Blood vessels in the tumor periphery have high pericyte coverage and are resistant to vascular disrupting agents (VDAs). VDA treatment resistance leads to a viable peripheral tumor rim that contributes to treatment failure and disease recurrence. Here, we provide evidence to support a hypothesis that shifting the target of VDAs from tumor vessel endothelial cells to pericytes disrupts tumor peripheral vessels and the viable rim, circumventing VDA treatment resistance. Through chemical engineering, we developed Z-GP-DAVLBH (from the tubulin-binding VDA desacetylvinblastine monohydrazide [DAVLBH]) as a prodrug that can be selectively activated by fibroblast activation protein α (FAPα) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAPα-expressing tumor pericytes, disrupting blood vessels both within the core and around the periphery of tumors. As a result, Z-GP-DAVLBH treatment eradicated the otherwise VDA-resistant tumor rim and led to complete regression of tumors in multiple lines of xenografts without producing the drug-related toxicity that is associated with similar doses of DAVLBH. This study demonstrates that targeting tumor pericytes with an FAPα-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments.

中文翻译：

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靶向周细胞的前药克服了肿瘤对血管分裂剂的耐药性

肿瘤周围的血管具有高周细胞覆盖率，并且对血管分裂剂（VDA）具有抵抗力。VDA治疗耐药性导致可行的外周肿瘤边缘，导致治疗失败和疾病复发。在这里，我们提供证据支持以下假设：将VDA的目标从肿瘤血管内皮细胞转移到周细胞会破坏肿瘤外周血管和有活力的边缘，从而规避VDA治疗的耐药性。通过化学工程，我们开发了Z-GP-DAVLBH（来自微管蛋白结合的VDA去乙酰长春碱单酰肼[DAVLBH]），可以被肿瘤周细胞中的成纤维细胞活化蛋白α（FAPα）选择性激活。Z-GP-DAVLBH选择性破坏表达FAPα的肿瘤周细胞的细胞骨架，破坏肿瘤核心和周围的血管。结果，Z-GP-DAVLBH治疗消除了原本对VDA耐药的肿瘤边缘，并导致多系异种移植物中肿瘤完全消退，而没有产生与DAVLBH相似剂量相关的药物相关毒性。这项研究表明，用FAPα激活的VDA前药靶向肿瘤周细胞代表了克服VDA治疗对肿瘤耐药性的潜在血管破裂策略。