Degradable double hydrophilic block copolymers and tripartite polyionic complex micelles thereof for small interfering ribonucleic acids (siRNA) delivery
Résumé
Polymer vectors for gene therapy have been largely investigated as an alternative to
viral vectors. In particular, double hydrophilic block copolymers (DHBCs) have shown
potential 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, we
synthesized 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 small
interfering ribonucleic acids (siRNA) to formulate tripartite polyionic complex (PIC) micelles
with poly(lysine) (PLL) was evaluated. We first studied the impact of the charge ratio (R) on
the size and the zeta potential of the resulting micelles. With a charge ratio R=1, one
formulation 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, which
allowed a pH-triggered siRNA release and proved the pH-stimuli responsive character of the
tripartite micelles. In addition, the tripartite PIC micelles were shown to be non-cytotoxic
below 40 µg/mL. The potential of these siRNA vectors was further evaluated in vitro: it was
found that the tripartite PIC micelles allowed siRNA internalization to be 3 times higher than
PLL polyplexes in murine mesenchymal stem cells, and were able to transfect human breast
cancer cells. Overall, this set of data pre-validates the use of degradable DHBC as non-viral
vectors for the encapsulation and the controlled release of siRNA, which may therefore
constitute a sound alternative to non-degradable and/or cytotoxic polycationic vectors.
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