NANOMÉDICAMENTS EN ONCOLOGIE: OÙ EN EST-ON?

Patrick COUVREUR, University Paris-Sud

Atelier du GPCO Groupe de Pharmacologie Clinique Oncologique

Nice, le 22 Novembre 2013

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CHIMIOTHERAPIE

ANTICANCÉREUSE

CONVENTIONNELLE

NANOMEDICAMENTS

(multifonctionnels)

100 nm

Ligand

PEG

Nanoparticle

Imaging

-Passage transmembranaire limité (faible disponibilité) - Instabilité/Métabolisation - Manque de spécificité cellulaire/tissulaire (faible activité + toxicité) - Pénétration intracellulaire insuffisante -Induction de résistances Moins de nouveaux médicaments

-Ciblage cellulaire/tissulaire (meilleur index thérapeutique) -Protection de la dégradation -Pénétration intracellulaire accrue -Contournement des résistances -Combiner des propriétés thérapeutiques et d’imagerie Grou

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NANOPARTICLES OF POLY(ALKYL CYANOACRYLATE) (PACA)

Nanocapsule

Nanosphere

d– d+

Nu-/ NuH

Alkyl chain length

Biodegradation

Couvreur et al., FEBS Lett., 84, 323-326 (1977) Couvreur et al., J. Pharm. Pharmacol., 31, 331-332 (1979)

Anionic polymerisation

Opsonins

Liver

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NANOPARTICLES MAKE DOXORUBICIN INVISIBLE FOR Pgp IN VIVO IN MDR RESISTANT HEPATOCARCINOMA

Huh7 (6 hour-drug exposure)

0

20

40

60

80

100

Log equivalent PIHCA-Dox (µg/mL)

Cel

l via

bil

ity (

%)

PIHCA Dox PIHCA-Dox

A

0.01 0.1 1.0 10.0

TUN

EL a

nal

ysis

of

apo

pto

tic

hep

ato

cyte

s (%

)

0

2

4

6

8

10

12

14

16

18

20

5%-glucose PIHCA Dox PIHCA-Dox

*

* ** †

His

tolo

gica

l co

un

tin

g o

f ap

op

toti

c h

epat

ocy

tes

(%)

5%-glucose PIHCA Dox PIHCA-Dox

0

2

4

6

8

10

12

14

16 * ** †

In vitro cytotoxicity

(Human Hepatocellular

Carcinoma)

hepatocarcinoma in transgenic mice

de Verdière, et al., Brit. J. Cancer, 76: 198-205 (1997)

Barraud, et al., J. of Hepatology, 42: 736-743 (2005)

Reddy and Couvreur, J of Hepatology, 55, 1461-1466 (2011)

doxorubicine

Collaboration C. Trepo and Bioalliance Groupe

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Baseline

4 weeks post treatment

showing tumor necrosis

® CLINICAL TRIAL (Bioalliance)

Patient #8: Presented with Single Unresectable Tumor in Segment II

Tumor measured 60 x 50 mm (3000mm2)

After one infusion of 30 mg/m2, tumor necrosis was evident

Survival rate is 89% after 18 months treatment

with doxorubicin-loaded PACA nanospheres

(Transdrug) whereas it is only 54% in patients

with standard treatment (chimioembolization).

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VERSATILE AND EFFICIENT TARGETING PACA NANOPARTICULATE PLATFORM

Le Droumaguet et al., ACS Nano, 6, 5866-5879 (2012a) Brambilla D. et al, Chem. Comm., 46, 2602-2604 (2010) Nicolas, J. et al., Soft Matter, 7, 6187-6193 (2011) Grou

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VERSATILE AND EFFICIENT TARGETING PACA NANOPARTICULATE PLATFORM: BIOTIN DECORATED AND RHODAMINE LABELLED PACA NANOPARTICLES

Le Droumaguet et al., ACS Nano, , 6, 5866-5879 (2012a)

Target cancer cell

Biotin Receptor

Biotin

MCF-7 Breast cancer

N0 Non functionalized NP N1 Biotin functionalized NPs

N1

Huvec Healthy cells

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IMPRESSIVE PROGRESSES HAVE BEEN MADE IN THE DESIGN OF DISEASE TARGETED NANOMEDICINES BUT IMPORTANT LIMITATIONS REMAIN…

DRUG LOADING (mg of biologically active

molecule/mg of drug transporter material)

BURST RELEASE

Drug molecule

New (bio)nanomaterials are needed to overcome those limitations Groupe

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In an extraordinary way, SQUALENE a precursor of the CHOLESTEROL’s

biosynthesis, takes a dynamically folded conformation in aqueous solutions

which helps it in reaching the hydrophobic pocket of the enzyme (i.e.

oxidosqualene cyclase) in which the cyclization occurs (LANOSTEROL)

A BIOMIMETIC APPROACH: THE « SQUALENOYLATION »

squalene

P. Couvreur et al., European Patent, 2011

P. Couvreur et al., US Patent, 2011

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i-Pr2NEt, HBTU, HOBt, DMF,

20 °C,48 h

O

OO

A

B

N

N

N

NH

O

HO

O

N

N

NH

O

HO

O

N

N

NH2

O

O

N

N

N

NH

O

HO

O

50%

51%

5'

4

4

5'

