%0 Journal Article %T Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-α %A CHAI Xiao-ping %A SUN Guang-long %A FANG Yan-fen %A HU Li-hong %A LIU Xuan %A ZHANG Xiong-wen %J Acta Pharmacologica Sinica %D 2018 %B 2018 %9 %! Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-α %K %X Abstract BF211, a bufalin (BF) derivative, exhibits stronger anti-cancer activity than BF but with potential cardiotoxicity. Fibroblast activation protein-α (FAPα) is a membrane-bound protease specifically expressed by carcinoma-associated fibroblasts, thus has been used for the selective delivery of anticancer agents. In this study, we used a FAPα-based prodrug strategy to synthesize a dipeptide (Z-Gly- Pro)-conjugated BF211 prodrug named BF211-03. BF211-03 was hydrolyzed by recombinant human FAPα (rhFAPα) and cleaved by homogenates of human colon cancer HCT-116 or human gastric cancer MGC-803 xenografts. In contrast, BF211-03 showed good stability in plasma and in the homogenates of FAPα-negative normal tissues, such as heart and kidney. In HCT-116 and MGC-803 cells with low levels of FAPα expression, BF211-03 displayed a lower in vitro cytotoxicity than BF211 with approximately 30 to 40-fold larger IC 50 values, whereas in human breast cancer MDA-MB-435 cells with high levels of FAPα expression, the IC 50 value difference between BF211-03 and BF211 was small (approximately 4-fold). Although the cytotoxicity of BF211-03 against tumor cells was dramatically decreased by the chemical decoration, it was restored after cleavage of BF211-03 by rhFAPα or tumor homogenate. In HCT-116 tumorbearing nude mice, doubling the dose of BF211-03, compared with BF211, caused less weight loss, but showing similar inhibitive effects on tumor growth. Our results suggest that BF211-03 is converted to active BF211 in tumor tissues and exhibits anti-tumor activities in tumor-bearing nude mice. FAPα-targeted BF211-03 displays tumor selectivity and may be useful as a targeting agent to improve the safety profile of cytotoxic natural products for use in cancer therapy. %U http://www.chinaphar.com/article/view/9742 %V 39 %N 3 %P 415-424 %@ 1745-7254