The goal of the proposed work is to develop a method for the targeting of nanoparticles (NPs) to endothelial cells that capitalizes on the intrinsic changes in mechanics of the cell surface accompanying diseases such as atherosclerosis and cancer. The main strategy to accomplish this goal is to measure the mechanical properties of the cell surface and how these properties change with disease state, and to design NPs that are more likely to be taken up by cells. The project will be specifically relevant to atherosclerosis since all studies will be on endothelial cells, the cells that line blod vessels, and the ones that are the initial mediators of the development of atherosclerosis.
The first aim i s to determine the effects of fluid shear stress on the membrane bending modulus in endothelial cells because blood-flow-induced shear stress is strongly associated with atherosclerosis.
The second aim i s to determine the relationship between membrane bending and ideal NP size for uptake.
This aim will provide the first measurements of bending moduli associated with disease and use this information to improve delivery of NPs to diseased tissues.
The third aim i s to develop a mathematical model that will assist in the design of experimental protocols and optimization of NP size for targeting of diseased cells. This research will provide the underlying relationship between cell surface mechanics and NP uptake. It will investigate this phenomenon in the context of atherosclerosis and lay a foundation for future studies on mechanobiology-related diseases such as cancer and bone degeneration.
The overall goal of this research is to develop a new method of nanoparticle (NP) drug delivery called mechanotargeting. This research will result in a new method to measure the mechanical properties of cell surfaces and their changes with diseases such as atherosclerosis. Since uptake depends on cell mechanics, it will provide a new strategy to determine the best NPs size for uptake in cells, thus improving the effectiveness of NP drug delivery.