000

2000 NC AS

1000

0
1 6 11 16 21

Fig. 4. Effect of antisense oligonucleotides in nanocapsules (NC AS), free antisense oligonucleotide (AS), sense oligo-
nucleotide (SE), NaCl 9 g/l (NaCl) and sense oligonucleotide in nanocapsules (NC SE) on tumour growth in nude mice
expressed in % of day 1 tumour volume. Eight injections were performed at day 1, 3, 6, 8, 10, 13, 15, 17. All oligo-
nucleotides, free or encapsulated, were used at a dose of 1.6 nmol for each injection. The cumulative dose of oligonu-
cleotide was 14.4 nmol (from Ref. [9]).

solutions: a polymer of poly-b-cyclodextrins (pbCD) and a dextran bearing alkyl side

chains (DM). When these solutions are mixed, the hydrophobic alkyl chains of dextran
spontaneously form inclusion complexes with CDs, thus forming a molecular superstructure.
The structure of these nanoparticles is a core rich in CD and a corona essentially made of
dextran, which sterically stabilizes them. Drugs or other molecules can be entrapped in the
free CD inside the cores.
In conclusion, the application of original physico-chemical concepts to the formulation
of particulate colloidal carriers may lead to the development of efficient systems for the
controlled administration of drugs to specific tissues, cells or even intracellular
compartments.

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