Simona MURA

Institut Galien Paris-Sud UMR CNRS 8612

Université Paris-Sud 11 Châtenay-Malabry

simona.mura@u-psud.fr

IT-FR seminar Grenoble, 21-22 October 2013

Nouvelles Stratégies de Ciblage Appliquées Au Cancer et au Système Nerveux Central

Team Patrick COUVREUR Professor Didier DESMAËLE Senior Researcher CNRS Ruxandra GREF Senior Researcher CNRS Sinda LEPÊTRE Associate Professor Simona MURA Associate Professor "CNRS-Higher Education chair” Julien NICOLAS Researcher CNRS Julie MOUGIN Engineer PhD students: 6 Post Docs: 8 Master: 5

Research activity Design and development of nanoscale drug delivery systems Design of new treatments for severe diseses (cancer, CNS diseases, intracellular infections) Use nanotechnology to bypass resistence mechanisms Design and development of muntifuctional nanocarriers and theranostic systems

Skills Organic, polymer and material chemistry, bioconjugation Physico-chemical characterization Pharmaceutical technology and drug delivery In vitro: cellular and molecular biology, In vivo: animal models, pharmacology, noninvasive high resolution imaging

The squalenoylation concept

•1 ERC Advanced Grant •Development of a start-up MedSqual •US and European Patents

Main Articles: Nature Mat. 2013, Angew. Chem. 2013, Bioconj. Chem. 2013, Chem. Soc. Rev. 2013, ACS Nano 2012, Chem. Rev. 2012, J. Med. Chem. 2011, ACS Nano 2011, J. Control. Rel. 2010, Soft Matter 2010, etc…

Research

The squalenoylation concept

•1 ERC Advanced Grant •Development of a start-up MedSqual •US and European Patents

Main Articles: Nature Mat. 2013, Angew. Chem. 2013, Bioconj. Chem. 2013, Chem. Soc. Rev. 2013, ACS Nano 2012, Chem. Rev. 2012, J. Med. Chem. 2011, ACS Nano 2011, J. Control. Rel. 2010, Soft Matter 2010, etc…

Nanoparticles for BBB crossing and diagnosis/treatment of Alzheimer disease

•1 EU Grant (FP7) « NAD »

Main Articles: , Nanomedicine 2011, Soft Matter 2011, Anal. Chem. 2010, Chem. Comm. 2010, etc…

Human brain endothelial cell line

Research

The squalenoylation concept

•1 ERC Advanced Grant •Development of a start-up MedSqual •US and European Patents

Main Articles: Nature Mat. 2013, Angew. Chem. 2013, Bioconj. Chem. 2013, Chem. Soc. Rev. 2013, ACS Nano 2012, Chem. Rev. 2012, J. Med. Chem. 2011, ACS Nano 2011, J. Control. Rel. 2010, Soft Matter 2010, etc…

Nanoporous Metal-Organic Frameworks (NanoMOF)

•1 Initial Training Networks (ITN) - Marie Curie Actions EU Grant (FP7) « CYCLON » •US and European Patents

Main Articles: Nanomedicine 2011, Chem. Rev. 2011, J. Mater. Chem. 2011, Nature Mat. 2010, Angew. Chem. 2010, etc… Liver

Porous cage nanoMOF

Challenging drug incorporation

Imaging properties

Nanoparticles for BBB crossing and diagnosis/treatment of Alzheimer disease

•1 EU Grant (FP7) « NAD »

Main Articles: , Nanomedicine 2011, Soft Matter 2011, Anal. Chem. 2010, Chem. Comm. 2010, etc…

Human brain endothelial cell line

Research

The squalenoylation concept

Chemically conjugation of squalene to a biologically active drug molecule leading to bioconjugates which self-assemble as nanoparticles in water

•Nucleosides analogues (antitumoral and antiviral) •Oligonucleotides •Beta lactam antibiotics

The squalenoylation concept

Chemically conjugation of squalene to a biologically active drug molecule leading to bioconjugates which self-assemble as nanoparticles in water

•Nucleosides analogues (antitumoral and antiviral) •Oligonucleotides •Beta lactam antibiotics

• Stable nanoparticles (100–150 nm) • Encapsulation efficiency ~50% • No “burst release”

Control

Sq-Gem NPs (20mg/kg)

Gem (100 mg/kg)

L1210 murine leukemia subcutaneous tumor model

The terpenoylation concept

Squalene

Polyisoprene

Enlarge the new and ground-breaking concept of squalenoylation

Use other drug molecules and macromolecules with various physico-chemical properties

