Simona MURA. Institut Galien Paris-Sud UMR CNRS 8612 Université Paris-Sud 11 Châtenay-Malabry.
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1 Simona MURA Institut Galien Paris-Sud UMR CNRS 8612 Université Paris-Sud 11 Châtenay-Malabry IT-FR seminar Grenoble, October 2013
2 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
3 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
4 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» Human brain endothelial cell line Main Articles:, Nanomedicine 2011, Soft Matter 2011, Anal. Chem. 2010, Chem. Comm. 2010, etc
5 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» Human brain endothelial cell line Main Articles:, Nanomedicine 2011, Soft Matter 2011, Anal. Chem. 2010, Chem. Comm. 2010, etc Porous cage nanomof Challenging drug incorporation Liver 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 Imaging properties
6 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
7 The squalenoylation concept Chemically conjugation of squalene to a biologically active drug molecule leading to bioconjugates which self-assemble as nanoparticles in water Stable nanoparticles ( nm) Encapsulation efficiency ~50% No burst release L1210 murine leukemia subcutaneous tumor model Control Nucleosides analogues (antitumoral and antiviral) Oligonucleotides Beta lactam antibiotics Gem (100 mg/kg) Sq-Gem NPs (20mg/kg)
8 The terpenoylation concept Enlarge the new and ground-breaking concept of squalenoylation Squalene Polyisoprene 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
9 The squalenoylation-terpenoylation concept: a general platform sirna RET/PTC1 DMF, PBS Microwave irradiation Penicillin G-Squalene Nanoparticles Intracellular bacteria killing efficiency (live bacteria in green, dead ones in red) Penicillin G ->ACS Nano, 2012,6, 3820 sirna -> J. Med. Chem., 2011, 54,4067
10 The squalenoylation-terpenoylation concept: a general platform sirna RET/PTC1 DMF, PBS Microwave irradiation Penicillin G-Squalene Nanoparticles Intracellular bacteria killing efficiency (live bacteria in green, dead ones in red) Penicillin G ->ACS Nano, 2012,6, 3820 sirna -> J. Med. Chem., 2011, 54,4067 Drug Angew. Chem., 2013, 52, 6 Bioconj. Chem, 2013, DOI: /bc400210x
11 Nanotheranostic Contrast agent + Therapeutic molecule Nanotheranostic Amphiphilic gadolinium complexes USPIOs Maghemite (γ-fe 2 O 3 ) γ-fe 2 O 3
12 Nanotheranostic Contrast agent + Therapeutic molecule Nanotheranostic Amphiphilic gadolinium complexes USPIOs Maghemite (γ-fe 2 O 3 ) γ-fe 2 O 3 Gem-Squalene + USPIO Control USPIO Sq-Gem NPs Sq-Gem NPs Gem USPIO Sq-Gem NPs Magnetic resonance imaging ACS Nano, 2011,5, 1513
13 Versatile functionalization of nanoparticles Collaborations: Projet NAD (PACA), Sanofi (PLA) Cancer Alzheimer Biodegradable polymer matrix PACA PLA Demande PCT, Sanofi 2012 Macromolecules 2008, 41, 8418 Biotin Selegiline Folic acid Curcumine Anisamide Antibody Ligand (targeting) Int. J. Pharm. 2011, 416, 453 ACS Nano 2012, 6, 5866 Stealth shell PEG Imaging agent (theragnostic) Anal. Chem. 2010, 82, ACS Nano 2012, 6, 5897 Drug Rhodamine Dansyl QDs FP547 FP581 Paclitaxel Docetaxel Chem. Soc. Rev. 2013, 42, 1147 Chem. Commun. 2010, 46, 2602 Soft Matter 2011, 7, 6187
14 NPs to target the Aβ peptide Bloodstream BBB Brain Effet Sink Aβ peptide Hepatic accumulation and elimination Anal. Chem. 2010, 82, 10083
15 Nanoporous Metal-Organic Frameworks (NanoMOF) Iron MIL Material Institut Lavoisier Nature Mat., , 172 Angew. Chem., , 6260
16 Nanoporous Metal-Organic Frameworks (NanoMOF) Magnetic resonance images Iron MIL Material Institut Lavoisier Nature Mat., , 172 Angew. Chem., , 6260
17 Summary of research activity Publications 151 (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 ( )
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