CO2H

O

HO

O

FOH

FH

HH

N

N

NH

O

HO

O

FOH

FH

HH

N

N

NH2

O

1) ClCO2Et, Et3N, THF, -15 °C2) DMF, 20 °C, 3 days

"C27 Squalenic acid"

55%

4-(N)-trisnorsqualenoylgemcitabine

i-Pr2NEt, HBTU, HOBt, DMF,

20 °C,48 h

THE CONCEPT OF “SQUALENIZATION”

ddI

ddC

Nanoparticles 100-150 nm

Also AZT, ARA-C, thymidine etc.

ddC-SQ

ddI-SQ

gem

Gem-SQ

Couvreur et al., Nano Letters, 6, 2544-2548 (2006) Couvreur et al., Small, 4, 247-253 (2008) Aoun et al., Adv Funct. Mater., 18, 1-11 (2008)

50% Loading !

NUCLEOSIDES ANALOGUES

+ Rapid metabolism

+ Poor diffusion through biological barriers

+ Induction of resistances

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Untreated

Squalene 100mg/kg

Cytarabine 100mg/kg

SQgem nanoassemblies 20mg/kg

Gemcitabine 100mg/kg

0

20

40

60

80

100

0 20 40 60 80 100

Days

Su

rviv

al (%

)

IN VIVO ANTICANCER ACTIVITY

Harivardhan Reddy et al.,. J.Control. Rel., 124,20-27 (2007) Harivardhan Reddy et al., J. Pharmacol. Exp. Ther., 325, 484-490 (2008) Harivardhan Reddy et al., Molecular Pharmaceutics, 6, 1526-1535, (2009) Soukaina et al., Nanomedicine, 7, 841-849 (2011)

L1210 murine Leukemia iv/iv Orthotopic Panc1 human pancreatic cancer

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Tunable terpene-based nanoparticles by nitroxide-mediated polymerization (NMP)

Harrisson et al., Angewandte Chemie Int Ed., 52, 1678-82 (2013)

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0

1000

2000

3000

4000

5000

0 5 10 15 20 25

Days after tumor inoculation

Tu

mo

r v

olu

me

(m

m3)

*****

**

MAGNETICALLY GUIDED NANOPARTICLES (Leukmia L1210 sc/iv)

gemcitabine ( )

Untreated ( )

SQgem nanoassemblies ( )

Mag-SQgem composite nanoassemblies ( )

Mag-SQgem composite nanoassemblies (without magnet) ( )

Arias et al., ACS Nano, 22, 1513-1521 (2011)

magnet tumor

« NANOTHERAGNOSTICS» !

5 mg/Kg

Ultrasmall iron oxide nanoparticles

SQgem anticancer prodrug

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versus

DOXORUBICIN-SQUALENE : A NEW LONG CIRCULATING NON PEGYLATED NANODEVICE

Maksimenko et al, PNAS, ASAP on the web (2013)

Nanoprecipitation

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DOXORUBICIN-SQUALENE NPs : INCREASED ANTICANCER ACTIVITY

Maksimenko et al, PNAS, ASAP on the web (2013) MiaPaca

MiaPaca

M109 M109

M109

MiaPaca

MiaPaca

MiaPaca

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DOXORUBICIN-SQUALENE NPs : DECREASED TOXICITY

Maksimenko et al, PNAS, ASAP on the web (2013)

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MIL-89 MIL-88A MIL-100 MIL-101_NH2 MIL-53

muconic acid

fumaric acid

trimesic acid

Amino

terephthalic acid

terephthalic acid

11Å

6Å

25Å

29Å

11 Å

29Å

34Å

8.6Å

HO

O

O

OH

HO OH

OO

HO

O

O

OH

HO OH

OO

HO

HO OH

O O

O

NH2

HO OH

OO

HO OH

OO

100 nm

MIL-88A MIL-100

200 nm

MIL-88A-PEG

200

nm

Iron

HYBRID NANOPARTICLES OF METAL OXIDE FRAMEWORKS (NANOMOFs) (Iron carboxylates)

MIL Material Institut Lavoisier

Horcajada et al., Nature Materials, 9, 172-178 (2010) Mc Kinley et al., Angew. Chem. Int. Ed. , 23, 6260-6266 (2010) Horcajada et al., Chem Rev. , 112, 1232-1268 (2012)

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FUTUR CHALLENGES …

• Develop multifunctional nanodevices with high drug loading and without « burst release »

• Use of nanotechnologies for overcoming resistance mechanisms

• Use of nanotechnologies for the design of « theragnostics »

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ACKNOWLEDGEMENTS

A. HAJRI (Univ. Freiburg, Germany)

G. FEREY and C. SERRE (Univ Versailles)

UMR CNRS 8612

K. ANDRIEUX

JL. ARIAS

L. BILDSTEIN

C. BOURGAUX

D. BRAMBILLA

T. CHALATI

D. DESMAELE

C. DIMEO

C. DUBERNET

L. HARIVARDHAN

R. GREF

B. LEDROUMAGUET

S. LEPETRE

J. NICOLAS

F. SAID-HASSANE

N. SEMIRAMOTH

E. SOMA

B. STELLA

F. ZOUHIRI

BIOALLIANCE

MEDSQUAL

ERC ADVANCED GRANT « TERNANOMED » http://www.erc_ternanomed.u-psud.fr/

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