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

Yaqi Lyu,Qingqing Xiao,Lifang Yin,Wei He,Lei Yang

doi:10.1038/s41392-019-0054-9

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.

Highlights

The tumor microenvironment (TME) consisting of noncancer cells, extracellular matrix (ECM), blood vessels, and lymphatics is a suitable environment for cancer cells.[1,2] Critically, ECM composed of various components, such as collagen, laminins, fibronectin, proteoglycans, and glycosaminoglycans[3] markedly affects tumor initiation, progression, invasion, and migration.[4]
Determination by dynamic light scattering (DLS) revealed that MATT-lysolipid-containing thermosensitive liposomes (LTSLs) had a diameter of approximately 100 nm with a polydispersity index (PdI)
The MATT-LTSLs + HT group exhibited 15-fold tumor growth vs. 35-fold growth exhibited by the saline treatment in 4T1 tumor-bearing mice, demonstrating that LTSLs are a promising carrier for improved MATT antitumor efficacy

Summary

Introduction

The tumor microenvironment (TME) consisting of noncancer cells, extracellular matrix (ECM), blood vessels, and lymphatics is a suitable environment for cancer cells.[1,2] Critically, ECM composed of various components, such as collagen, laminins, fibronectin, proteoglycans, and glycosaminoglycans[3] markedly affects tumor initiation, progression, invasion, and migration.[4]. The tumor microenvironment (TME) consisting of noncancer cells, extracellular matrix (ECM), blood vessels, and lymphatics is a suitable environment for cancer cells.[1,2]. ECM composed of various components, such as collagen, laminins, fibronectin, proteoglycans, and glycosaminoglycans[3] markedly affects tumor initiation, progression, invasion, and migration.[4]. Through the degradation of the components in the ECM by matrix metalloproteinases (MMPs), tumor angiogenesis and metastasis is promoted.[3,5]. Inhibiting the expression and activity of MMPs in the TME is essential to inhibit metastasis and angiogenesis. More than 10 synthetic MMP inhibitors (MMPIs) have been developed since the 1980s, including batimastat, marimastat (MATT), tanomastat, prinomastat, and rebimastat.[6]. MATT is able to inhibit tumor growth and was a candidate chemotherapeutic agent; a clinical study indicated that

Methods

Results

Conclusion