FAPα酶激活式前药Z-GP-DAVLBH靶向BM-MSCs抑制三阴性乳腺癌肺转移作用及机制研究

肿瘤转移是三阴性乳腺癌(TNBC)患者死亡的主要原因，迄今临床上仍缺乏治疗TNBC的有效药物。骨髓间充质干细胞(BM-MSCs)是促进TNBC转移的关键因素，因此选择性杀伤BM-MSCs可能是抑制TNBC转移的有效途径。酶激活式前药策略可提高母药对酶表达细胞的靶向性，基于BM-MSCs高表达FAPα，本课题组设计并合成FAPα酶激活式长春碱前药Z-GP-DAVLBH，以期靶向杀伤BM-MSCs从而抑制TNBC转移。前期研究发现该前药可在体外选择性杀伤BM-MSCs，在体内抑制TNBC细胞MDA-MB-231肺转移。本项目拟在前期工作的基础上，利用BM-MSCs/MDA-MB-231体外3D共培养系统和原位移植瘤模型，研究Z-GP-DAVLBH依赖于FAPα靶向BM-MSCs从而抑制TNBC转移的作用及机制，为把Z-GP-DAVLBH发展成为临床抗TNBC药物提供科学依据。

Metastasis is the major cause of cancer related death for patients with triple negative breast cancer (TNBC), however, effective drugs for the treatment of TNBC is unavailable so far. Bone marrow-mesenchymal stem cells (BM-MSCs) play an important role in metastasis of TNBC, therefore selective targeting BM-MSCs may be an effective approach to inhibit the metastasis of TNBC. The enzyme activated prodrug strategy improves the targeting efficiency of chemotherapy drugs in cells expressing the enzyme. Since fibroblast activation protein-alpha (FAPα) is overexpressed in BM-MSCs, our group designed and synthesized an FAPα-activated vinblastine prodrug, Z-GP-DAVLBH, in order to achieve targeted killing BM-MSCs to inhibit the metastasis of TNBC. Our preliminary study showed that Z-GP-DAVLBH could selectively kill BM-MSCs in vitro and inhibit lung metastasis of TNBC cell line MDA-MB-231 in vivo. Based on these results, using three dimensional co-culture systems of BM-MSCs/MDA-MB-231 in vitro and orthotopic xenografts, this proposal aims to further investigate the effects and the underlying mechanisms of Z-GP-DAVLBH targeting BM-MSCs in an FAPα dependent manner to inhibit TNBC metastasis. This study will provide scientific rationales for the development of Z-GP-DAVLBH as a therapeutic strategy in the treatment of TNBC.