Abstract :
[en] Synthesis of aliphatic polycarbonate for Antisense Oligomers targeted delivery in gene therapy
A. Baronia,b , P. Duboisa, L. Mespouillea, B. Blankertb
a Laboratory of Polymeric and Composite Materials (LPCM), Center of Innovation and Research in Materials and Polymers (CIRMAP)
b Laboratory of Pharmaceutical Analysis, Research Insitute for Health and Science Technology
University of Mons (UMONS), 23 Place du Parc, 7000 Mons, Belgium
alexandra.baroni@umons.ac.be
Gene therapy has attracted increasing attention worldwide as prominent strategy to treat diseases at the gene level. The use of antisense oligomers (AO's) into the cytoplasm of functional cells is a promising therapy strategy for neuromuscular disorders as FSHD (Facio-Scapulo-Humeral muscular Distrophy). While these therapeutics hold high promises, the administration of oligonucleotides as a drug is very challenging because of their rapid clearance from the bloodstream and the lack of tissue selectivity. Synthetic polymers have attracted attention in the field of gene therapy owing to the ease of synthesis and modification, allowing the design of polymer vectors safer than viral ones and presenting some advantageous characteristics enabling overcoming obstacles met in gene therapy. The use of tailor-made aliphatic poly(carbonate)s (APCs) synthetized by ring-opening polymerization (ROP) using a metal-free and non-toxic catalyst1 is highlighted. This family of polymers is biocompatible and biodegradable2,3 which is really advantageous compared to the highly toxic golden standard poly(ethylenimine) (PEI)4. In a preliminary study5, the presence of hydrophobic tail of polytrimethylene carbonate (PTMC) as well as introduction of guanidinum and morpholino groups in the composition of the vector led to powerful polymer vector for siRNA delivery. In order to promote cell targeting to muscle cells, introduction of efficient Click coupling functionality will be investigated.
Herein we report the synthesis of copolymers fulfilling the aptitude to 'click reacting' with bis-TAD molecule6; a strategy that may allow us to facilitate conjugation with ligands selective to some muscular cell lines. Monomers are synthetized from bis-MPA synthon according to well-established procedures2. 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 PEO5000 or BzOH as precursors. Polymers are characterized by RMN-1H in CDCl3 and Gel Permeation Chromatography (GPC) in THF/NEt3.
References
1 A. Nachtergael et al. Biomacromolecules 2015, accepted, DOI 10.1021/bm5015443
2 S. Tempelaar et al. Chem. Soc. Rev. 2013, 42, 1312-1336
3 L. Mespouille et al. Progress in Polymer Science 2014, 39, 1144-1164
4 J. Zhou et al. Nature Mater. 2012, 11, 82
5 A. Frere et al. Biomacromolecules 2015, accepted, DOI 10.1021/bm501676
6 S. Billiet et al. Nature Chemistry 2014, 6, 815-821
