Polymeric and lipidic nanomedicines are developed for the administration of poorly water soluble drugs, peptides, vaccines and nucleic acids. Our research mainly focuses on (i) oral delivery of lipidic and polymeric nanoparticles loaded with drugs, proteins or antigens (ii) intravenous delivery of drug-loaded of nanoparticles targeting the tumoral endothelium and cancer cells.
Different strategies of nanoencapsulation for the oral delivery of drugs have been compared with a special emphasis on their mechanisms of drug transport (Figure 1).
Figure 1: Schematic representation of the fate of polymeric nanoparticles and micelles after oral delivery
Therefore, we have developed in vitro models of intestinal epithelium and follicle-associated epithelium containing M cells. The transport of PLGA-based and chitosan-based nanoparticles is endocytosis-mediated and enhanced by M cells, in particular if RGD ligand that targets integrin overexpressed at the apical pole of M cells are grafted. In contrast, the transport of self-assembling lipid-based systems and nanostructured lipid carriers is not enhanced by M cells. Several biomedical applications of oral delivery of nanomedicines are investigated: i) enhancement of poorly soluble drug delivery e.g. antimicrobial and antimalarial drugs ii) mucosal immunization with untargeted nanoparticles and nanoparticles grafted with RGD or mannose iii) treatment of experimental colitis iv) oral peptide delivery.
Several main mechanisms of delivery of drug-loaded nanoparticles to tumors have been reported (Figure 2): (i) passive targeting through leaky vasculature surrounding the tumors, described as the enhanced permeability and retention effect (EPR) (ii) “active” targeting by grafting specific ligands of cancer cells or angiogenic endothelial cells to the surface of the nanocarrier (iii) magnetic targeting of SPIO (small paramagnetic iron oxides) loaded nanoparticles. We formulated various nanocarriers (micelles and untargeted or targeted nanoparticles) loaded with several anti-cancer drugs to specifically target tumors and improve the therapeutic index of anti-cancer drugs by nanomedicines. For example, PLGA-based nanoparticles formulated for the delivery of paclitaxel, a new cyclin dependent kinase inhibitor and doxorubicin induced a higher regrowth delay of tumors in vivo than free drugs. Micelles allowed a better therapeutic response in vivo than nanoparticles, due to their more adapted size for the EPR effect (20 nm) than nanoparticles (200 nm). Exploiting the αvβ3 integrin overexpression by tumoral endothelium and tumor cells, we designed PLGA-based nanoparticles grafted with the RGD peptide and demonstrated the “active” targeting of these PLGA-based nanoparticles. We formulated multi-functional nanoparticles for the encapsulation of a therapeutic drug and a contrast agent (SPIO) that can be targeted by magnets and significantly enhanced drug biodistribution and tumors. Our current projects are focussed on the mechanisms of action of nanomedicines, in particular their effect on the tumor microenvironment. Anticancer drug-loaded nanomedicines are developed for the treatment of glioblastoma.
Coentrapment of melanoma-associated antigens and Toll like receptor ligands in mannose-functionalizes nanoparticles potentiated Th1 immune response and decreased tumor growth in therapeutic settings.
Figure 2: Passive, active and magnetic targeting of anticancer drug-loaded nanomedicines