Matrix metalloproteinases (MMPs) are essential for embryonic development as well as adult tissue homeostasis, and dysregulation of MMP activity is associated with a plethora of disease states including arthritis, fibrosis, cardiovascular disease, and cancer. MMP expression is elevated in almost all tumor types, including breast, colon, pancreas, and melanoma, and increased expression is often correlated with decreased survival. While MMPs are widely acknowledged as key players during tumor progression, most screening assays for potential cancer therapeutics do not assess the effect on MMP activity due to the lack of methods for measuring MMP activity in a high throughput manner.  To overcome this barrier, we have recently developed a functionalized hydrogel biomaterial for cell encapsulation and measurement of MMP activity. This material is composed of fluorogenic MMP sensitive peptide biosensors covalently tethered to a poly(ethylene glycol) (PEG) hydrogel network, and upon exposure to active MMPs from the encapsulated cells, an increase in fluorescence is observed. The increased fluorescence can be read with a microplate reader and monitored over time.  This nanosensor functionalized system was then used to investigate the response of melanoma cells to pharmacological inhibition of the kinases, BRAF and MEK. Surprisingly, we observed an increase in MMP activity in several treatment conditions, and this increase corresponded with increased cell spreading and migration within the 3D hydrogel. These results highlight the importance of proteinase activity and the need for better <i>in vitro</i> tools to study the effect of cancer therapeutics on MMP activity in physiologically relevant microenvironments.

Functionalization of hydrogels with matrix metalloproteinase-sensitive fluorogenic biosensors to measure cancer cell response to drug treatment

249th National Meeting (2015)

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