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

Author:

Liu Ying,Tang Rui,Cao Yuting,Wu Nianhong,Qin Qiaoxi,Chen Yuanyuan,Wei Xi,Ren Jianli,Sun Yang,Zhou Hong,Zhou Yang,Li Pan

Abstract

Abstract Background 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. Results 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. Conclusions 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. Graphical Abstract

Funder

National Natural Science Foundation Project

Chongqing Natural Science Foundation project

Sichuan Natural Science Foundation Project

Chengdu Science and Technology Bureau technology innovation research and development project

Science and technology project of Sichuan Provincial Health Commission

The Third People’s Hospital of Chengdu Scientific Research Project

Natural Science Foundation of Sichuan Province

Publisher

Springer Science and Business Media LLC

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