Mise au point de nanoparticules polymères pour l'administration parentérale d'agents anticancéreux hydrophobes

Many highly potent anticancer drugs are characterized by poor aqueous solubility and can impart significant systemic toxicity. This toxicity can be attributed in part to the solubilisation of these anticancer agents with low molecular weight surfactants that are known to cause serious biological side effects on their own. Moreover, following their intravenous (IV) injection, the anticancer agents distribute throughout the body, causing deleterious effects in healthy organs and tissues. Colloidal polymeric drug carriers have been investigated as a means to circumvent these drawbacks. First, polymeric materials can be tailored to meet specific requirements in terms of biocompatibility, biodegradability and affinity for the cargo molecule. Second, associating a drug to a carrier system can drastically alter its distribution throughout the body, enhancing its deposition at the target site, e.g. the tumour, while sparing healthy tissues, thus minimizing systemic toxicity.   Previous work in our group has led to the design of block copolymer micelles based on poly(N-vinyl-pyrrolidone)-block-poly(D,L-lactide) (PVP-b-PDLLA) that were shown to solubilise hydrophobic anticancer agents such as paclitaxel (PTX). PTX is commercially available as Taxol®, a Cremophor EL (CrEL)-based formulation. CrEL is a low molecular weight surfactant that has been linked to severe side effects including life-threatening hypersensitivity reactions. Although PTX-loaded PVP-b-PDLLA micelles have demonstrated much improved tolerability compared to Taxol®, they did not increase PTX tumoral concentrations and exhibited anticancer efficacy similar to Taxol® at equivalent dosage. This was attributed to rapid destabilisation of the micelles and release of their cargo following IV administration.    We chose to pursue our work with a colloidal drug carrier that exhibits greater stability compared to block copolymer micelles, i.e. polymeric nanoparticles. The main objective of this project was to develop polymeric nanoparticles for the parenteral delivery of hydrophobic anticancer drugs. The nanoparticles had to meet certain requirements such as be able to encapsulate hydrophobic anticancer drugs and release them in a controlled fashion over several days. Furthermore, the nanoparticles should confer prolonged plasma residence times to the encapsulated drug and favour its passive accumulation at its intended site of action, i.e. the tumour. The first part of this work focussed on applying PVP-b-PDLLA for the first time as polymeric emulsifier for the preparation of PDLLA nanoparticles with appropriate mean diameters (250 nm) using an oil-in-water emulsion method. Two hydrophobic anticancer drugs, PTX and etoposide (ETO), were successfully incorporated into the nanoparticles. A salting-out method was applied to enhance the loading efficiency of ETO, which was initially low given its slightly higher aqueous solubility compared to PTX. Both drugs were released in a controlled fashion from the PDLLA nanoparticles in vitro. Because of the lyoprotective effect of PVP, the polymer corona allowed for the particles to be easily redispersed in aqueous media following lyophilisation. The second part of the thesis aimed at evaluating whether the PVP coating could confer “stealth” properties to the PDLLA nanoparticles. Our study provided direct comparison between PVP and PEG, the most widely employed surface agent in drug delivery. In vitro protein adsorption and phagocytosis studies corroborated the in vivo findings, which showed that PVP-coated nanoparticles were rapidly cleared from circulation following their uptake by the mononuclear phagocyte system. Hence, our results indicated that PVP as coating materiel is not as efficient as PEG in conferring “stealth” properties to polymeric nanoparticles. Consequently, in the last section of this thesis, PEG was selected as coating agent while various biodegradable polymers were investigated as core-forming materials. Both synthetic (PDLLA and lactide/glycolide copolymers) and natural (polyhydroxyalkanoates (PHAs)) polyesters were tested. Our results demonstrated that the physicochemical properties of the polyesters significantly influenced the loading efficiency and release kinetics of PTX. While nanoparticles based on synthetic polyesters exhibited high encapsulation levels and controlled PTX release in vitro, PHA-based nanoparticles exhibited immediate unloading of their cargo. Pharmacokinetic and biodistribution studies in rodents revealed that encapsulating PTX in PEG-coated PDLLA-based nanoparticles led to enhanced plasma residence time and tumour deposition of the drug compared to Taxol®. Polymeric nanoparticles thus represent an appealing alternative to Taxol®.

Keyphrases: poly(N-vinyl-pyrrolidone)-b-poly(D,L-lactide), polyesters, phagocytose, biodistribution, paclitaxel, Polymeric nanoparticles, poly(N-vinyl-pyrrolidone)-b-poly(D,L-lactide), polyesters, phagocytosis, biodistribution, hydrophobic anticancer drugs, paclitaxel