Résumé
Polymer vectors for gene therapy have been largely investigated as an alternative toviral vectors. In particular, double hydrophilic block copolymers (DHBCs) have shownpotential in this domain, but to date studies mainly focus on non-degradable copolymers,which may be a restriction for further development. To overcome this limitation, wesynthesized a DHBC (PEG43-b-PCL12(COOH)6.5) composed of a poly(ethylene glycol) (PEG)non-ionic and bioeliminable block and a degradable carboxylic acid-functionalized poly(εcaprolactone) (PCL) block. The potential of this DHBC as an original vector for smallinterfering ribonucleic acids (siRNA) to formulate tripartite polyionic complex (PIC) micelleswith poly(lysine) (PLL) was evaluated. We first studied the impact of the charge ratio (R) onthe size and the zeta potential of the resulting micelles. With a charge ratio R=1, oneformulation with optimized physico-chemical properties showed the ability to complex 75 %of siRNA. We showed a stability of the micelles at pH 7.4 and a disruption at pH 5, whichallowed a pH-triggered siRNA release and proved the pH-stimuli responsive character of thetripartite micelles. In addition, the tripartite PIC micelles were shown to be non-cytotoxicbelow 40 µg/mL. The potential of these siRNA vectors was further evaluated in vitro: it wasfound that the tripartite PIC micelles allowed siRNA internalization to be 3 times higher thanPLL polyplexes in murine mesenchymal stem cells, and were able to transfect human breastcancer cells. Overall, this set of data pre-validates the use of degradable DHBC as non-viralvectors for the encapsulation and the controlled release of siRNA, which may thereforeconstitute a sound alternative to non-degradable and/or cytotoxic polycationic vectors.