Original articles
Wenhui Tao, Dongyang Zhao, Guanting Li, Lingxiao Li, Songhao Li, Hao Ye, Chutong Tian, Yutong Lu, Shuying Li, Yinghua Sun, Zhonggui He, Jin Sun. Artificial tumor microenvironment regulated by first hemorrhage for enhanced tumor targeting and then occlusion for synergistic bioactivation of hypoxia-sensitive platesomes[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1487-1499

Artificial tumor microenvironment regulated by first hemorrhage for enhanced tumor targeting and then occlusion for synergistic bioactivation of hypoxia-sensitive platesomes
Wenhui Taoa, Dongyang Zhaoa, Guanting Lia, Lingxiao Lia, Songhao Lia, Hao Yea, Chutong Tiana, Yutong Lua, Shuying Lib, Yinghua Sunc, Zhonggui Hea, Jin Suna
a. Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China;
b. Department of Pharmaceutical and Engineering, College of Pharmaceutical and Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China;
c. Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
The unique characteristics of the tumor microenvironment (TME) could be exploited to develop antitumor nanomedicine strategies. However, in many cases, the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity. Given the amplified characteristics of TME regulated by vascular disrupting agents (VDAs), nanomedicines may achieve unexpected improved efficacy. Herein, we fabricate platelet membrane-fusogenic liposomes (PML/DP&PPa), namely "platesomes", which actively load the hypoxia-activated pro-prodrug DMG-PR104A (DP) and physically encapsulate the photosensitizer pyropheophorbide a (PPa). Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate (CA4P), PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P. First, CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention (EPR) effect, and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa. Besides, CA4P-induced vascular occlusion inhibits oxygen supply, followed by photodynamic therapy-caused acute tumor hypoxia. This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis. Thus, such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation, and provides a preferable solution to high-efficiency cancer therapy.
Key words:    Tumor microenvironment    Vascular disrupting agents    Biomimetic platesomes    Photosensitizers    Hypoxia-activated prodrugs    Nanomedicine delivery    Combination therapy    Antitumor and antimetastasis   
Received: 2021-04-18     Revised: 2021-06-20
DOI: 10.1016/j.apsb.2021.08.010
Funds: This work was financially supported by the National Natural Science Foundation of China (No. 81773656), Liaoning Revitalization Talents Program (No. XLYC1808017, China), Shenyang Youth Science and Technology Innovation Talents Program (No. RC190454, China), College Student Innovation and Entrepreneurship Training Program of Shenyang Pharmaceutical University (No. X202010163141, China).
Corresponding author: Jin Sun,E-mai:sunjin@syphu.edu.cn     Email:sunjin@syphu.edu.cn
Author description:
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Wenhui Tao
Dongyang Zhao
Guanting Li
Lingxiao Li
Songhao Li
Hao Ye
Chutong Tian
Yutong Lu
Shuying Li
Yinghua Sun
Zhonggui He
Jin Sun

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