Mechano-targeting of nanoparticles to atherogenic endothelium

描述(由申请人提供)：拟议工作的目标是开发一种将纳米颗粒(NPs)靶向内皮细胞的方法，该方法利用伴随动脉粥样硬化和癌症等疾病的细胞表面内在机制的变化。实现这一目标的主要策略是测量细胞表面的机械性能，以及这些性能如何随着疾病状态的变化而变化，并设计更容易被细胞摄取的NPs。该项目将与动脉粥样硬化特别相关，因为所有的研究都将针对内皮细胞，即血管内皮细胞，以及那些作为动脉粥样硬化发展的初始中介的细胞。第一个目的是确定流体剪应力对内皮细胞膜弯曲模数的影响，因为血流诱导的剪应力与动脉粥样硬化密切相关。第二个目的是确定膜弯曲与理想的摄取NP大小之间的关系。这一目标将提供与疾病相关的弯曲模数的第一次测量，并利用这些信息来改善NPs对疾病组织的输送。第三个目标是开发一个数学模型，帮助设计实验方案和优化靶向病变细胞的NP大小。这项研究将提供细胞表面力学和NP摄取之间的潜在关系。它将在动脉粥样硬化的背景下研究这一现象，并为未来癌症和骨骼退化等与机械生物学相关的疾病的研究奠定基础。

DESCRIPTION (provided by applicant): 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 is 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 is 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 is 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.