Mise au point de complexes liposome/polymere sensibles au pH pour la vectorisation d'agents anticancereux (French text)

pH-Sensitive liposomes are vesicles that are stable at neutral pH and become leaky and/or fusion competent under acidic conditions. They have been suggested as a means to increase the cytoplasmic delivery of drug following their endocytosis. The purpose of this doctorate work was to develop a pH-sensitive liposomal formulation in which contents release would be triggered by a polymer at a pH corresponding to the endosomal pH. Moreover, this formulation had to be stable in the presence of biological fluids and to demonstrate a prolonged circulation time. Thus, different liposome/N-isopropylacrylamide (NIPAM) copolymer complexes were prepared and characterized as delivery systems for anticancer drugs.; Alkylated copolymers of NIPAM and methacrylic acid were complexed with liposomes. Formulations were characterized with regard to their pH-sensitivity, stability in serum and pharmacokinetic profile in rats. Vesicles of different compositions were complexed with different pH-sensitive NIPAM copolymers.; All formulations were stable at neutral pH and efficiently released their contents at mildly acidic pH (i.e. 4.9 to 5.8). In general, incubation of these formulations in serum did not affect their release properties.; In order to gain additional information for the rational design of a pH-sensitive formulation, pH- and temperature triggered conformational change of one of the synthesized copolymer was studied. Differential scanning calorimetry and infrared spectroscopy experiments revealed that at pH 7.4 and 37°C, although the polymer was water-soluble, it was not in a random coil conformation and was partly dehydrated. Thus, these studies showed that some polymers were not in an optimal conformation to provide liposomes with an optimal steric protection at neutral pH.; The pharmacokinetics of different pH-sensitive formulations was also studied. Two NIPAM copolymers were found to increase the systemic circulation time of liposomes following their intravenous administration. As only a slight increase in the circulation time was obtained with NIPAM copolymers, optimization of the in vivo pharmacokinetics was achieved by incorporating poly(ethylene glycol) (PEG)-lipid derivatives to the formulation.; This work showed that it was possible to develop a pH-sensitive liposomal formulation that releases its content at acidic pH while maintaining its stability at neutral pH in the presence of serum. Moreover, these liposomes exhibited a long circulation time. The best formulation was obtained by combining a terminally alkylated NIPAM copolymer with a PEG-lipid derivative of a molecular weight of 5000.