title: Enhanced gene delivery efficiency of cationic liposomes coated with PEGylated hyaluronic acid for anti P-glycoprotein siRNA: a potential candidate for overcoming multi-drug resistance.
abstract: RNA interference is an effective method to achieve highly specific gene regulation. However, the commonly used cationic liposomes have poor biocompatibility, which may lead to systematic siRNA delivery of no avail. PEGylation is a good strategy in shielding the positive charge of cationic liposomes, but the enhanced serum stability is often in company with compromised cellular uptake and endosome escape. In this study, PEG was covalently linked to negatively charged hyaluronic acid and it was used to coat the liposome-siRNA nanoparticles. The resulting PEG-HA-NP complex had a diameter of 188.6 ± 10.8 nm and a dramatically declined zeta-potential from +34.9 ± 4.0 mV to -18.2 ± 2.2 mV. Owing to the reversed surface charge, PEG-HA-NP could remain stable in fetal bovine serum (FBS) to up to 24h. In contrast with normal PEGylation, hyaluronic acid and PEG co-modified PEG-HA-NP provided comparable cellular uptake and P-glycoprotein downregulation efficacy in MCF-7/ADR cells compared with Lipofectamine RNAiMAX and naked NP regardless of its anionic charged surface. Because of its good biocompatibility in serum, PEG-HA-NP possessed the best tumor accumulation, cellular uptake and subsequently the strongest P-glycoprotein silencing capability in tumor bearing mice compared with naked NP and HA-NP after i.v. injection, with a 34% P-glycoprotein downregulation. Therefore, PEG-HA coated liposomal complex was demonstrated to be a promising siRNA delivery system in adjusting solid tumor P-glycoprotein expression, which may become a potential carrier in reversing MDR for breast cancer therapy.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Ran
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Yayuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Huile
authors.initials: H
authors.lastname: Gao
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Kuang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Qianyu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China. Electronic address: qinhe@scu.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D002412:Cations; D002470:Cell Survival / Q000235:genetics; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D006820:Hyaluronic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D061986:MCF-7 Cells; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D013678:Technology, Pharmaceutical / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002412:Cations; D004337:Drug Carriers; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid
keywords: Cationic liposome; P-glycoprotein downregulation; PEGylated hyaluronic acid; Tumor targeting delivery; siRNA delivery