| Polymeric micelles represent a distinct class of micelles made of amphiphilic copolymers. They have several advantages over surfactant micelles, particularly their increased solubilization of hydrophobic compounds and, in most cases, their lower toxicity. The principal objective of this doctoral thesis was to develop polymeric micelles in the formulation of hydrophobic anticancer agents for parenteral administration.;In the course of various experiments, it was demonstrated that incorporation of the comonomer of N-vinyl-2-pyrrolidone (VP) in NIPAM copolymers slightly decreased pH transition but did not affect micellization. These pH-sensitive polymeric micelles showed much less toxicity in vitro than Cremophor®EL. After their intravenous injection in mice, pH-sensitive micelles allowed us to limit AlClPc capture by the MPS without, however, promoting its tumoral accumulation. At sub-therapeutic doses, the antitumoral activity of A1C1Pc incorporated in these poly(N-isopropylacrylamide) (PNIPAM) micelles was superior to that of AlClPc in Cremophor® EL micelles.;The second part of these investigations consisted of developing biodegradable diblock copolymer-based polymeric micelles. These polymeric micelles had to have the capacity to incorporate anticancer agents from the family of taxanes and podophyllotoxins. The drugs are generally solubilized with low-molecular weight surfactants, such as Cremophor®EL and polysorbate 80 (Tween 80®), known for their intrinsic toxicity. These formulations of polymeric micelles base had to be non-toxic in vitro and in vivo, present prolonged circulation times and anti-tumoral efficacy superior to commercial formulations.;Thus, biodegradable polymeric micelles of poly(N-vinyl-2-pyrrolidone)- b-poly(D,L-lactide) (PVP-b-PDLLA)-based diblock copolymers were developed as alternative formulations to low-molecular weight surfactants. Polymeric micelles permitted the solubilization of taxanes and podophyllotoxins by different incorporation methods. Unlike surfactants, the copolymer PVP-b-PDLLA demonstrated no toxicity in vitro and in vivo. The maximum tolerated dose (MTD) of these micellar formulations of paclitaxel (PTX) in mice could be multiplied by 5 in comparison to that of the commercial formulation Taxol® (20 mg/kg). In contrast, in the case of docetaxel (DCTX), the MTDs in mice were the same whatever the formulation, and despite polysorbate 80 toxicity much higher than that of PVP-b-PDLLA. The pharmacokinetics and tumoral accumulation of PTX and DCTX incorporated in polymeric micelles could not be improved in comparison to those of commercial formulations. However, at 60 mg/kg of PTX, they demonstrated anti-tumoral efficacy superior to Taxol ® at its MTD (20 mg/kg). PVP-b-PDLLA micelles incorporating PTX thus constitute an interesting alternative to Taxol ®.;The first part of this work consisted of optimizing a pH-sensitive micellar formulation by increasing the hydrophilicity of alkyl copolymers of N-isopropylacrylamide (NIPAM) and methacrylic acid (MAA) to diminish capture by organs of the mononuclear phagocytic system (MPS). This formulation was aimed at improving the in vivo biodistribution and efficacy of a photosensitive hydrophobic anticancer drug, aluminium chloride phthalocyanine (AlClPc).;Keywords. Polymeric micelles, poly(N-isopropylacrylamide), poly(N-vinylpyrrolidone)-b-poly(D,L-lactide), pH-sensitivity, anticancer drugs. |
