Nanoparticle-Crosslinked Hydrogels as an Injectable Myocardial Infarction Therapy

Polymeric nanoparticles have been widely utilized in the delivery of therapeutic agents both to provide a protective barrier to the encapsulated therapy and to achieve predictable release kinetics. Direct injection into the local tissue target site can significantly reduce off-target side effects often hinder systemic delivery. Unfortunately, local delivery to mechanically active tissue, such as the beating heart, typically results in low retention of the injected nanoparticles. As the myocardium contracts, the delivered material is expelled from the tissue and washed away by blood flow, carrying the cargo into undesirable areas.<br/> <br/>To address this critical problem, we have developed a hydrogel that utilizes the therapeutic eluting nanoparticles as the crosslinkers, anchoring them in place and preventing the dispersion of the particles into nearby tissues and organs. We accomplished this by synthesizing a derivative lactone synthetic polymer, poly(spirolactide) (PSLA), containing norbornene functional groups in the backbone. Nanoparticles formulated from lactone-based polymers have several advantages, including ease of fabrication, predictable release kinetics based on hydrolytic degradation, and a good safety profile for clinical translation. The resulting PSLA nanoparticles display norbornene functional groups at their surfaces, where they can readily serve as crosslinking sites to induce gelation of polymers with complementary tetrazine functional groups through a biorthogonal click-chemistry reaction. Here we have selected recombinant elastin-like protein (ELP) and hyaluronic Acid (HA) as our polymeric components, as they are biodegradable and mimic the native extracellular matrix of the myocardium. <br/> <br/>Dynamic light scattering was utilized to ascertain the range of our nanoparticle size (500-800 nm), and Fourier-transform infrared spectroscopy (FTIR) was used to characterize the particle surface pre- and post-modification. Furthermore, the molecular weight of the PSLA can be modulated to tailor the degradation and hence the release kinetics of an encapsulated statin drug. Statins have been shown to aid in the regenerative process after acute myocardial infarction. Upon crosslinking with the ELP and HA biopolymers, the resulting gels are evaluated for their viscoelastic properties using oscillatory shear rheology. To potentially improve the injectability of these hydrogels through a clinically relevant catheter, we are also evaluating a complementary nanoparticle-polymer crosslinking strategy based on dynamic covalent chemistry. In this strategy, the norbornene functional groups on the nanoparticle surface are modified with hydrazines via thiol-ene click-chemistry. The HA and ELP biopolymers are bioconjugated with aldehydes, enabling formation of hydrazone crosslinks, which are thermodynamically reversible at physiological conditions. Both the dynamic and non-dynamic crosslinked versions of the gel have been formulated to achieve moduli that match the range of soft cardiac tissue.<br/> <br/>In summary, we have developed a nanoparticle-crosslinked hydrogel to prevent the undesirable dispersion of statins following direct injection into the beating heart. We hypothesize that by designing the hydrogel to use the PSLA nanoparticles both as drug depots and as network crosslinking sites, we can deliver an extensive reservoir of therapeutic agent, improve the local retention within the beating heart, and achieve sustained release of statins; thus, providing a novel injectable therapy for myocardial infarction.