Development of a liposomal nanoparticle formulation of 5-Fluorouracil for parenteral administration: Formulation design, pharmacokinetics and efficacy
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
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.
Copper, Polyethylenimine, Complexation, 5-fluorouracil, Nanoparticle liposomes, Colorectal cancer
Research subject Chemistry
IdentifiersURN: urn:nbn:se:uu:diva-147450DOI: 10.1016/j.jconrel.2010.11.018ISI: 000289701200012PubMedID: 21094191OAI: oai:DiVA.org:uu-147450DiVA: diva2:400376