Nanoparticle Based Delivery of Protease Inhibitors to Cancer Cells

Proteases are involved in a variety of processes associated with tumor development and progression. Because of their integral role in extracellular matrix and basal lamina degradation they play important roles in cancer cell migration, invasion, angiogenesis and metastasis. They are also involved in cancer cell signaling, the epithelial-mesenchymal transition, the antitumor immune response, cell de-differentiation and cancer stem cell remodeling. Their involvement in pro-tumorigenic processes makes them interesting targets for anticancer therapy. The most promising are matrix metalloproteases, cysteine cathepsins, the urokinase-type plasminogen activator system and proteasome; these constitute the focus of this review. Several inhibitors have been developed for reducing their activities that are in different phases of development, with some already in clinical use. However, systemic delivery of protease inhibitors can result in undesired reduction of proteolytic activity in normal tissues, leading to adverse effects and limited therapeutic efficacy. This caveat can be circumvented by nanoparticle delivery systems that direct protease inhibitors specifically to cancer cells. In this article we review the current state of nanoparticle delivery systems for delivering protease inhibitors to cancer cells.