P. Couvreur UMR CNRS 8612, Centre D'études Pharmaceutiques, University of Paris South, 92296 Chatenay-Malabry, France

NANOTECHNOLOGIES FOR DRUG DELIVERY: APPLICATION TO
CANCER AND AUTOIMMUNE DISEASES

P. Couvreur
UMR CNRS 8612, Centre d'tudes Pharmaceutiques, University of Paris South, 92296
Chatenay-Malabry, France
Particulate colloidal carriers (ie liposomes or
nanospheres
or
nanocapsules)
were
developed and are now proposed as a new
approach for drug administration and
vaccines (8, 9, 10). A better fundamental
knowledge of their in vivo interaction with
the biological fluids has led to the tailoring
of systems efficient, after their 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 cells distribution is due to
the opsonization processes which occur at
the surface of these carriers. Therapeutic
applications of these systems include the
treatment of cancer liver deseases or the
targeting of antibiotics for the treatment of
intramacrophagic opportunistic infections
(1).
On the contrary, avoiding the recognition by
the liver and the spleen is also possible by
developping long circulating colloidal
carriers ("stealth" systems) able to avoid the
opsonization process and the recognition by
the macrophages. The design of such carriers
is based on the physico-chemical concept of
the
steric
repulsion:
by
grafting
polyethyleneglycol or polysaccharidic (2)
chains at the surface of nanoparticles or
liposomes, the adsorption of seric proteins
may be dramatically reduced due to steric
hindrance. Such an approach allows to
maintain the drug carrier for a longer period
of time into the blood circulation and the
resulting
extravasation
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 tortuosity, 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 diffuse 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 (3). During neurological
diseases, the blood brain barrier (BBB)
permeability increases dramatically, too and
it has been hypothesized that drug carrier
systems such as polymeric 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) (4). By the same way, tamoxifenloaded onto nanoparticles were found to be
able to reduce experimental autoimmune
uveitis (EAU) by entering into the ocular
tissues and delivering the drug specifically
to the inflammatory cells (5).
If the physico-chemical characteristics of
colloidal carriers allow to target certain
tissues or cells, 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 antisens
oligonucleotides against junction oncogenes
which are found in cancers such as certain
leukemias, Ewing sarcoma and thyroid
papillary carcinomas. These tumours are
particularly interesting targets since they
originate from a chromosomal translocation
and are therefore only found in the tumor
cells. However, successful results have never
been obtained with antisens oligonucleotides
directed against junction genes on solid
tumors in vivo, probably because of their
short biological life and limited cellular

uptake. We have shown recently that
antisens oligonucleotides against EWS-Fli-1
oncogene may inhibit with high specificity
the growth of an EWS-Fli-1 dependent
tumor grafted to nude mice provided they are
delivered by nanocapsules or nanospheres
(6). In this experience, the antisense effect
was confirmed by the specific
downregulation of EWS-Fli-1 mRNA.
Similar observation was done with siRNA
against EWS-Fli-1, showing dramatic tumor
regression in vivo (11).
Thus, it is out of question that
nanotechnologies open now new and
exciting perspectives for the discovery of
new medicines, more efficient because
delivered at the right place in the body.
However, the preparation methods are often
complex and need the use of organic
solvents and surfactants which clearly
represent a limitation for further medical
applications. To overcome these
inconveniences, we recently developed a
new concept to obtain self-assembling
nanoparticles in water without requiring any
organic solvent or surfactant (7). These
nanoparticles are made in a simple way, by
mixing two aqueous solutions: a polymer of
poly-cyclodextrins (pCD) 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, this lecture is showing that the
application of original physico-chemical
concepts to the formulation of particulate
colloidal carriers may led to the development
of efficient systems for the controlled
administration of drugs to specific tissues,
cells or even intracellular compartments.
References
1. M. Youssef, E. Fattal, M.J. Alonso, L.
Roblot-Treupel, J. Sauzires, C. Tancrde,
A. Omns, P. Couvreur, A. Andremont,
Antimicr. Agents Chemother., 32, 12041207 (1988).
2. R. Gref, R. Rodrigues, P. Couvreur,
Macromolecules, 35, 9861-9867 (2002)
3. I. Brigger, J. Morizet, G. Aubert, H.
Chacun, M.J. Terrier-Lacombe, P. Couvreur,
G. Vassal, Journal of Pharmacology and
Experimental Therapeutics, 303, 928-936
(2002).
4. P. Calvo, B. Gouritin, H. Villaroya, F.
Eclancher, C . Giannavola, C. Klein, J-P
Andreux, P. Couvreur, Europ. J. Neurosci.,
15, 1317-1326 (2002)
5. Y de Kozak, K. Andrieux, H. Villaroya,
C. Klein, B. Thillaye-Goldenberg, M-C
Naud, E. Garcia, P. Couvreur, European
Journal of Immunology, 34, 3702-3712
(2004)
6. G. Lambert, J.R. Bertrand, E. Fattal, F.
Subra, H. Pinto-Alphandary, C. Malvy,
C. Auclair, P. Couvreur, Biochem. and
Biophys. Research Communications, 279,
401-406 (2001)
7. Gref R, Amiel C, Molinard K, DaoudMahammed S, Sebille B, Gillet B, Beloeil
JC, Ringard C, Rosilio V, Poupaert J,
Couvreur P. J. Control. Rel., 111, 316-324
(2006)
8. Brannon-Peppas L, Blanchette JO. , Adv
Drug Deliv Rev. 56, 1649-59 (2004)
9. Brigger I, Dubernet C, Couvreur P. Adv
Drug Deliv Rev. 54, 631-51 (2002)
10. Koping-Hoggard M, Sanchez A, Alonso
MJ. Expert Rev Vaccines. 4, 185-96 (2005)
11. Toub N, Bertrand JR, Tamaddon A,
Elhamess H, Hillaireau H, Maksimenko A,
Malvy C, Fattal E, Couvreur P, Pharm. Res,
23, 892-900 (2006)

P. Couvreur UMR CNRS 8612, Centre D'études Pharmaceutiques, University of Paris South, 92296 Chatenay-Malabry, France

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NANOTECHNOLOGIES FOR DRUG DELIVERY: APPLICATION TO

CANCER AND AUTOIMMUNE DISEASES

short biological life and limited cellular

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