Mucus-penetrating PEGylated polysuccinimide-based nanocarrier for intravaginal delivery of siRNA battling sexually transmitted infections

• Published in: Colloids and surfaces, B, Biointerfaces B, Biointerfaces, 2020-12, Vol.196, p.111287-111287, Article 111287
• Main Authors: Currie, Sarah, Kim, Seungil, Gu, Xiaochen, Ren, Xiaoou, Lin, Francis, Liu, Shangxi, Yang, Chengbo, Kim, Ji-Heung, Liu, Song
• Format: Article
• Language: English
• Subjects: HSV-2 prevention; Intravaginal nanomedicine; Mucus-penetrating siRNA nanocarrier; Polysuccinimide (PSI)-based nanocarrier; Preventing sexually transmitted infections
• ISSN: 0927-7765; 1873-4367
• DOI: 10.1016/j.colsurfb.2020.111287

[Display omitted] •A new poly(amino acid)-based intravaginal nanocarrier has been fabricated for intravaginal delivery of siRNA.•siRNA loaded PSI-PEG-API-PMA (PPAP) achieved enhanced mucus penetration efficiency, 2.4 times greater than free siRNA.•A higher cellular uptake of siRNA and gene knockdown by siRNA loaded PPAP than free siRNA. 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-NH2, 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.