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LIFU/MMP-2 dual-responsive release of repurposed drug disulfiram from nanodroplets for inhibiting vasculogenic mimicry and lung metastasis in triple-negative breast cancer

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机构： [1]Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Institute of Ultrasound Imaging of Chongqing Medical University, Chongqing, China. [2]Department of Ultrasound, The Third People's Hospital of Chengdu City, The Affiliated Hospital of Southwest Jiaotong University, No. 82 Qinglong Street, Chengdu, 610031, Sichuan, China. [3]Department of Pathology, The Third People's Hospital of Chengdu City, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, China. [4]Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China. [5]Department of Ultrasound, The Third People's Hospital of Chengdu City, The Affiliated Hospital of Southwest Jiaotong University, No. 82 Qinglong Street, Chengdu, 610031, Sichuan, China. zhouyang@swjtu.edu.cn. [6]Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, State Key Laboratory of Ultrasound in Medicine and Engineering of Chongqing Medical University, No.76 Linjiang Road, Yuzhong District, Chongqing, 400010, China.

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关键词： Vasculogenic mimicry Matrix metalloproteinase-2 Low-intensity focused ultrasound Disulfiram Drug penetration

摘要：

Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment.Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis.Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings.© 2024. The Author(s).

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大类 | 1 区

生物学

小类 | 1 区生物工程与应用微生物 2 区纳米科技

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第一作者机构： [1]Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Institute of Ultrasound Imaging of Chongqing Medical University, Chongqing, China. [2]Department of Ultrasound, The Third People's Hospital of Chengdu City, The Affiliated Hospital of Southwest Jiaotong University, No. 82 Qinglong Street, Chengdu, 610031, Sichuan, China.

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LIFU/MMP-2 dual-responsive release of repurposed drug disulfiram from nanodroplets for inhibiting vasculogenic mimicry and lung metastasis in triple-negative breast cancer

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