Abstract
Gemcitabine (2′,2′-difluorodeoxyribofuranosylcytosine; dFdC) is an anticancer nucleoside analog 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 [4-(N)-trisnorsqualenoyl-gemcitabine (SQdFdC)] by covalently coupling gemcitabine with the 1,1′,2-trisnorsqualenic acid; the resultant nanomedicine displayed impressively greater anticancer activity compared with 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 t1/2 (∼3.9-fold), mean residence time (∼7.5-fold) compared with 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, compared with dFdC. Additionally, the elimination of SQdFdC nanoassemblies was considerably lower compared with 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 reticuloendothelial system, such as spleen and liver (p < 0.05), both after single- or multiple-dose administration schedule. Herein, this paper brings comprehensive pharmacokinetic and biodistribution insights that may explain the previously observed greater efficacy of SQdFdC nanoassemblies against experimental leukemia.
Footnotes
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This study was supported by the Agence Nationale de la Recherche (Grant SYLIANU), by the Centre National de la Recherche Scientifique (Grant Ingénieur de Valorisation), by the Université Paris-Sud (postdoctoral fellowship to L.H.R.), and by the Institut Gustave Roussy (postdoctoral fellowship to H.K.).
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L.H.R. and H.K. contributed equally to this work.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.020735.
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ABBREVIATIONS: dFdC, gemcitabine, 2′,2′-difluorodeoxyribofuranosylcytosine; dFdU, difluorodeoxyuridine; SQdFdC, squalenoyl gemcitabine, 4-(N)-trisnorsqualenoyl-gemcitabine; LC, liquid chromatography; MS, mass spectrometry; HPLC, high-performance liquid chromatography; THU, tetrahydrouridine; AUC, area(s) under the plasma concentration-time curve; Cl, total body clearance; Vss, volume of distribution; dFdCNA, dFdC released from SQdFdC nanoassemblies; MRT, mean residence time.
- Received January 31, 2008.
- Accepted May 9, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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