Nanoparticles for an efficient and biofriendly drug encapsulation Ruxandra GREF Research director CNRS, University Paris Sud, Institut Galien Châtenay Malabry, France Highly porous metal organic frameworks (MOF) nanoparticles as efficient drug carriers Supertetrahedra Trimesic acid Iron Fe3+ trimers NanoMOF Porous cages Synthesis optimisation MIL-100 Institut Lavoisier Horcajada P. et al. Nature Materials, 9, 172-178, 2010 Patents: FR0706873, FR0706875, FR1255065 (2007) Europe, Japan, Canada and USA Nanoparticle one step hydrothermal synthesis FeCl3 + 1,3,5 BTC + H2O Nanoparticle cristallization Microwave irradiation Centrifugation Iron trimesate MIL-100 Purification (ethanol) size : 60 nm up to 200 nm specific surface (BET) ~2000 m2/g Chalati T. et al., J Mater Chem 21, 2220-7, 2011 Agostoni V. et al., Green Materials, 2013 Drug entrapment in nanoMOFs Remarkable capacity to encapsulate a variety of active molecules: Loadings in the 20 -70 wt% range HYDROPHOBIC docetaxel, doxorubicin, ibuprofen, topotecan, benzophenone HYDROPHILIC azidothimidin-TP, gemcitabin-MP, cidofovir, amoxicillin etc... AMPHIPHILIC busulfan, caffein Incubation in water « nanosponges » High affinity -> rapid adsorption (< 15 min) of the whole amount of drug even from very diluted drug solutions Horcajada et al. Nature Materials, 9, 172-178, 2010; Agostoni, Adv Healthcare Mater 2013 Interaction nanoMOF – antiviral drug AZT-TP ~ 9 Å 2 AZT-TP 2 H2O AZT-TP (~ 12 x 9 x 4 Å) I. Adsorption in the pores II. Coordination P-O-Fe Monte Carlo simulations : Strong interaction drug – Iron site Agostoni et al., Adv Healthcare Mater, 2013 In vitro pharmacological activity in infected cells Human mononuclear cells (donors) infected with HIV-1-LAI 30 AZT-TP nanoMOF+AZT-TP % AZT-TP Inside the cells 25 ED50 (nM) 20 15 NP >1000 10 NP AZT-TP 54 34 5 AZT-TP 599 401 0 0 0,5 2 4 6 24 Time (hours) * AZT-TP cannot cross the cell membrane * Using NPs : ~ 25 % AZT-TP penetrates in the cells * drug-loaded NPs : > 10 times more effective than free AZT-TP Biological applications of iron carboxylate nanoparticles (Bio)degradability Lack of toxicity in vitro & in vivo T. Baati et al. Chemical Science, 2013, 4, 1597-1607. Horcajada et al. Encapsulation & controlled release Nature Materials, 9, 172-178, 2010 Imaging theranostics Stable non covalent McKinlay et al., surface modification Angewandte Chemie, 2010, 49, 6260-6266 Chalati et al. Nanomedicine 2011, 6, 1683–1695 Agostoni et al. J Materials Chemistry 2013 1, 4231-42. Agostoni et al. Green Chemistry 2013 A non-covalent approach to coat nanoMOFs β-CDP Incubation in water • Rapidity : ~ 75% of the coating is achieved in < 15 min • Integrity of nanoMOFs is preserved • no drug release during coating • Stability in biological media Technology patented by CNRS in 2012 NanoMOFs : a wide range of development opportunities Three biofriendly, one-step, easy to scale-up and efficient procedures : 1. Hydrothermal synthesis (no solvent) 2. Drug loading (soaking in water) PEG CD 3. Surface coating (soaking in water) Business opportunity and contact We offer: - Strategic partnership for co-developing drug-loaded nanoMOFs - Licensing Contacts: - Ruxandra Gref, Research Director Institut Galien, CNRS 91198 Gif-sur-Yvette, France [email protected] - Stéphane Mottola Director of International Development FIST SA-France Innovation Scientifique et Transfert 83, boulevard Exelmans 75016 Paris, France [email protected]
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