Potent delivery of an MMP inhibitor to the tumor microenvironment with thermosensitive liposomes for the suppression of metastasis and angiogenesis

Abstract

Metastasis is a major cause of chemotherapeutic failure and death. Degradation of a specific component of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) affects the physical barrier of the tumor microenvironment (TME) and induces metastasis. Here, lysolipid-containing thermosensitive liposomes (LTSLs) were prepared to deliver an MMP inhibitor, marimastat (MATT), to the TME to inhibit MMP activity and expression. LTSLs rapidly released their payloads at 42 °C. Compared with the saline control, MATT-LTSLs exhibited enhanced accumulation in the tumor and a 20-fold decrease in tumor growth in 4T1 tumor-bearing mice; moreover, MATT-LTSLs reduced MMP-2 and MMP-9 activity by 50% and 43%, respectively, and downregulated MMP-2 and MMP-9 expression in vivo by 30% and 43%, respectively. Most importantly, MATT-LTSL treatment caused a 7-fold decrease in metastatic lung nodules and a 6-fold reduction in microvessels inside the tumor. We believe this study provides an effective approach for the suppression of metastasis, and the use of a cytotoxic agent in combination with MATT is a potential strategy for metastatic cancer treatment.