Protease-Activated Delivery and Imaging Systems

Abstract

Proteolysis has been cited as an important contributor to cancer initiation and progression. But advantage can be taken of tumor-associated proteases to selectively deliver therapeutic or imaging agents. Protease-activated prodrugs, nanotechnology-based drug delivery systems, hydrogels, gene delivery systems, and imaging systems have been described for cancer applications. Activation is modulated by substrates designed for hydrolysis by members of the matrix metalloproteinase family, prostate-specific antigen, hK2, plasmin, urokinase plasminogen activator, legumain, neprilysin/CD10, or cathepsins B, D, or L. The first generation of protease-activated agents has demonstrated proof of principle as well as provided impetus for in vivo applications. One common problem has been a lack of agent stability at nontargeted tissues and organs due to activation by multiple proteases. Second-generation agents may need to incorporate more selective substrates, which can be achieved by consideration of both the sequence specificity and the topological preferences of proteases.