Investigating histidinylated highly branched poly(lysine) for siRNA delivery

Alazzo, Ali; Gumus, Nurcan; Gurnani, Pratik; Stolnik, Snjezana; Rahman, Ruman; Spriggs, Keith; Alexander, Cameron

Abstract

The temporary silencing of disease-associated genes utilising short interfering RNA (siRNA) is a potent and selective route for addressing a wide range of life limiting disorders. However, the few clinically approved siRNA therapies rely on lipid based formulations, which although potent, provide limited chemical space to tune the stability, efficacy and tissue selectivity. In this study, we investigated the role of molar mass and histidinylation for poly(lysine) based non-viral vectors, synthesised through a fully aqueous thermal condensation polymerisation. Formulation and in vitro studies revealed that higher molar mass derivatives yielded smaller polyplexes attributed to a greater affinity for siRNA at lower N/P ratios yielding greater transfection efficiency, albeit with some cytotoxicity. Histidinylation had a negligible effect on formulation size, yet imparted a moderate improvement in biocompatibility, but did not provide any meaningful improvement over silencing efficiency compared to non-histidinylated derivatives. This was attributed to a greater degree of cellular internalisation for non-histidinylated analogues, which was enhanced with the higher molar mass material. This journal is

Citation

Alazzo, A., Gumus, N., Gurnani, P., Stolnik, S., Rahman, R., Spriggs, K., & Alexander, C. (2022). Investigating histidinylated highly branched poly(lysine) for siRNA delivery. Journal of Materials Chemistry B, 10(2), 236-246. https://doi.org/10.1039/d1tb01793d

• Journal Article Type: Article
• Acceptance Date: Nov 22, 2021
• Online Publication Date: Nov 23, 2021
• Publication Date: Jan 14, 2022
• Deposit Date: Dec 2, 2021
• Publicly Available Date: Dec 10, 2021
• Journal: Journal of Materials Chemistry B
• Print ISSN: 2050-750X
• Electronic ISSN: 2050-7518
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 2
• Pages: 236-246
• DOI: https://doi.org/10.1039/d1tb01793d
• Keywords: General Materials Science; Biomedical Engineering; General Chemistry; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/6847055
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2022/TB/D1TB01793D