Simona MURA
Institut Galien Paris-Sud UMR CNRS 8612
Université Paris-Sud 11 Châtenay-Malabry
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