Nanomedicine harnessing disease microenvironments for the treatment of cancer and atherosclerosis

Abstract

The ultimate goal of therapeutic nanomedicine is to enhance therapeutic efficacy and reduce side effects of drugs. While nanoparticles exhibit excellent pharmacokinetics and biodistribution mostly due to their size, they can be engineered to have additional functions to further enhance the therapeutic efficacy. Some diseases exhibit characteristic microenvironments that can be harnessed for the mode of action of nanoparticles in the microenvironment. In the thesis, I developed novel nanoparticles that can harness disease microenvironments in cancer and atherosclerosis. In cancer, the efficacy of targeted therapies is compromised due to the heterogeneity of targets. However, the issue of heterogeneity could not overcome successfully thus far. To challenge the issue, I harnessed extracellular vesicles that are known to mediate intercellular communications by transferring biologicals by modifying and utilizing them to deliver synthetic receptors to cancer cells. To modify extracellular vesicles, I developed a cooperative drug delivery system by using membrane fusogenic liposomes that can fuse with cellular membrane and facilitate the secretion of extracellular vesicles incorporated with the synthetic receptor by the cell. Consequently, I could achieve uniform distribution of synthetic receptors throughout cancer and greatly enhance targeted therapy. In atherosclerosis, macrophages and cholesterol play crucial functions as the main components and inflammation-triggering sources. However, no medication thus far could remove both of them from plaques. To challenge the issue, I harnessed cholesterol in plaques to promote the action of nanoparticles. I developed cargo-switching nanoparticles that can release the anti-inflammatory drug in the presence of cholesterol via cargo-switching between the two molecules wherein cholesterol is dissolved and macrophages are killed. Consequently, I could effectively inhibit atherogenesis and regress established plaques. The results in the thesis are expected to contribute to the field of therapeutic nanomedicine and show the importance of harnessing disease microenvironments.