Background: Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that
play a key role in both physiological and pathological tissue degradation. MMPs have reportedly shown
great potentials in the degradation of the Extracellular Matrix (ECM), have shown great potentials in
targeting bioactive and imaging agents in cancer treatment. MMPs could provoke Epithelial to Mesenchymal
Transition (EMT) of cancer cells and manipulate their signaling, adhesion, migration and invasion
to promote cancer cell aggressiveness. Therefore, targeting and particularly inhibiting MMPs
within the tumor microenvironment is an effective strategy for cancer treatment. Based on this idea, different
MMP inhibitors (MMPIs) have been developed to manipulate the tumor microenvironment towards
conditions appropriate for the actions of antitumor agents. Studies are ongoing to improve the selectivity
and specificity of MMPIs. Structural optimization has facilitated the discovery of selective inhibitors
of the MMPs. However, so far no selective inhibitor for MMP-7 has been proposed.
Aims: This study aims to comprehensively review the potentials and advances in applications of MMPs
particularly MMP-7 in targeted cancer treatment approaches with the main focus on targeted drug delivery.
Different targeting strategies for manipulating and inhibiting MMPs for the treatment of cancer are
discussed. MMPs are upregulated at all stages of expression in cancers. Different MMP subtypes have
shown significant targeting applicability at the genetic, protein, and activity levels in both physiological
and pathophysiological conditions in a variety of cancers. The expression of MMPs significantly increases
at advanced cancer stages, which can be used for controlled release in cancers in advance stages.
Methods: Moreover, this study presents the synthesis and characteristics of a new and highly selective
inhibitor against MMP-7 and discusses its applications in targeted drug delivery systems for therapeutics
and diagnostics modalities.
Results: Our findings showed that the structure of the inhibitor P3’ side chains play the crucial role in
developing an optimized MMP-7 inhibitor with high selectivity and significant degradation activities
Conclusion: Optimized NDC can serve as a highly potent and selective inhibitor against MMP-7 following
screening and optimization of the P3’ side chains, with a Ki of 38.6 nM and an inhibitory selectivity
of 575 of MMP-7 over MMP-1.