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In vitro and in vivo effects of polyethylene glycol (PEG)-modified lipid in DOTAP/cholesterol-mediated gene transfection

Authors Gjetting T, Arildsen, Christensen C, Poulsen T, Roth J, Handlos, Poulsen HS

Published 25 May 2010 Volume 2010:5 Pages 371—383

DOI https://doi.org/10.2147/IJN.S10462

Review by Single-blind

Peer reviewer comments 2

Torben Gjetting1, Nicolai Skovbjerg Arildsen1, Camilla Laulund Christensen1, Thomas Tuxen Poulsen1, Jack A Roth3, Vagn Neerup Handlos2, Hans Skovgaard Poulsen1

1Department of Radiation Biology, Finsen Center, 2RH Pharmacy, Copenhagen University Hospital, Copenhagen, Denmark; 3Thoracic Medical Oncology, MD Anderson Cancer Centre, Houston, TX, USA

Background: DOTAP/cholesterol-based lipoplexes are successfully used for delivery of plasmid DNA in vivo especially to the lungs, although low systemic stability and circulation have been reported. To achieve the aim of discovering the best method for systemic delivery of DNA to disseminated tumors we evaluated the potential of formulating DOTAP/cholesterol lipoplexes with a polyethylene glycol (PEG)-modified lipid, giving the benefit of the shielding and stabilizing properties of PEG in the bloodstream.

Method: A direct comparison of properties in vitro and in vivo of 4 different DOTAP/cholesterol-based lipoplexes containing 0%, 2%, 4%, and 10% PEG was performed using reporter gene activity and radioactive tracer lipid markers to monitor biodistribution.

Results: We found that 10% PEGylation of lipoplexes caused reduced retention in lung and heart tissues of nude mice compared to nonPEGylated lipoplexes, however no significant delivery to xenograft flank tumors was observed. Although PEGylated and nonPEGylated lipoplexes were delivered to cells the ability to mediate successful transfection is hampered upon PEGylation, presumably due to a changed uptake mechanism and intracellular processing.

Conclusion: The eminent in vivo transfection potency of DOTAP/cholesterol-based lipoplexes is well established for expression in lung tumors, but it is unsuitable for expression in non first pass organs such as xenograft flank tumors in mice even after addition of a PEG-lipid in the formulation.

Keywords: gene delivery, DOTAP, polyethylene glycol (PEG), biodistribution, lung cancer, xenograft tumor model

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