(600c) Hydrogel Delivery of Statin-Eluting Nanoparticles for Myocardial Infarction Therapy | AIChE

(600c) Hydrogel Delivery of Statin-Eluting Nanoparticles for Myocardial Infarction Therapy

Authors 

Navarro, R. - Presenter, University of Michigan
Paiva, N., Stanford University
Heilshorn, S. C., Stanford University
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. While direct injection into the local tissue target site can significantly reduce off-target side effects, 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.

To address this critical problem, we have developed a hydrogel that utilizes the 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.

A family of PSLA polymers with varying molecular weight (5, 30, and 100 kDa) have been synthesized to tailor the degradation and hence the drug release kinetics. Statins have been shown to aid in the regenerative process after acute myocardial infarction. Dynamic light scattering was utilized to confirm nanoparticle size (500-800 nm), and Fourier-transform infrared spectroscopy (FTIR) was used to characterize the particle surface pre- and post-modification. Scanning electron microscopy (SEM) was used to visualize the particles for surface smoothness and lack of inclusions. Upon crosslinking with the ELP and HA biopolymers, the resulting gels are evaluated for their viscoelastic properties using oscillatory shear rheology. Elution of the statin drug from the gel was characterized using UV-Vis, and daily dose was quantified by comparing to a standard curve.

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.