MMP responsive polymeric materials for treating acute myocardial infarction

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Summary Heart failure (HF) remains the leading cause of death in the U.S., and the rest of the western world. Approximately 37% of myocardial infarction (MI) patients will die from HF within 1 year, and of those who do survive, two-thirds do not make a complete recovery. Each year it is estimated that ~550K Americans will have a new MI, and ~200K will have a recurrent MI, leading to a large body of patients suffering from HF.1 Therefore, our long-term goal is the development of new, minimally invasive, targeted biomaterial based therapies for the treatment of acute MI (AMI), thereby limiting the number of patients that progress to HF. Over the past two decades, there has been significant progress in the development injectable biomaterials that stimulate endogenous repair on their own or through the controlled release of additional therapeutics. This approach is attractive since potential therapies could be delivered minimally invasively via catheter, would be off the shelf and cost-effective, and in the case of therapeutic delivery, would provide targeted delivery limiting systemic off- target effects that plague traditional pharmaceuticals. However, direct injection of these biomaterials, either through minimally invasive surgery or percutaneous transendocardial injection, is unlikely to be translated to AMI patients because of serious safety concerns with the injection procedures, thereby missing the critical therapeutic window immediately post-MI. Together, the PIs developed enzyme-responsive, injectable nanoparticles (NPs), capable of responding to matrix metalloproteinases (MMPs) associated with AMI. The particles accumulate efficiently in infarcted myocardium following systemic administration, by virtue of an enzyme-induced phase transition from small NP to micron-sized scaffold. While we had initial success with this system and observed better targeting compared to traditional modalities, this system suffers the same drawback as most nanoparticles, which have significant off-target accumulation, as they are phagocytosed and transported to the liver following opsonization. Leveraging our success with the general MMP responsive targeting strategy, we propose that a new MMP responsive material comprised of a completely aqueous soluble polymer displaying therapeutic peptides at high densities will have superior biodistribution patterns nanoparticles. Upon systemic administration, these polymers exhibit exceptionally favorable pharmacokinetics (week-long half-lives) and biodistribution characterized by kidney clearance combined with very little liver/spleen accumulation. These polymers are protein like in molecular weight (MW), physicochemical properties and size. They are therapeutic proteomimetic polymers, designed to accumulate at the site of AMI. Here, we aim to develop new MMP responsive polymeric systems (termed protein-like polymers, PLPs) and demonstrate proof-of-concept for using these novel biomaterials for the targeted delivery of therapeutics for AMI.