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Regioselective thioacetylation of chitosan end-groups for nanoparticle gene delivery systems

Vincent Pickenhahn, Vincent Darras, F. Dziopa, K. Biniecki, Gregory De Crescenzo, Marc Lavertu and Michael D. Buschmann

Article (2015)

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Chitosan (CS) end-group chemistry is a conjugation strategy that has been minimally exploited in the literature to date. Although the open-chain form of the CS reducing extremity bears a reactive aldehyde moiety, the most common method to generate a reactive end-group on CS is nitrous acid depolymerization, which produces a 2,5-anhydro-D-mannose unit (M-Unit) bearing also an aldehyde moiety. However, the availability of the latter might be low, since previous literature suggests that its hydrated and non-reactive form, namely the gem-diol form, is predominant in acidic aqueous conditions. Oxime-click chemistry has been used to react on such aldehydes with various degrees of success, but the use of a co-solvent and additional chemical reagents remain necessary to obtain the desired and stable covalent linkage. In this study, we have assessed the availability of the aldehyde reactive form on chitosan treated with nitrous acid. We have also assessed its reactivity towards thiol-bearing molecules in acidic conditions where CS amino groups are fully protonated and thus unreactive towards aldehyde. LC-MS and NMR spectroscopy methods (H-1 and DOSY, respectively) confirmed the regioselective thioacetylation of the reactive aldehyde with conversion rates between 55 and 70% depending on the thiol molecule engaged. The stabilization of the hemithioacetal intermediates into the corresponding thioacetals was also found to be facilitated upon freeze-drying of the reaction medium. The PEGylation of the CS M-Unit aldehyde by thioacetylation was also performed as a direct application of the proposed conjugation approach. CS-b-PEG(2) block copolymers were successfully synthesized and were used to prepare block ionomer complexes with plasmid DNA, as revealed by their spherical morphology vs. the rod-like/globular/toroidal morphology observed for polyplexes prepared using native unmodified chitosan. This novel aqueous thiol-based conjugation strategy constitutes an alternative to the oxime-click pathway; it could be applicable to other polymers.

Subjects: 1800 Chemical engineering > 1800 Chemical engineering
1900 Biomedical engineering > 1900 Biomedical engineering
Department: Department of Chemical Engineering
Institut de génie biomédical
Funders: CRSNG / NSERC, ANRis Pharmaceuticals
PolyPublie URL: https://publications.polymtl.ca/3472/
Journal Title: Chemical Science (vol. 6, no. 8)
Publisher: Royal Society Of Chemistry
DOI: 10.1039/c5sc00038f
Official URL: https://doi.org/10.1039/c5sc00038f
Date Deposited: 09 Jan 2019 15:18
Last Modified: 01 Nov 2023 12:56
Cite in APA 7: Pickenhahn, V., Darras, V., Dziopa, F., Biniecki, K., De Crescenzo, G., Lavertu, M., & Buschmann, M. D. (2015). Regioselective thioacetylation of chitosan end-groups for nanoparticle gene delivery systems. Chemical Science, 6(8), 4650. https://doi.org/10.1039/c5sc00038f


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