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Gene delivery with active targeting to ovarian cancer cells mediated by folate receptor alpha.

Journal of biomedical nanotechnology (2013-06-28)
Zhiyao He, Yiyi Yu, Ying Zhang, Yongdong Yan, Yu Zheng, Jun He, Yongmei Xie, Gu He, Yuquan Wei, Xiangrong Song
ABSTRACT

Folate receptor alpha (FRalpha) is overexpressed on ovarian cancer cells and is a promising molecular target for ovarian cancer gene therapy, but there was still no related report. In this study, folate modified cationic liposomes (F-PEG-CLPs) for ovarian cancer gene delivery were developed for the first time. Folate-poly(ethylene glycol)-succinate-cholesterol (F-PEG-suc-Chol) was firstly synthesized and then used to prepare folate-targeted cationic liposomes/plasmid DNA complexes (F-targeted lipoplexes). F-targeted lipoplexes were prepared by post-insertion method, and displayed membrane structure by transmission electron microscopy observation with the diameter of 193 nm-200 nm and the zeta potential of 35 mV-38 mV. DNase degradation experiments showed that plasmid DNA could be effectively shielded by F-targeted lipoplexes in vitro. F-targeted lipoplexes could transfer gene into human ovarian carcinoma cell line SKOV-3, and 0.1% F-PEG-CLPs composed by DOTAP/Chol/mPEG-Chol/F-PEG-suc-Chol (50:45:5:0.1, molar ratio) had the highest transfection efficiency. The transfection activity of F-targeted lipoplexes could be competitively inhibited by free folic acid, demonstrating that folate-FRalpha interaction caused high transfection efficiency of F-targeted lipoplexes. The uptake mechanism of F-targeted lipoplexes was further validated on human oral carcinoma cell line KB and human liver carcinoma cell line HepG2. The concentration-dependent and time-dependent cytotoxicity of targeted material F-PEG-suc-Chol was observed by MTT assay on SKOV-3 cell and its application would not increase the cytotoxicity of F-targeted lipoplexes in SKOV-3 cells. All the data indicated that F-PEG-CLPs would be a promising gene vector targeting for ovarian cancer therapy.

MATERIALS
Product Number
Brand
Product Description

SAFC
Cholesterol, Plant-Derived, SyntheChol®, NF, Ph. Eur., JP
Folic acid, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Folic acid, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥97%
Sigma-Aldrich
Folic acid, ≥97%
Sigma-Aldrich
Folic acid, meets USP testing specifications
Sigma-Aldrich
Succinic acid, BioXtra, BioRenewable, ≥99.0%
Sigma-Aldrich
Succinic acid, BioReagent, BioRenewable, suitable for cell culture, suitable for insect cell culture
Sigma-Aldrich
Succinic acid, ReagentPlus®, BioRenewable, ≥99.0%
Supelco
Succinic acid, certified reference material, TraceCERT®
Sigma-Aldrich
Succinic acid, purum p.a., ≥99.0% (T)
Sigma-Aldrich
Succinic acid, ACS reagent, ≥99.0%
Supelco
Folic acid, analytical standard
Sigma-Aldrich
Succinic acid, puriss. p.a., ACS reagent, ≥99.5% (T)
Supelco
Folic acid, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Cholesterol, powder, BioReagent, suitable for cell culture, ≥99%
Supelco
Cholesterol solution, certified reference material, 10 mg/mL in chloroform
Sigma-Aldrich
Cholesterol, Sigma Grade, ≥99%
Sigma-Aldrich
SyntheChol® NS0 Supplement, 500 ×, synthetic cholesterol, animal component-free, aqueous solution, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Cholesterol, from sheep wool, ≥92.5% (GC), powder
Sigma-Aldrich
Cholesterol, tested according to Ph. Eur.