Department of Biosystems Engineering, Faculty of Agricultural and Food Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Biomedical Engineering, Faculty of Engineering, University of Manitoba, Winnipeg, Manitoba, Canada; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Colloids Surf B Biointerfaces. 2020 Dec;196:111287. doi: 10.1016/j.colsurfb.2020.111287. Epub 2020 Jul 29.
Intravaginal delivery of siRNA for prevention of sexually transmitted infections faces obstacles such as the acidic environment and vaginal mucus barrier. To achieve effective protection and delivery of siRNA, we developed a polysuccinimide (PSI)-based nanocarrier (PSI-PEG-API-PMA, PPAP) by conjugating methoxy polyethylene glycol amine (Me-PEG-NH, Mw 5000), 1-(3-aminopropyl)imidazole (API), and 1-pyrenemethylamine hydrochloride (PMA) to PSI. PPAP demonstrated a spherical self-assembled nanostructure before and after encapsulation of a model siRNA. Variable electrostatic interaction between API and siRNA at acidic vs. neutral pH accomplished significantly lower burst release at pH 4.2 (4 ± 1%) than pH 7.0 (26 ± 5%) within 1 h. PEGylation enabled siRNA-PPAP to achieve higher mucus penetration efficiency (64 ± 17%) than free siRNA (27 ± 5%) for 24 h. Moreover, in vitro study showed minimal toxicity, successful internalization of siRNA-PPAP in HeLa cells and improved gene knockdown (97.5 ± 0.4%). Overall, PPAP is promising for developing preventative treatments for battling sexually transmitted infections.
阴道内递送 siRNA 以预防性传播感染面临诸多障碍，如酸性环境和阴道黏液屏障。为了实现 siRNA 的有效保护和递送，我们通过将甲氧基聚乙二醇胺（Me-PEG-NH，Mw 5000）、1-(3-氨基丙基)咪唑（API）和 1-芘甲胺盐酸盐（PMA）连接到聚琥珀酰亚胺（PSI）上，开发了一种基于聚琥珀酰亚胺（PSI）的纳米载体（PSI-PEG-API-PMA，PPAP）。PPAP 在封装模型 siRNA 前后均表现出球形自组装纳米结构。在酸性 pH 下，API 与 siRNA 之间的可变静电相互作用使得在 1 h 内，PPAP 在 pH 4.2 时的突释率（4±1%）显著低于 pH 7.0 时的突释率（26±5%）。PEG 化使 siRNA-PPAP 能够实现比游离 siRNA（27±5%）更高的黏液穿透效率（64±17%），持续 24 h。此外，体外研究表明，siRNA-PPAP 具有最小的毒性，能够成功地将 siRNA 内化到 HeLa 细胞中，并提高基因敲低（97.5±0.4%）。总的来说，PPAP 有望开发出用于预防性治疗性传播感染的治疗方法。
