Highly efficient transduction of endothelial cells by targeted artificial virus-like particles.
Targeting the tumor vasculature by gene therapy is a potentially powerful approach, but suitable vectors have not yet been described. We have designed a new type of liposomal vector, based on the composition of anionic retroviral envelopes, that is serum-resistant and nontoxic. These artificial virus-like envelopes (AVEs) were endowed with a cyclic RGD-containing peptide as a targeting device for the a(v)beta3-integrin on tumor endothelial cells (ECs). The packaging of plasmid DNA complexed with low-molecular-weight, nonlinear polyethyleneimine into these AVEs yielded artificial virus-like particles (AVPs) that transduced ECs with efficiencies of up to 99%. In contrast, transduction of a variety of other cell types by these RGD-AVPs was comparably inefficient under the same experimental conditions. This EC selectivity was mediated, in part, but not exclusively, by the RGD ligand, as suggested by the reduced, but still relatively high, transduction efficiency seen with AVPs lacking RGD. The interaction of anionic lipids of the AVPs with ECs may therefore contribute to the observed selective and highly efficient transduction of this cell type. These findings suggest that the targeted AVE technology is a useful approach to create highly efficient nonviral vectors.
Institute of Pharmaceutical Technology and Biopharmaceutics, Philipps University, Marburg, Germany. mueller@imt.uni-marburg.de
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Müller
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Nahde
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Fahr
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Müller
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Brüsselbach
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000378:metabolism*; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D016023:Integrins / Q000235:genetics; D008081:Liposomes; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000235:genetics; D009842:Oligopeptides / Q000627:therapeutic use*; D011094:Polyethyleneimine; D014161:Transduction, Genetic
D000970:Antineoplastic Agents; D016023:Integrins; D008081:Liposomes; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D011094:Polyethyleneimine