Abstract
Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes capable of degrading extracellular matrix components. Previous studies have shown that the upregulation of MMP-2 is closely related to metastatic cancers. While Western blotting, zymography, and Enzyme-Linked Immunosorbent Assays (ELISA) can be used to measure the amount of MMP-2 activity, it is not possible to visualize the dynamic MMP-2 activities of cancer cells using these techniques. In this study, MMP-2-activated poly(lactic-co-glycolic acid) with polyethylenimine (MMP-2-PLGA-PEI) nanoparticles were developed to visualize time-dependent MMP-2 activities. The MMP-2-PLGA-PEI nanoparticles contain MMP-2-activated probes that were detectable via fluorescence microscopy only in the presence of MMP-2 activity, while the Rhodamine-based probes in the nanoparticles were used to continuously visualize the location of the nanoparticles. This approach allowed us to visualize MMP-2 activities in cancer cells and their microenvironment. Our results showed that the MMP-2-PLGA-PEI nanoparticles were able to distinguish between MMP-2-positive (HaCat) and MMP-2-negative (MCF-7) cells. While the MMP-2-PLGA-PEI nanoparticles gave fluorescent signals recovered by active recombinant MMP-2, there was no signal recovery in the presence of an MMP-2 inhibitor. In conclusion, MMP-2-PLGA-PEI nanoparticles are an effective tool to visualize dynamic MMP-2 activities of potential metastatic cancer cells.
Highlights
Cancer is one of the major diseases affecting humans throughout the world
Itoh et al demonstrated that Matrix metalloproteinases (MMPs)-2 plays an important role in angiogenesis and tumor progression in mice intradermally implanted by B16-BL6 melanoma cells or Lewis lung carcinoma cells [7]
Dong et al found that the expression of MMP-2 was much higher in colorectal cancer than in normal colorectal tissues, which indicated that high levels of MMP-2 were linked with the tumor size, lymph node metastasis, and tumor invasion [11]
Summary
Cancer is one of the major diseases affecting humans throughout the world. Over the past decades, many research groups have studied cancer cell mutations related to proliferation, survival, and metastasis. Zheng et al have demonstrated that MMP-2 plays a leading role in the angiogenesis of gastric carcinomas [14] These studies suggest that overexpressed MMP-2 is a potential marker of metastasis. Several methods such as Western blotting, zymography, and Enzyme-Linked Immunosorbent Assay (ELISA) have been applied for the detection of active MMP-2 in biological samples [15,16]. All these methods suffer from limitations in the detection of dynamic MMP-2 activities and visualization of the distribution of MMP-2 activity in cancer cells and their microenvironment. Our results suggest that the MMP-2-PLGA-PEI nanoparticles are a promising tool for visualizing the dynamic MMP-2 activities of potential metastatic cancer cells
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