POLYMERS FONCTIONNELS BIOCOMPATIBES POUR L'INTERNALISATION CELLULAIRE PAR ENDOCYTOSE – POFOBICE

Specific human tissue targeting by therapeutic agents, whatever the field of application, remains a challenge for biologists and chemists. These agents must avoid biological transformations leading to rapid clearance out of the body and, at the cellular level, active molecules must distinguish between different types of cells, be internalized by passing through membranes, and reach their final target, while resistance mechanisms, found in tumor cells, should be avoided. Lots of researches were done in order to improve the selectivity between types of cells, to give higher bioavailability or better penetrating properties in the cell. For anti cancer treatments, the strategies developed can be summarized in two ways, active targeting and passive targeting, which were sometimes coupled for better efficiency. Passive targeting focused on physiological differences between normal and tumor environments. Tumor tissues have a vascularization with higher permeability than normal vessels, with a deficient lymphatic system, both leading to a better accumulation of nutriments required for angiogenesis. This property was called enhanced permeability and retention (EPR). High molecular weight macromolecules circulate in the blood vessels until they can be trapped by EPR and finally be internalized in the cells by endocytosis, where they are chemically or physically modified by the increasing acidity of the endosome/lysosome pathways. These pH dependant modifications are exploited to design vectors able to release their therapeutic agents in such environment. Conjugated to the EPR effect, endocytosis has been used for drug delivery based on biopolymer using passive targeting. Polymeric systems were prepared with convenient sizes, having long circulation time in the body, avoiding both elimination and trapping by the reticuloendothelial system. These biopolymers significantly reduce the resistance of tumor cells to the therapeutic agents and reduce toxicities. Some malignancies still require efficient treatment to overcome side effects. Development of alternative treatments appears to be of great interest and a better targeting of such therapeutics may lead to a decrease in toxicity. Recent therapeutic approaches involve the reactivation of regulatory genes repressed in tumoral cells. The molecules developed for these objectives are histones deacetylases inhibitors (HDI) and DNA methyl transferases inhibitors (DMTI). HDI and DMTI are both molecules able to regulate epigenetic mechanisms. HDI and DMTI are currently involved in clinical trials alone or in combination. Despite the encouraging results, important side effects can be observed during these treatments mainly due to non selective action of the molecules. Parameters such as low maximum efficiency, cellular penetrating properties or tumor targeting must be improved to diminish the doses. In vivo and in vitro specific epigenetic mechanisms can be exploited to control cell death and differential expression of cancer associated antigen genes in human cancers. From a clinical perspective, DMTI and HDI could promote the expression of tumor antigens, as well as class I major histocompatibility complex (MHC I) and immune responses, additional parameters that would improve the anti tumor therapies. This project presents an innovative approach with acid cleavable prodrugs of HDI and DMTI and their conjugation to a polymeric vector. Subsequent applications in immunotherapies for cancer treatments are presented.