Vascular-targeted carriers (VTCs) offer unique opportunities for improving diagnosis and treatment of many serious human ailments, including coronary artery disease (CAD), by non-invasively providing localized delivery of imaging agents or potent therapeutics. CAD is the leading cause of morbidity and mortality in the world. Current remedies for CAD include surgical bypass of the affected artery, percutaneous coronary interventions, and oral administration of statin drugs. Improvements in these treatments are necessary since, for instance, major coronary events can still occur in 50% of patients who have undergone aggressive statin therapy. Chronic inflammation and associated processes (e.g. angiogenesis) are involved at all stages of CAD, and VTCs directed to CAD via biomolecules expressed on the vascular wall in association with these processes may provide a viable, non-surgical approach to preventing or even reversing established CAD. However, nanoparticles (NPs) that are typically proposed for use as carriers in targeting therapeutics to the vascular wal have been recently shown to not effectively transport to the vascular wall in blood flow due to high entrapment in the red blood cell core of blood flow. Conversely, microparticles (MPs), particularly in the 2 - 3 ?m diameter size range, effectively localize to the vascular wall in bloo flow. Nevertheless, NPs remain highly attractive over MPs for targeted disease intervention owing to their high potential for achieving intracellular (e.g., gene) and interstitial delivery. Or overall goal is to develop a smart delivery system to dramatically improve NP transport in blood flow, thus fully realizing the potential of vascular-targeted NPs (VTNPs) for disease intervention. Specifically, we propose to develop protease-degradable hydrogel MPs with tunable geometries, surface characteristics, and deformability to serve as carriers for the delivery of agent- loaded VTNPs to the vascular wall in medium to large blood vessels relevant in CAD. The proposed specific aims are: (1) to fabricate and characterize the hemodynamics of NP-loaded, protease-degradable hydrogel MPs in human blood flow, and (2) to evaluate protease-induced degradation of VTNP-loaded hydrogel MPs. We hypothesize that highly deformable and degradable hydrogel MPs loaded with VTNPs can be fabricated and in the size range that would allow for their high capacity to localize to the vascular wall from human blood flow and that protease-degradable cross-linkers within the hydrogel MPs matrix can be effectively cleaved to release loaded VTNPs upon contact with disease-associated proteases that are upregulated by the inflamed endothelium. Overall, our systematic integration of the advantages of the high vascular wall localization efficiency of MPs and the internalization capabilities of th embedded NPs can serve as a more effective strategy for targeting agent for diagnosis and treatment of CAD. Drug carriers engineered with the understanding of hemodynamics, vessel architecture, and disease-specific epitopes will offer improved in vivo efficacy over contemporary carriers whose design are focused on targeting epitope alone.
The proposed work (1) will develop vascular-targeted nanoparticle-loaded, protease-degradable hydrogel microparticles with tunable geometries, surface characteristics, and deformability and (2) use in vitro flow assays with human blood in channels of varying dimensions and physiological flow patterns to optimize and validate the capacity for NP-loaded hydrogel microparticles to serve as carriers for the effective delivery of agent-loaded NPs to the vascular wall for the treatment of CAD. Targeted delivery of therapeutics to specific sites in the body can allow for the administration of highly potent therapeutics to diseased tissues without affecting healthy ones;thereby, enhancing drug efficacy with no deleterious side effects. This can significant decrease the high mortality rate attributed to serious diseases and lowered healthcare cost associated with current treatments.
|Fish, Margaret B; Fromen, Catherine A; Lopez-Cazares, Genesis et al. (2017) Exploring deformable particles in vascular-targeted drug delivery: Softer is only sometimes better. Biomaterials 124:169-179|