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Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-α

   
@article{APS9742,
	author = {Xiao-ping CHAI and Guang-long SUN and Yan-fen FANG and Li-hong HU and Xuan LIU and Xiong-wen ZHANG},
	title = {Tumor-targeting efficacy of a BF211 prodrug through hydrolysis by fibroblast activation protein-α},
	journal = {Acta Pharmacologica Sinica},
	volume = {39},
	number = {3},
	year = {2018},
	keywords = {},
	abstract = {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 IC50 values, whereas in human breast cancer MDA-MB-435 cells with high levels of FAPα expression, the IC50 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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/9742}
}