Characterization of Cationic Liposome Formulations Designed to Exhibit Extended Plasma Residence Times and Tumor Vasculature Targeting Properties |
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Authors: | Emmanuel A Ho Euan Ramsay Mihaela Ginj Malathi Anantha Isaiah Bregman Jonathan Sy Janet Woo Maryam Osooly-Talesh Donald T Yapp Marcel B Bally |
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Institution: | 1. Department of Advanced Therapeutics, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, Canada V5Z 1 L3;2. Centre for Drug Research and Development, 364-2259 Lower Mall, Vancouver, BC, Canada V6T 1Z4;3. Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Westbrook, Mall, Vancouver, BC, Canada V6T 2B5;4. Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3 |
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Abstract: | Cationic liposomes exhibit a propensity to selectively target tumor-associated blood vessels demonstrating potential value as anti-cancer drug delivery vehicles. Their utility however, is hampered by their biological instability and rapid elimination following i.v. administration. Efforts to circumvent rapid plasma elimination have, to date, focused on decreasing cationic lipid content and incorporating polyethylene glycol (PEG)-modified lipids. In this study we wanted to determine whether highly charged cationic liposomes with surface-associated PEG could be designed to exhibit extended circulation lifetimes, while retaining tumor vascular targeting properties in an HT29 colorectal cancer xenograft model. Cationic liposomes prepared of DSPC, cationic lipids (DODAC, DOTAP, or DC-CHOL), and DSPE-PEG2000 were studied. Our results demonstrate that formulations prepared with 50 mol% DODAC or DC-CHOL, and 20 mol% DSPE-PEG2000 exhibited circulation half-lives ranging from 6.5 to 12.5 h. Biodistribution studies demonstrated that DC-CHOL formulations prepared with DSPE-PEG2000 accumulated threefold higher in s.c. HT29 tumors than its PEG-free counterpart. Fluorescence microscopy studies suggested that the presence of DSPE-PEG2000 did not adversely affect liposomal tumor vasculature targeting. We show for the first time that it is achievable to design highly charged, highly pegylated (20 mol% DSPE-PEG2000) cationic liposomes which exhibit both extended circulation lifetimes and tumor vascular targeting properties |
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