Targeted delivery of peptide-based matrix metalloproteinase-2 (MMP-2) inhibitor in dual sensitive nanoparticles with platelet membrane camouflage for ischemic limb treatment

Statement of Purpose: Peripheral artery disease is a pathological condition with low blood perfusion, and degenerated skeletal muscle. Upregulated MMP-2 has been considered as an important player in the adverse tissue remodeling. It is hypothesized that control of MMP-2 bioactivity will benefit tissue repair. In this study, pH and thermal dual sensitive hydrogel nanoparticles have been developed to deliver MMP-2 inhibitor to ischemic limbs to decrease MMP-2 bioactivity. The nanoparticles had propylacrylic acid (PAA, pKa ~ 6.3) component that enables them to aggregate specifically at the ischemic area where local pH is 6-7. The nanoparticles also had thermosensitive component N-Isopropylacrylamide (NIPAAM) that allows them to solidify at 37^oC before degradation and dissolve in the body fluid after degradation. Platelet membranes were incorporated on the nanoparticles to help reducing cellular uptake by macrophage-like cells. In order for the nanoparticles to target ischemic limb area, a peptide CSTSMLKA (CST) was conjugated to the platelet membrane. A peptide, CTTHWGFTLC (CTT), was used as MMP-2 specific inhibitor.