Résumé :
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Communication n° 656 Introduction : Pluronics (Poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) PEO-PPO-PEO) were used in vivo for gene delivery to muscles and appeared to be valuable for this application. In solution, owing to their amphiphilic character, Pluronics form micelles which can be used to incorporate drug molecules and transport them into cells. Objectives : An important goal is to understand the respective roles of the hydrophobic (PPO) and hydrophilic (PEO) sequences of the block copolymers in the transfection efficiency. Two methods of functionalization of PPO (Mn=2000 kDa) by tosylate end group are described in order to obtain suitable polymers able to initiate the polymerization of 2-methyl-2-oxazoline (MeOXZ) for synthesis of new triblock copolymers poly(methyloxazoline-b-propylene oxide-b-methyloxazoline). Results : The PPO was functionalized by two ways: i) direct tosylation, ii) synthetic route (allylation, hydroboration and tosylation) to obtain respectively the a,w-di-(4-toluene sulphonate) poly(propylene oxide) having a secondary tosylate group and the a,w-di-(3-n-propyl-(4-toluene sulphonate)) poly(propylene oxide) with a primary tosylate group in the ends of PPO. After optimisation, a complete functionality without side-reactions and with satisfactory yields was obtained. These two macroinitiators were used to initiate the polymerisation of MeOXZ in acetonitile at 80°C. Analysis by 1H NMR and size exclusion chromatography of copolymers obtained in the two cases showed that the polymerization initiation step was slow and not complete. The primary was more tosylate end group efficient than secondary. Consequently, the polymerization medium was composed of diblock and triblock copolymers. The triblock was isolated by selective precipitation. Evaluation of these new block copolymers as complexing and transfer agents for DNA by in vivo determination on Balb/C mice will be described. Conclusions : Using a,w-di-(3-n-propyl-(4-toluene sulphonate)) poly(propylene oxide), the triblock copolymer based PPO and PMeOXZ was synthesized. The biological assays of these block copolymers will allow to determine whether there is an advantage to replace the PEO segments of Pluronics by an other more hydrophilic segment such as polymethyloxazoline which revealed to be of low toxicity.
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