Received for publication January 31, 2008.
Revised May 9, 2008.
Accepted for publication May 9, 2008.

Squalenoylation favourably modifies the in vivo pharmacokinetics and biodistribution of gemcitabine in mice

Abstract

Gemcitabine (dFdC) is an anticancer nucleoside analogue active against wide variety of solid tumors. However, this compound is rapidly inactivated by enzymatic deamination and can also induce drug resistance. To overcome the above drawbacks, we recently designed a new squalenoyl nanomedicine of dFdC (SQdFdC) by covalently coupling gemcitabine with the 1,1',2-trisnorsqualenic acid; the resultant nanomedicine displayed impressively greater anticancer activity comparatively to the parent drug in an experimental murine model. In the present study, we report that SQdFdC nanoassemblies triggered controlled and prolonged release of dFdC, and displayed considerably greater half-life (t_1/2) (~3.9-fold), mean residence time (MRT) (~7.5-fold) comparatively to the dFdC administered as a free drug in mice. It was also observed that the linkage of gemcitabine to the 1,1',2-trisnorsqualenic acid noticeably delayed the metabolism of dFdC into its inactive difluorodeoxyuridine (dFdU) metabolite, comparatively to dFdC. Additionally, the elimination of SQdFdC nanoassemblies was considerably lower comparatively to free dFdC, as indicated by lower radioactivity found in urine and kidneys, in accordance with the plasmatic concentrations of dFdU. SQdFdC nanoassemblies also underwent considerably higher distribution to the organs of the reticulo-endothelial system such as spleen and liver (p<0.05) both after single-dose or multiple-dose administration schedule. Herein, this paper brings comprehensive pharmacokinetic and biodistribution insights which may explain the previously observed greater efficacy of SQdFdC nanoassemblies against experimental leukemia.

Key words: anticancer agents, drug delivery, drug disposition, pharmacokinetics