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Development of a liposomal nanoparticle formulation of 5-Fluorouracil for parenteral administration: Formulation design, pharmacokinetics and efficacy
Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
Center for Drug Research and Development, 364-2259 Lower Mall, Vancouver, BC, Canada.
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2011 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 150, no 2, 212-219 p.Article in journal (Refereed) Published
Abstract [en]

5-Fluorouracil (5-FU) is a small, very membrane permeable drug that is poorly retained within the aqueous compartment of liposomal nanoparticles (LNP). To address this problem a novel method relying on formation of a ternary complex comprising copper, low molecular weight polyethylenimine (PEI) and 5-FU has been developed. More specifically, in the presence of entrapped copper and PEI, externally added 5-FU can be efficiently encapsulated (>95%) in DSPC/Chol (1,2-Distearoyl-sn-Glycero-3-Phosphocholine/cholesterol; 55:45mol%) liposomes (130-170nm) to achieve drug-to-lipid ratios of 0.1 (mol:mol). Drug release studies completed using this LNP formulation of 5-FU demonstrated significant improvements in drug retention in vitro and in vivo. Plasma concentrations of 5-FU were 7- to 23-fold higher when the drug was administered intravenously to mice as the LNP 5-FU formulation compared to free 5-FU. Further, the therapeutic effects of the LNP 5-FU formulation, as determined in a HT-29 subcutaneous colorectal cancer model where treatment was given QDx5, was greater than that which could be achieved with free 5-FU when compared at equivalent doses. This is the first time an active loading method has been described for 5-FU. The use of ternary metal complexation strategy to encapsulate therapeutic agents may define a unique platform for preparation of LNP drug formulations.

Place, publisher, year, edition, pages
2011. Vol. 150, no 2, 212-219 p.
Keyword [en]
Copper, Polyethylenimine, Complexation, 5-fluorouracil, Nanoparticle liposomes, Colorectal cancer
National Category
Chemical Sciences
Research subject
URN: urn:nbn:se:uu:diva-147450DOI: 10.1016/j.jconrel.2010.11.018ISI: 000289701200012PubMedID: 21094191OAI: oai:DiVA.org:uu-147450DiVA: diva2:400376
Available from: 2011-02-25 Created: 2011-02-25 Last updated: 2011-05-09Bibliographically approved

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