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2017-09-26 - Colloque/Présentation - poster - Anglais - 1 page(s)

Baroni Alexandra , Frère Antoine, Dubois Philippe , mottet denis, Piel Géraldine, Blankert Bertrand , Mespouille Laetitia , "Synthesis of aliphatic polycarbonates for siRNA delivery in cancer therapy" in ICONAN 2017, Barcelone, Espagne, 2017

  • Codes CREF : Chimie macromoléculaire (DI1315), Chimie des polymères de synthèse (DI131C), Chimie pharmaceutique (DI3413)
  • Unités de recherche UMONS : Matériaux Polymères et Composites (S816), Analyse pharmaceutique (M130)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
  • Centres UMONS : Centre d’Innovation et de Recherche en Matériaux Polymères (CIRMAP)

Abstract(s) :

(Anglais) INTRODUCTION Gene therapy has attracted increasing attention worldwide as prominent strategy to treat diseases at the gene level. While therapeutic gene has reached clinical evaluation, their administration as a drug is very challenging because of their rapid clearance from the bloodstream and the lack of tissue selectivity. Synthetic polymers have become a well-known solution to overcome these issues owing to the ease of synthesis and their ability to drive genetic materials toward targeted cells. Aliphatic poly(carbonate)s (APCs) are biocompatible and biodegradable1,2 and they constitute an excellent family on this purpose MATERIALS AND METHODS In this work, APCs are synthetized by ring-opening polymerization (ROP) using a metal-free and non-toxic catalyst3. The tailoring of the polymer is done using monomers carrying the desired function. The obtained block copolymers should over-come biological barriers as the endosomal escape, the gene loading or the cell internalization. PEGylated copolymers are also considered and compared with the hydrophobic one. Monomers are synthetized from bis-MPA synthon according to well-established procedures1. The polymerization is carried out in CH2Cl2 in the presence of DBU with an initial monomers concentration of 1 M. The reaction is performed under protected atmosphere (glove box) during 4 hours at ambient temperature using PEO (hydrophilic) or BzOH (lipophilic) (macro-)initiators. Polymers are characterized by 1H-NMR in CDCl3 and SEC in THF/NEt3. The association polymer – gene (polyplexe) is evaluated in terms of physico-chemistry (size and zeta potential), siRNA incorporation, cellular transfection and mRNA shut-down. RESULTS AND DISCUSSION The results demonstrate that the introduction of guanidinum and morpholino groups in the composition led to a powerful polymer vector for siRNA delivery4. The presence of a hydrophilic tail has a strong impact on gene release and knock down efficiency (PEG dilemma)5. CONCLUSIONS This work proves that tailor-made APCs are competitively efficient in gene delivery offering an excellent alternative to the highly toxic golden standard poly(ethyleneimine). REFERENCES 1 S. Tempelaar et al., Chem. Soc. Rev. 2013, 42, 1312-1336 2 L. Mespouille et al., Progress in Polymer Science 2014, 39, 1144-1164 3 A. Nachtergael et al., Biomacromolecules 2015, 16 (2), 507-514 4 A. Frère et al., Biomacromolecules, 2015, 16 (3), 769-779 5 A. Frère et al., ACS Appl. Mater. Interfaces, 2017, 9 (3), 2181-2195