RGD-based active targeting of novel polycation liposomes bearing siRNA for cancer treatment.
For the purpose of systemic delivery of siRNA, we previously developed polycation liposomes (PCLs) containing dicetylphosphate-tetraethylenepentamine (DCP-TEPA) as an effective siRNA carrier. In the present study, to endow these PCLs (TEPA-PCL) actively target cancer cells and angiogenic vessels, we decorated the PCLs with cyclic RGD, by using cyclic RGD-grafted distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG), and investigated the usefulness of this type of carrier (RGD-PEG-PCL) for active targeting. Firstly, the gene-silencing efficacy of siRNA for luciferase (siLuc2) formulated in RGD-PEG-PCL (RGD-PEG-PCL/siLuc2) was examined in vitro by using B16F10-luc2 murine melanoma cells stably expressing the luciferase 2 gene, where the siRNA was grafted with cholesterol at the 3'-end of the sense strand (siRNA-C) for the stable association of the siRNA with the PCL. RGD-PEG-PCL/siLuc2 showed high knockdown efficiency compared with siLuc2 formulated in PEGylated TEPA-PCL without cyclic RGD (PEG-PCL). Next, the gene-silencing efficacy of RGD-PEG-PCL/siLuc2 was examined in vivo by use of B16F10-luc2 lung metastatic model mice. The intravenous injection of RGD-PEG-PCL/siLuc2 showed high knockdown efficiency against metastatic B16F10-luc2 tumors in the lungs of the mice, as assessed with an in vivo imaging system. These data strongly suggest that systemic and active targeting siRNA delivery using RGD-PEG-PCL is useful for cancer RNAi therapy.
Department of Medical Biochemistry and Global COE Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Norihito
N
Yonenaga
Eriya
E
Kenjo
Tomohiro
T
Asai
Atsushi
A
Tsuruta
Kosuke
K
Shimizu
Takehisa
T
Dewa
Mamoru
M
Nango
Naoto
N
Oku
D000818:Animals; D002412:Cations; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D005029:Ethylenediamines / Q000737:chemistry; D015316:Genetic Therapy / Q000379:methods*; D008081:Liposomes; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000737:chemistry*; D010755:Organophosphates / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D002412:Cations; D004337:Drug Carriers; D005029:Ethylenediamines; D008081:Liposomes; D009842:Oligopeptides; D010755:Organophosphates; D034741:RNA, Small Interfering; C002290:dicetylphosphate; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; C034269:tetraethylenepentamine