title: EGFR-specific PEGylated immunoliposomes for active siRNA delivery in hepatocellular carcinoma.
abstract: The development of immunoliposomes for systemic siRNA (small interfering RNA) delivery is highly desired. We reported previously the development of targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab' (TLPD-FCC) for siRNA delivery, which showed superior gene silencing activity in EGFR-overexpressing breast cancers. However, TLPD-FCC did not achieve satisfactory gene silencing activity in EGFR-overexpressing hepatocellular carcinoma (HCC). In this study, some modifications including increased antibody conjugation efficiency and reduced PEGylation degree were made to TLPD-FCC to increase gene silencing activity in HCC. The resultant optimized liposomes denoted as TLPD-FP75 efficiently bound and delivered to EGFR-overexpressing HCC, resulting in enhanced gene silencing activity compared to untargeted LPD (NTLPD-FP75). Tissue distribution in vivo revealed that the accumulation of TLPD-FP75 was higher than NTLPD-FP75 in orthotopic HCC model of mice. The promoted uptake of TLPD-FP75 in HCC cells was confirmed by confocal microscopy. To investigate the in vivo gene silencing activity, we administered TLPD-FP75 by intravenous injections into mice bearing orthotopic HCC. The results showed TLPD-FP75 potently suppressed luciferase expression, while little silencing was observed in NTLPD-FP75. TLPD-FP75 was demonstrated to possess potent gene silencing activity in HCC and will potentially increase the feasibility of HCC gene therapy.
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai 200433, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Yu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jinjing
authors.initials: J
authors.lastname: Song
authors.forename: Huaiwen
authors.initials: H
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.forename: Li
authors.initials: L
authors.lastname: Deng
authors.forename: Geng
authors.initials: G
authors.lastname: Kou
authors.forename: Jianming
authors.initials: J
authors.lastname: Chen
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D066246:ErbB Receptors; D020868:Gene Silencing; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry*; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy*; D008297:Male; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000502:physiology
chemical_list: D008081:Liposomes; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols; D066246:ErbB Receptors