Department of Clinical Pharmacology, College of Pharmacy, Jinan University, Guangzhou, PR China.
J Drug Target. 2011 Aug;19(7):487-96. doi: 10.3109/1061186X.2010.511225. Epub 2011 Feb 2.
Fibroblast activation protein-α (FAPα) is a tumor-associated antigen uniquely expressed by reactive stromal fibroblasts in the majority of human epithelial tumors. FAPα also possesses both post-prolyl peptidase and endopeptidase activities. Consequently, FAPα is increasingly considered as a potential pan-tumor target for designing tumor-targeted prodrugs. We previously conjugated Doxorubicin (Dox) with a FAPα-specific dipeptide (Z-Gly-Pro) to develop a FAPα-targeting prodrug of Dox (FTPD). The aim of current work was to validate the tumor targeting of this targeted-delivery strategy. The results demonstrated that FTPD could effectually release Dox upon the hydrolysis of FAPα as well as the incubation with tumor homogenate of FAPα-positive tumor (4T1 tumor), while it was highly stable in mouse plasma and a variety of tissue homogenates including heart, liver, and so on. And the FAPα-cleaved FTPD exhibited significantly higher cytotoxicity against 4T1 cells in vitro than the uncatalyzed prodrug. Additionally, FTPD produced similar antitumor efficacy in 4T1 tumor-bearing mice to free Dox without obvious cardiotoxic effect. Moreover, subsequent study indicated that the accumulation of FTPD reduced significantly in the heart compared to free Dox. These findings suggest that such FAPα-based prodrug strategy is promising to achieve targeted delivery of antitumor agents.
成纤维细胞激活蛋白-α（FAPα）是一种肿瘤相关抗原，仅在大多数人类上皮肿瘤的反应性基质成纤维细胞中表达。FAPα 还具有脯氨酰肽后酶和内肽酶活性。因此，FAPα 被越来越多地认为是设计肿瘤靶向前药的潜在泛肿瘤靶点。我们之前将阿霉素（Dox）与 FAPα 特异性二肽（Z-Gly-Pro）缀合，开发了 FAPα 靶向阿霉素（FTPD）的前药。目前工作的目的是验证这种靶向递药策略的肿瘤靶向性。结果表明，FTPD 可以在 FAPα 水解以及与 FAPα 阳性肿瘤（4T1 肿瘤）的肿瘤匀浆孵育时有效地释放 Dox，而在小鼠血浆中和包括心脏、肝脏等在内的各种组织匀浆中高度稳定。并且 FAPα 切割的 FTPD 对体外 4T1 细胞的细胞毒性明显高于未催化的前药。此外，FTPD 在 4T1 荷瘤小鼠中的抗肿瘤疗效与游离 Dox 相似，无明显心脏毒性。此外，后续研究表明，与游离 Dox 相比，FTPD 在心脏中的蓄积明显减少。这些发现表明，基于 FAPα 的前药策略有望实现抗肿瘤药物的靶向递送。
