58. enzyme-targeted nanoparticles for delivery to ischemic muscle

Department: Bioengineering
Faculty Advisor(s): Karen L. Christman

Primary Student
Name: Jessica Leigh Ungerleider
Email: jlungerl@ucsd.edu
Phone: 858-246-1593
Grad Year: 2018

Peripheral artery disease is a type of cardiovascular disease caused by plaque buildup in the arteries supplying blood to the lower limbs, leading to pain, muscle atrophy, and eventual amputation. Surgical interventions are ineffective due to the diffuse nature of the vascular disease, and pharmacologic interventions are plagued by poor delivery. Enzyme-responsive nanoparticles can be a valuable minimally invasive approach for targeted imaging or drug delivery applications. However, application of these platforms have been mainly used thus far only for cancer imaging/treatment. In this study, we show for the first time enzyme-directly assembly of minimally invasive nanoparticles in ischemic muscle, which has applications for drug delivery to damaged muscle such as in the case of peripheral artery disease. Specifically, micellar nanoparticles are cleavable by matrix metalloproteinases, causing them to undergo a morphologic switch and thus aggregate and target to tissues where these enzymes are upregulated, like ischemic muscle in peripheral artery disease. Here, we demonstrated noninvasive in vivo imaging of these IV-injected nanoparticles through near-infrared dye labeling and in vivo imaging (IVIS) particle tracking in a rat hindlimb ischemia model. Near-IR labeled nanoparticles were injected 4 days after unilateral hindlimb ischemia and were monitored over 28 days using IVIS imaging. Nanoparticles targeted to ischemic muscle over healthy muscle, and ex vivo biodistribution analysis at 7 and 28 days post-injection confirmed targeting to the ischemic muscle as well as off target accumulation in the liver and spleen. Ex vivo histology confirmed particle localization in ischemic but not healthy muscle. Altering the surface charge of the nanoparticles through addition of zwitterionic dye species resulted in improved targeting to the ischemic muscle. To our knowledge, this is the first study to demonstrate a non-invasive, enzymatically-targeted delivery system for peripheral artery disease. Future studies will combine this targeted delivery system with a therapeutic to improve perfusion to the ischemic tissue.

Industry Application Area(s)
Life Sciences/Medical Devices & Instruments | Materials

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