Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents
Minfeng Chen, … , Dongmei Zhang, Wencai Ye
Minfeng Chen, … , Dongmei Zhang, Wencai Ye
Published October 2, 2017
Citation Information: J Clin Invest. 2017;127(10):3689-3701. https://doi.org/10.1172/JCI94258.
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Categories: Research Article Oncology Therapeutics

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 1

Vessels in the tumor periphery with higher pericyte coverage show resistance to DAVLBH.

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Vessels in the tumor periphery with higher pericyte coverage show resist...
For in vivo experiments, mice bearing MDA-MB-231 xenografts received i.v. injection of 2 μmol/kg DAVLBH, and the tumors were harvested 2 hours, 4 hours, or 2 days later. (A) H&E, CD31, and FAPα/CD31 staining show a marked vascular disruption in tumor core, but not in peripheral tumor, after 4 hours of treatment (n = 5). The black arrowheads indicate the loss of ECs, and autofluorescent rbc appear as pink points in FABα/CD31-stained sections. Top row scale bars: 200 μm. Middle row scale bars: 50 μm. Bottom row scale bars: 50 μm. (B) The transmission electron microscope images show the effects of DAVLBH on tumor vessels. The yellow arrowheads indicate EC blebbing, and the blue arrowheads indicate the loss of ECs. L, lumen; PC, pericyte. Top row scale bars: 5 μm. Bottom row left scale bar: 2 μm. Bottom row right scale bar: 10 μm. (C) H&E staining shows extensive necrosis Top row scale bars: 1 mm. Middle row scale bars: 200 μm. Bottom row scale bars: 50 μm. (N) in tumor core after 2 days of treatment; Ki67 staining shows similar proliferation between 2 groups (n = 5). (D) The EC- (red) and pericyte-cocultured (green) systems show DAVLBH selectively damages the HUVEC tubes (white arrows), but has negligible effect on the HBVPNC-HUVEC and HBVPFAPα-WT-HUVEC–cocultured tubes (n = 3). Scale bars: 100 μm.