Treatment of Colon Cancer by Degradable rrPPC Nano-Conjugates Delivered STAT3 siRNA

• Published in: International journal of nanomedicine 2020-01, Vol.15, p.9875-9890
• Main Authors: Zhang, Hongjia, Men, Ke, Pan, Congbin, Gao, Yan, Li, Jingmei, Lei, Sibei, Zhu, Guonian, Li, Rui, Wei, Yuquan, Duan, Xingmei
• Format: Article
• Language: English
• Subjects: Biocompatibility; Cancer; Cancer therapies; Care and treatment; Cell Line, Tumor; Cholesterol; Cholesterol - chemistry; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - therapy; Colorectal cancer; Cytotoxicity; Development and progression; Drug Carriers - chemistry; Drug therapy; Efficiency; Ethylene; Fourier transforms; Gene therapy; Genetic aspects; Health aspects; Humans; Molecular weight; nanoparticle; Nanoparticles; Nanoparticles - chemistry; NMR; Nuclear magnetic resonance; Original Research; Peptides; Peptides, Cyclic - chemistry; Polyethylene Glycols - chemistry; Polyethyleneimine - analogs & derivatives; Polyethyleneimine - chemistry; RNA Interference; rna interfering; RNA, Small Interfering - chemistry; RNA, Small Interfering - genetics; Spectrum analysis; stat3; STAT3 Transcription Factor - deficiency; STAT3 Transcription Factor - genetics; Transfection
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S277845

Drugs that work based on the mechanism of RNA interference have shown strong potential in cancer gene therapy. Although significant progress has been made in small interfering RNA (siRNA) design and manufacturing, ideal delivery system remains a limitation for the development of siRNA-based drugs. Particularly, it is necessary to focus on parameters including delivery efficiency, stability, and safety when developing siRNA formulations for cancer therapy. In this work, a novel degradable siRNA delivery system cRGD-R9-PEG-PEI-Cholesterol (rrPPC) was synthesized based on low molecular weight polyethyleneimine (PEI). Functional groups including cholesterol, cell penetrating peptides (CPPs), and poly(ethylene oxide) were introduced to PEI backbone to attain enhanced transfection efficiency and biocompatibility. The synthesized rrPPC was dispersed as nanoparticles in water with an average size of 195 nm and 41.9 mV in potential. rrPPC nanoparticles could efficiently deliver siRNA into C26 clone cancer cells and trigger caveolae-mediated pathway during transmembrane transportation. By loading the signal transducer and activator of transcription 3 (STAT3) targeting siRNA, rrPPC/STAT3 siRNA (rrPPC/siSTAT3) complex demonstrated strong anti-cancer effects in multiple colon cancer models following local delivery. In addition, intravenous (IV) injection of rrPPC/siSTAT3 complex efficiently suppressed lung metastasis tumor progression with ideal in vivo safety. Our results provide evidence that rrPPC nanoparticles constitute a potential candidate vector for siRNA-based colon cancer gene therapy.