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靶向纳米颗粒（NPs）到内皮细胞的方法，该方法利用细胞表面伴随疾病（如动脉粥样硬化和癌症）的内在力学变化。实现这一目标的主要策略是测量细胞表面的机械特性以及这些特性如何随疾病状态而变化，并设计更容易被细胞吸收的NPs。该项目将特别与动脉粥样硬化相关，因为所有的研究都是关于内皮细胞的，内皮细胞排列在血管上，是动脉粥样硬化发展的初始介质。第一个目的是确定流体剪切应力对内皮细胞膜弯曲模量的影响，因为血流诱导的剪切应力与动脉粥样硬化密切相关。第二个目的是确定膜弯曲和理想NP大小之间的关系。该目标将提供与疾病相关的弯曲模量的首次测量，并利用该信息改善NPs向病变组织的输送。第三个目标是建立一个数学模型，该模型将有助于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，并为未来研究与机械生物学相关的疾病如癌症和骨变性奠定基础。

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.