Cette thèse porte sur l'élaboration d'un vecteur particulaire lipidique reconnaissant activement<br />les tissus cérébraux après son administration par voie intraveineuse. Ce système devrait favoriser l'accumulation au sein du cerveau, de molécules thérapeutiques dans le cadre du traitement des maladies cérébrales comme les gliomes malins. La première partie de notre travail consistait à greffer sur la surface de nanocapsules lipidiques (LNC) des anticorps<br />monoclonaux d'origine murine (OX26) ou des fragments Fab' dirigés contre le récepteur à la transferrine de rat, surexprimé sur l'endothélium cérébral. Des immunonanocapsules portant entre 16 et 183 anticorps entiers et entre 42 et 173 fragments Fab' ont été obtenues. Leur capacité à s'associer aux cellules endothéliales cérébrales de rat a ensuite été vérifiée. De<br />plus, 24 h après leur administration chez le rat, la concentration dans le cerveau des OX26-<br />immunonanocapsules et des Fab'-immunonanocapsules était respectivement 2 et 1,5 fois plus<br />élevée que celle des LNC dépourvues de ligands.

Liposomal nanocarriers offer much promise in chemotherapeutic drug delivery because they may be specifically targeted to tumors thereby shielding healthy organs from toxic side effects of incorporated drugs. Passive targeting of liposomes is achieved through the inclusion of PEG to evade the RES and prolong circulation in the bloodstream. Since tumor vasculature exhibits increased permeability, prolonged circulation results in passive accumulation of liposomes to tumor. Active targeting is accomplished through the inclusion of agents targeted to over-expressed receptors on tumor cells. In vitro studies have demonstrated increased cytotoxicity of actively targeted liposomes due to specific uptake by tumor cells. In vivo, however, actively targeted liposomal nanocarriers have failed to meet the expectations established by the promising outcomes of in vitro studies. This is attributed to the fact that the inclusion of targeting agents results in accelerated clearance from the bloodstream and reductions in passive targeting to tumor thereby offsetting the benefits of active targeting. The central focus of this thesis was to engineer a multi-functional nanoscale drug delivery system which would enable active targeting without compromising RES evasion and passive accumulation to tumor. It was shown that the use of folate in liposomal formulations significantly reduced blood circulation times. To prevent RES recognition of folate on targeted liposomal formulations, a cysteine cleavable phospholipid-PEG conjugate was utilized to "mask" targeting ligands while liposomes were in circulation. Once passive accumulation at the tumor was achieved, cysteine was administered to detach PEG chains, expose folate, and promote uptake by tumor cells. In vivo studies demonstrated that cleavable DSPE-PEG5000 was capable of concealing folate on liposomes to maintain prolonged circulation times. In vitro studies verified the ability to conceal and expose folate on demand, permitting receptor mediated targeting and delivery of drug to target cells. Studies conducted to analyze drug uptake by tumor cells in vivo confirmed that delivery was enhanced when tumor-inoculated animals received targeted liposomes containing cleavable PEG chains followed by a cysteine infusion to expose folate. These results indicate that detachable PEG chains can be used in targeted liposomal formulations to enhance efficacy of chemotherapy in the treatment of glioma.