title: Efficient and Tumor Targeted siRNA Delivery by Polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol)-folate (PEI-PCL-PEG-Fol).
abstract: Efficient delivery of functional nucleic acids into specific cells or tissues is still a challenge for gene therapy and largely depends on targeted delivery strategies. The folate receptor (FR) is known to be overexpressed extracellularly on a variety of human cancers and is therefore an outstanding gate for tumor-targeted Trojan horse-like delivery of therapeutics. In this study, an amphiphilic and biodegradable ternary copolymer conjugated with folate as ligand, polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol)-folate (PEI-PCL-PEG-Fol) was synthesized and evaluated for targeted siRNA delivery via folate-FR recognition. The amphiphilic character of similar polymers was shown previously to support endosomal release of endocytosed nanocarriers and to promote formation of long circulating micelles. The obtained PEI-PCL-PEG-Fol exhibited less cytotoxicity in comparison with the corresponding ternary copolymer without folate (PEI-PCL-PEG) and with unmodified PEI25kDa. Stable micelle-like polyplexes with hydrodynamic diameters about 100 nm were found to have a zeta potential of +8.6 mV, which was lower than that of micelleplexes without folate-conjugation (+13-16 mV). Nonetheless, increased cellular uptake and in vitro gene knockdown of PEI-PCL-PEG-Fol/siRNA micelleplexes were observed in SKOV-3 cells, an FR overexpressing cell line, in comparison with the nonfolate-conjugated ones. Moreover, PEI-PCL-PEG-Fol/siRNA micelleplexes exhibited excellent stability in vivo during the analysis of 120 min and a longer circulation half life than hyPEI25kDa/siRNA polyplexes. Most interestingly, the targeted delivery system yielded 17% deposition of the i.v. injected siRNA per gram in the tumor after 24 h due to the effective folate targeting and the prolonged circulation.
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps-University Marburg , Ketzerbach 63, 35032 Marburg, Germany.|School of Pharmacy, Shanghai Jiao Tong University , 200240 Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps-University Marburg , Ketzerbach 63, 35032 Marburg, Germany.
authors.forename: Mengyao
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of Nuclear Medicine, University of Hospital Giessen and Marburg GmbH , Baldingerstrasse, 35043 Marburg, Germany.
authors.forename: Damiano
authors.initials: D
authors.lastname: Librizzi
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps-University Marburg , Ketzerbach 63, 35032 Marburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Renette
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps-University Marburg , Ketzerbach 63, 35032 Marburg, Germany.|Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , 259 Mack Avenue, Detroit, Michigan 48201, United States.
authors.forename: Olivia M
authors.initials: OM
authors.lastname: Merkel
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps-University Marburg , Ketzerbach 63, 35032 Marburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kissel
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D018014:Gene Transfer Techniques; D006801:Humans; D007097:Imines / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011094:Polyethyleneimine / Q000031:analogs & derivatives* / Q000737:chemistry; D011095:Polyethylenes / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D007097:Imines; D011091:Polyesters; D011095:Polyethylenes; D011108:Polymers; D034741:RNA, Small Interfering; C552831:poly(ethylene glycol)-folate; C505405:poly(ethylene imine); C576039:polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol); C016240:polycaprolactone; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D005492:Folic Acid
keywords: SKOV-3 tumor xenograft; SPECT imaging; folate targeting; prolonged circulation; siRNA delivery; tumor targeting