Change the nature of the polyterpene used for the drug conjugation

Functionalize the resulting nanoassemblies in order to promote more efficient targeting

Expected results ❶ Knowledge of the structure/activity relationships which will allow to identify the conditions for the bioconjugates to self-organize as nanoassemblies, depending on the nature of the drug/polyterpene pair

❷ Design of new nanomedicines with high drug loading and absence of “burst” release

❸ Develop an universal platform for the discovery of new nanomedicines

The squalenoylation-terpenoylation concept: a general platform

Penicillin G-Squalene Nanoparticles

Intracellular bacteria killing efficiency (live bacteria in green, dead ones in

red)

Penicillin G ->ACS Nano, 2012,6, 3820

siRNA RET/PTC1

DMF, PBS Microwave irradiation

siRNA -> J. Med. Chem., 2011, 54,4067

The squalenoylation-terpenoylation concept: a general platform

Penicillin G-Squalene Nanoparticles

Intracellular bacteria killing efficiency (live bacteria in green, dead ones in

red)

Penicillin G ->ACS Nano, 2012,6, 3820

siRNA RET/PTC1

DMF, PBS Microwave irradiation

siRNA -> J. Med. Chem., 2011, 54,4067

Angew. Chem., 2013, 52, 6

Drug

Bioconj. Chem, 2013, DOI: 10.1021/bc400210x

Maghemite (γ-Fe2O3)

Nanotheranostic

Contrast agent + Therapeutic molecule Nanotheranostic

Amphiphilic gadolinium complexes USPIOs

γ-Fe2O3

Maghemite (γ-Fe2O3)

Nanotheranostic

Contrast agent + Therapeutic molecule Nanotheranostic

Gem-Squalene

Control

Sq-Gem NPs

Gem

USPIO Sq-Gem NPs

USPIO

USPIO Sq-Gem NPs +

Magnetic resonance

imaging

ACS Nano, 2011,5, 1513

Amphiphilic gadolinium complexes USPIOs

γ-Fe2O3

Versatile functionalization of nanoparticles

Paclitaxel

Docetaxel

Drug

Biodegradable polymer matrix

PACA

PLA

Macromolecules 2008, 41, 8418

Demande PCT, Sanofi 2012

Imaging agent (theragnostic)

Rhodamine

Dansyl

QDs

FP547

FP581

Chem. Commun. 2010, 46, 2602

Soft Matter 2011, 7, 6187

Ligand (targeting)

Biotin

Folic acid

Anisamide

Selegiline

Curcumine

Antibody

Cancer Alzheimer

Int. J. Pharm. 2011, 416, 453

ACS Nano 2012, 6, 5866

Stealth shell

PEG

Anal. Chem. 2010, 82, 10083

ACS Nano 2012, 6, 5897

Chem. Soc. Rev. 2013, 42, 1147

Collaborations: Projet NAD (PACA), Sanofi (PLA)

Aβ peptide

Hepatic accumulation and elimination

Effet Sink

Bloodstream BBB

Brain

NPs to target the Aβ peptide

Anal . Chem. 2010, 82, 10083

Nanoporous Metal-Organic Frameworks (NanoMOF)

MIL Material Institut Lavoisier

Iron

Nature Mat., 2010 9, 172 Angew. Chem., 2010 36, 6260

Nanoporous Metal-Organic Frameworks (NanoMOF)

MIL Material Institut Lavoisier

Nature Mat., 2010 9, 172 Angew. Chem., 2010 36, 6260

Magnetic resonance images

Iron

Publications151 (18 avec IF>10) Advanced Functional Materials (1); Advanced Drug Delivery Reviews (6); Angewandte Chemie (2); Nature Materials (2); Accounts of Chemical Research (1); Chemical Reviews (2); ACS Nano (3); Progress in Polymer Science (1)

Patents: 13

PhD thesis: 10

Financial Support: 1 ERC Advanced Grant (2,2 M €), 2 EU grants NAD (880 K€) and CYCLON (348 K€), ANR grants: Jeune chercheur (179K€), SQUALONC (162 K€), VIRMIL (288 K€) Industrial contracts: LFB (113 K€), Sanofi « Alliance » (750 K€), Sanofi Alzheimer (225 K€), Other contracts: pôle compétitivité MEDICEN (872 K€), projet C’Nano IdF (50K€), projet LebEX NanoSaclay (15 K€)

Prix European Inventor Award 2013 Médaille de l’Innovation CNRS 2012 Pharmaceutical Scientist Award 2011 Institut Universitaire de France (2010-2015)

Summary of research activity 2008-2013