Controlled siRNA Release of Nanopolyplex for Effective Targeted Anticancer Therapy in Animal Model

Abstract

Jingchao Jia,1,2,* Jing Yang,3,* Leimin Qian,2 Biao Zhou,2 Xiaodong Tang,2 Shuanghai Liu,2 Li Wu,4 Jifeng Chen,5 Yuting Kuang1 1Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of General Surgery, Jiangyin Hospital Affiliated to Nantong University, Wuxi, People’s Republic of China; 3Jiangnan University Medical Center, Wuxi, People’s Republic of China; 4Department of Pharmaceutics, People’s Hospital of Shanggao, Yichun, People’s Republic of China; 5The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, Jinan University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuting Kuang, Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China, Email [email protected] Jifeng Chen, The Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation, Jinan University, Guangzhou, People’s Republic of China, Email [email protected]: Spatiotemporally controlled release of siRNA for anti-tumor therapy poses significant challenges. Near-infrared (NIR) light, known for its exceptional tissue penetration and minimal tissue invasiveness, holds promise as a viable exogenous stimulus for inducing controlled siRNA release in vivo. However, the majority of light-responsive chemical bonds exhibit absorption wavelengths in the ultraviolet (UV) or short-wavelength visible light range.Methods: To achieve NIR-controlled siRNA release, the study synthesized a UV-sensitive triblock copolymer cRGD-poly(ethylene glycol)-b-poly(aspartic acid ester-5-(2’-(dimethylamino)ethoxy)-2-nitrobenzyl alcohol)-b-polyphenylalanine, abbreviated as cRGD-PEG-PAsp(EDONB)-PPHE. This copolymer is composed of a cRGD-capped PEG block (cRGD-PEG), a poly(aspartate) block modified with cationic moieties through UV-cleavable 2-nitrobenzyl ester bonds [PAsp(EDONB)], and a hydrophobic polyphenylalanine block (PPHE). The cationic amphiphilic polymer cRGD-PEG-PAsp(EDONB)-PPHE can assemble with hydrophobic upconversion nanoparticles (UCNPs) to form a cationic micelle designated as T-UCNP, which subsequently complexes with siRNA to create the final nanopolyplex T-si/UCNP. siRNA-PLK1 was employed to prepare T-PLK1/UCNP nanopolyplex for anti-tumor therapy.Results: T-PLK1/UCNP not only exhibited outstanding tumor cell targeting through cRGD modification but also achieved 980 nm NIR-controlled PLK1 gene silencing. This was achieved by utilizing the encapsulated UCNPs to convert NIR into UV light, facilitating the cleavage of 2-nitrobenzyl ester bonds. As a result, there was a significant suppression of tumor growth.Conclusion: The UCNPs-encapsulated nanopolyplex T-si/UCNP, capable of co-delivering siRNA and UCNPs, enables precise NIR-controlled release of siRNA at the tumor site for cancer RNAi therapy. This nanopolyplex can enhance the controllability and safety of RNAi therapy for tumors, and it also holds the potential to serve as a platform for achieving controlled release and activation of other drugs, such as mRNA and DNA.Keywords: NIR-controlled siRNA release, nanopolyplex, UCNPs, anti-tumor therapy

Keywords

• nir-controlled sirna release
• nanopolyplex
• ucnps
• anti-tumor therapy