Bio-inspired multifunctional block copolymers for the dissolution of risky atherosclerotic plaques

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Cardiovascular disease represents a major cause of morbidity and mortality worldwide. The most frequent underlying pathology is atherosclerosis, which leads to intimal plaque formation in arterial blood vessels. Atherogenesis is initiated by endothelial dysfunction leading to the accumulation of oxidized lipoproteins and recruitment of inflammatory cells to the nascent plaque. This lipid-driven chronic inflammation results in extracellular lipid deposition in the necrotic core. Alongside the amount of lipid in the necrotic core, the formation of calcific nodules in the intima implies a higher susceptibility for plaque rupture. Yet, current preventive therapeutic strategies focussing on systemic lipid lowering show little impact on reverting plaque development clinically. In this proposal, we intend to directly extract lipid and calcium deposits from preexisting atherosclerotic plaques using nanoparticle technology to accelerate plaque regression.In order to reverse or prevent the agglomeration of unwanted crystalline substances in arteries, a synthesis strategy based on bio-inspired and biocompatible poly(2-oxazoline) block copolymers has been developed. A design is chosen that the first block of the block copolymer is made of hydrophilic poly(2-methyl-2-oxazoline), which should give the copolymers stealth properties in the organism. The other blocks contain double or triple bond side chains. To give them water soluble and cholesterol and calcium dissolving properties, the polymers are post-modified via both thiol-ene click reaction to introduce lipophilic thiocholesterol side chains and azide-alkyne Huisgen cycloaddition to introduce poly carboxylate and poly phosphate moieties, which are supposed to interact with calcium ions electrostatically. Our preliminary results show that our polymers dissolve cholesterol (23.5 wt%) and hydroxyapatite (Ca2+ 4.7 wt%). As part of this project, we aim at testing the therapeutic potential of our polymer designs in experimental models of atherosclerosis and human tissue cultures and optimize the polymer structure according to these results. Initial in vivo experiments testing the bioavailability, biodistribution and elimination of polymers in murine model are followed by analysis of the efficacy of polymer treatment to reduce atherosclerotic plaque size and composition. Histologic and flow cytometric readouts are enhanced by gene expression profiling of atherosclerotic lesions. Potential adverse effects of polymer treatment on bone density are evaluated as well. Finally, we will treat human atherosclerotic plaque tissue slices with our polymers in vitro to test the therapeutic and translational potential for humans.