PLGA-Based Molecular Contrast Agent for PPOCT and Vascular-Targeted Multistage Delivery System

Abstract

Atherosclerosis, a condition in which plaque accumulates on the inner wall of arteries, is often recognized as a precursor to cardiovascular diseases (CVDs), the most common causes of death in the US. Optical Coherence Tomography (OCT) is an optical diagnosis tool, which can be used to obtain high resolution morphological images of atherosclerotic plaque. However, atherosclerotic plaque vulnerability is often misclassified due to the signal similarities produced from different plaque components. An accurate plaque diagnosis is critical for the selection of treatments and procedures required to preserve the patients life. This thesis explores the fabrication and characterization of a vascular targeted MB-based contrast agent to enhance molecular imaging of PumpProbe OCT (PPOCT). Methylene blue (MB) was encapsulated into poly lactic-co-glycolic acid (PLGA) micro and nanoparticles by a single emulsion solvent evaporation method. The surface of particles was modified with ligands that can target molecular biomarkers involved in atherosclerotic plaque formation such as vascular cell adhesion molecules (VCAM-1) and apoptotic macrophages. Although nanoparticles have been extensively utilized as drug carriers due to their capabilities in intracellular localization, they exhibited poor margination in blood flow and consequently low concentrations at the vascular targets. Since microparticles (2-5 µm) have demonstrated significantly superior margination in human blood flows, a PLGA-based multistage delivery system (MDS) was developed to enable localization of nanoparticles to the vascular wall. This PLGA-based MDS consists of two stages: 1) a micron-sized outer shell and 2) encapsulated nanoparticles, aiming to achieve both effective margination and intracellular entry. Overall, this study demonstrates the capabilities of MB particles as contrast agents for PPOCT and the potential of our Multi Stage Delivery System, as tools for atherosclerosis research and therapeutics.