title: Sialic Acid-Targeted Nanovectors with Phenylboronic Acid-Grafted Polyethylenimine Robustly Enhance siRNA-Based Cancer Therapy.
abstract: Small interference RNA (siRNA)-based therapy holds great potential for cancer treatment. However, its clinical application remains unsatisfied due to the lack of a safe and effective RNA delivery system. Aberrantly elevated sialyation on cell membrane has been reported as an attractive target for cancer diagnosis and therapy. In this study, phenylboronic acid (PBA) was conjugated onto low molecular weight polyethylenimine (PEI1.8k) to generate amphiphilic PBA-grafted PEI1.8k (PEI-PBA) nanovector, which was designed to facilitate cancer-targeted RNA delivery through the recognition of sialic structures on a cancer cell membrane. PEI-PBA simultaneously encapsulated siRNA to form PEI-PBA/siRNA nanocomplexes with great biocompatibility, serum stability and RNase resistance. The cell culture study showed that PEI-PBA/siRNA dramatically increased siRNA uptake up to 70-90% in several cancer cell lines, which relied on the interaction between PBA and sialic acid on cell membrane. Moreover, the PEI-PBA nanovector effectively promoted the lysosome escape of siRNA, decreasing the expression of target gene Polo-like kinase 1 (PLK-1) in cancer cells. The systemic administration of PEI-PBA/PLK-1 siRNA (PEI-PBA/siPLK1) nanocomplexes not only facilitated tumor-targeted siRNA delivery but also significantly decreased PLK-1 expression in tumors, thereby robustly inducing tumor apoptosis and cell cycle arrest. Additionally, the administration of PEI-PBA/siPLK1 did not cause significant systemic toxicity or immunotoxicity. Hence, sialic acid-targeted PEI-PBA could be a highly efficient and safe nanovector to improve the efficacy of cancer siRNA therapy.
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055, People's Republic of China.|Nano Science and Technology Institute, University of Science and Technology of China , Suzhou 215123, People's Republic of China.
authors.forename: Manyi
authors.initials: M
authors.lastname: Ji
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055, People's Republic of China.|Nano Science and Technology Institute, University of Science and Technology of China , Suzhou 215123, People's Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Sheng
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055, People's Republic of China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Pan
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055, People's Republic of China.
authors.forename: Ce
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055, People's Republic of China.
authors.forename: Lintao
authors.initials: L
authors.lastname: Cai
authors.affiliation: Key Lab of Health Informatics of Chinese Academy of Sciences, Guangdong Key Laboratory of Nanomedicine, Shenzhen Laboratory of Fully Human Antibody Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055, People's Republic of China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008819:Mice, Nude; D019158:N-Acetylneuraminic Acid / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D011094:Polyethyleneimine / Q000138:chemical synthesis / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D034741:RNA, Small Interfering / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D034741:RNA, Small Interfering; D011094:Polyethyleneimine; D019158:N-Acetylneuraminic Acid; C010686:benzeneboronic acid
keywords: cancer-targeting; low molecular weight polyethylenimine; phenylboronic acid; siRNA delivery; sialic acid