The goal of the proposed project is to develop a novel drug and imaging agent carrier for improved diagnosis and treatment of many diseases, including Coronary Artery Disease (CAD). Current drug delivery methods flood the body without specificity, producing unwanted side effects and limiting the dosage of drugs may be administered safely. Vascular targeting is the design of drug carriers that preferentially accumulate in diseased tissue while protecting the drug from degradation and clearance, thus increasing drug efficiency and decreasing systemic toxicity. Vascular-targeted nanoparticles (VTNPs) are designed to target the endothelium, the barrier between blood flow and diseased tissue that plays an important pathophysiological role in many diseases. Unfortunately, VTNPs get trapped in the core of blood flow and fail to reach the endothelium. Rigid microparticles (MPs), particularly in the 2-3 ?m diameter size range, effectively localize to the vascular wall i blood flow but may cause capillary occlusions. Thus, we propose to develop deformable, protease-degradable, polymer-based hydrogel MPs as a carrier system for the delivery of VTNPs to the vascular wall in CAD. We plan to experimentally explore the VTNP-loaded hydrogel MP system in a variety of ways. First, the physical characteristics of the hydrogel MPs must be optimized for maximal localization to the vessel wall from blood flow, using a parallel plate flow channel, an in vitro model of realistic bulk blood flow. The localization of particles t the endothelium in blood flow will be reported as a function of the stiffness, size, and the chamber wall shear rate. The enzymatic degradation of the particles is built in with peptides that degrade in the presence of MMP-9, a CAD-associated protease present in higher concentrations in diseased endothelium. We will assess protease degradation of the particles in solution and over inflamed endothelium; selective degradation should occur. The hydrogel particles will be evaluated for preferential adhesion to and release of NP cargo over inflamed cells in vitro. Finally, the hydrogel MPs will be evaluated for targeting efficiency in vivo with a mouse model of human CAD using intravital microscopy, aortic dissections and holistic biodistributions. The key hypotheses for this exploratory work are: (1) targeted, deformable PEG hydrogel MPs loaded with VTNPs will localize and adhere to an inflamed endothelial wall from blood flow; (2) degradable cross- linkers within the hydrogel MP matrix can be cleaved to release loaded VTNPs upon contact with up-regulated proteases in CAD-associated inflamed endothelium; (3) these VTNPs can effectively interact with the vascular wall and deliver a payload; (4) deformable MPs are robust enough to traverse capillaries, lowering the risk of vessel occlusion versus to rigid MPs; and (5) hydrogel MPs will localize to areas of inflammation in vivo in mouse models of CAD. The proposed project aims to generally improve upon current non-invasive imaging agent and drug delivery systems for improved quality of life of the patients, minimized need for surgical intervention, and lowered health care costs by improving the early diagnosis and treatment efficacy of CAD.
This research project will revolutionize the diagnosis and treatment of cardiovascular diseases, which cause one in three deaths in the U.S, by providing improved, non-invasive delivery of drug or imaging agent directly to the diseased tissue. The goal is to selectively enhance the transport of nanoparticles by loading them into larger, targeted hydrogel particles, resulting in accumulation of the imaging agent or drug in only the diseased cells, greatly improving upon the currently available treatments. Additionally, this drug carrier system will shed light onto the behavior of deformable objects in complex flow and has the potential to deliver earlier, non- invasive diagnosis and treatment of many cardiovascular diseases.
| Fromen, Catherine A; Kelley, William J; Fish, Margaret B et al. (2017) Neutrophil-Particle Interactions in Blood Circulation Drive Particle Clearance and Alter Neutrophil Responses in Acute Inflammation. ACS Nano 11:10797-10807 |
| 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 |
