Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents
Minfeng Chen, Xueping Lei, Changzheng Shi, Maohua Huang, Xiaobo Li, Baojian Wu, Zhengqiu Li, Weili Han, Bin Du, Jianyang Hu, Qiulin Nie, Weiqian Mai, Nan Ma, Nanhui Xu, Xinyi Zhang, Chunlin Fan, Aihua Hong, Minghan Xia, Liangping Luo, Ande Ma, Hongsheng Li, Qiang Yu, Heru Chen, Dongmei Zhang, Wencai Ye
Minfeng Chen, Xueping Lei, Changzheng Shi, Maohua Huang, Xiaobo Li, Baojian Wu, Zhengqiu Li, Weili Han, Bin Du, Jianyang Hu, Qiulin Nie, Weiqian Mai, Nan Ma, Nanhui Xu, Xinyi Zhang, Chunlin Fan, Aihua Hong, Minghan Xia, Liangping Luo, Ande Ma, Hongsheng Li, Qiang Yu, Heru Chen, Dongmei Zhang, Wencai Ye
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Concise Communication Oncology

Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents

Abstract

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.

Authors

Minfeng Chen, Xueping Lei, Changzheng Shi, Maohua Huang, Xiaobo Li, Baojian Wu, Zhengqiu Li, Weili Han, Bin Du, Jianyang Hu, Qiulin Nie, Weiqian Mai, Nan Ma, Nanhui Xu, Xinyi Zhang, Chunlin Fan, Aihua Hong, Minghan Xia, Liangping Luo, Ande Ma, Hongsheng Li, Qiang Yu, Heru Chen, Dongmei Zhang, Wencai Ye

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Figure 5

MRI monitoring of the vascular disruption effects of Z-GP-DAVLBH on MDA-MB-231 xenografts.

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MRI monitoring of the vascular disruption effects of Z-GP-DAVLBH on MDA-...
(A) MRI images of tumors throughout therapy with Z-GP-DAVLBH (left). The white rings indicate the tumors. Quantification of Ktrans and ADC values is shown (right, n = 5). The mice bearing MDA-MB-231 xenografts received i.v. injection of Z-GP-DAVLBH (2 μmol/kg) once every 2 days. (B) H&E staining shows increased necrosis in both the tumor core and rim accompanied by prolonged treatment. The entire tumor was necrotic after 12 days of treatment. CD31 staining shows decreased microvascular density (MVD), and tumor sections stained with TUNEL show apoptotic tumor cells. Tumors were harvested at each MRI examination time point. Three images were obtained per tumor, and the quantification of images is shown (n = 5). Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 versus baseline group (1-way ANOVA with Tukey’s post hoc comparison).