Enzyme-Targeted Nanoparticles for Delivery to Ischemic Skeletal Muscle

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Regenerative Medicine

Background:

• Targeted nanoparticle delivery offers a minimally invasive approach for tissue imaging and drug delivery.
• Enzyme-responsive nanoparticles can be designed to assemble and accumulate in specific tissues.
• Peripheral artery disease (PAD) involves ischemic skeletal muscle, lacking effective non-surgical treatments.

Purpose of the Study:

• To demonstrate enzyme-directed assembly of intravenously delivered nanoparticles in ischemic skeletal muscle.
• To investigate the potential of these nanoparticles for noninvasive imaging and drug delivery in a hindlimb ischemia model.
• To evaluate nanoparticle targeting, retention, and the effect of surface charge modification.

Main Methods:

• Synthesis and optimization of polymer peptide amphiphilic nanoparticles for matrix metalloproteinase (MMP) cleavage and near-infrared (NIR) fluorescence.
• Intravenous injection of NIR-labeled nanoparticles into a rat hindlimb ischemia model.
• Noninvasive in vivo imaging using IVIS particle tracking and ex vivo biodistribution and histology analysis.

Main Results:

• Nanoparticles demonstrated enzyme-directed aggregation and targeting to ischemic muscle compared to healthy muscle.
• IVIS imaging tracked nanoparticle accumulation in ischemic tissue over 28 days.
• Ex vivo analysis confirmed nanoparticle localization in ischemic muscle, with some accumulation in the liver and spleen.
• Modification of nanoparticle surface charge with zwitterionic species improved targeting efficiency.

Conclusions:

• This study presents the first demonstration of enzyme-directed nanoparticle assembly and long-term retention in ischemic muscle.
• The developed nanoparticles show promise as noninvasive drug delivery vehicles for treating ischemic muscle conditions.
• This approach offers a potential minimally invasive, non-surgical therapeutic strategy for PAD and similar conditions.