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Abstract: Gemcitabine (GEM) is a nucleoside analog agent against a wide variety of tumors. To overcome its limitation of rapid metabolism in vivo that results in short circulation time and poor antitumor efficacy, a novel prodrug (CLA–GEM conjugate) has been developed through the covalent coupling of conjugated linoleic acid (CLA) to N4-amino group of GEM. The chemical structure of CLA–GEM conjugate was identified by NMR, FTIR and other methods. From in vitro tests, it was demonstrated that the linkage with CLA increased the plasma stability of GEM as well as the antitumor activity against human breast tumor cells (MCF-7). Importantly, it also altered the transport pattern of GEM across cell membrane (MCF-7 and MDA-MB-231), evidenced by the little effect of nucleoside transporter inhibitors (NBMPR and dipyridamole) on the IC50 values of CLA–GEM, instead of the great effect on that of unmodified GEM. In vivo pharmacokinetic study showed that the CLA–GEM conjugate had a longer plasma half-life and a higher bioavailability compared to that of unmodified GEM. Significant stronger antitumor activity was observed in the nude mice xenografted MCF-7 breast tumor after treated with CLA–GEM than that of unmodified GEM, while no significant body weight loss was found in all treatments. In conclusion, the novel CLA–GEM conjugate prepared in this study would be a promising prodrug of gemcitabine for future clinical use. [Copyright &y& Elsevier]