A strategic approach to improve the treatment of many diseases is to package a drug into carrier particles and then target that drug carrier for bloodstream delivery directly to the diseased tissue. Benefits of this approach include the possibility of an increase in the dose of the drug reaching diseased tissue (enhanced therapeutic efficacy) and a concomitant decrease in the dose of drug reaching normal tissue (reduced toxicity). Success of this approach relies in part on the development of technologies and clinical methods for injecting functionalized, targeted drug carriers into the blood stream close to the disease tissue. Success is directly dependent on the design and manufacture of carrier particles that have specific features such as particle size and surface coverage with binding molecules specific to the diseases being treated that lead to the desired, and necessary, initial event: binding of the carrier particle to endothelial cells in blood vessels within the diseased tissue. The complex interplay between targeted nanocarrier motion in flow, biomolecular receptor- ligand interactions governing specific binding, and thermal/transport dynamics of receptors on the cell membrane, is inherently a multiscale problem. The physical environment for binding ultimately defines the efficacy of nanocarrier arrest on the target cell. The nanocarrier binding and arrest are influenced by hydrodynamic forces resulting from blood flow, expression-levels of specific target determinants on the cell surface, their lateral diffusion on the membrane, the presence or absence of a glycocalyx, and membrane mobility. We hypothesize that experimental and design parameters such as receptor density on nanocarriers, carrier size, and binding response to flow characteristics such as shear stress levels can be optimized for enhancing the targeting the nanocarriers to specific (stressed) cells. To test this hypothesis, we propose four specific aims: 1) develop a spatially resolved stochastic multiscale model for predicting the energetic and kinetics of targeted spherical nanocarriers binding to endothelial cells; 2) experimentally quantify the kinetics of binding for ligand functionalized nanocarriers of varying size to fixed cells under static and shear conditions; 3) experimentally quantify the kinetics of binding for ligand functionalized nanocarriers of varying size to live cells under static and shear conditions and 4) extend the model in Aim 1 to a) include additional effects on binding due to membrane mobility, lateral diffusion of receptors and the mechano/hydrodynamic barrier posed by the glycocalyx in live cells; b) include effects of RBC-nanocarrier interactions and non-Newtonian rheology. We will develop a synergistic modeling and experimental platform for accessing and bridging the multiple length and time scales relevant for vascular delivery of targeted nanocarriers. Our objectives of quantitatively characterizing and predicting the transient nanoscale binding mechanics and dynamics for spherical nanocarrier binding to fixed and live endothelial cells under shear flow as a function of the various experimentally tunable parameters will lead to improvements in therapeutics for many diseases. A strategic approach to improve the treatment of many diseases is to package a drug into carrier particles and then target that drug carrier for bloodstream delivery directly to the diseased tissue. We will develop a synergistic experimental and computational platform addressing bloodstream delivery of targeted nanocarriers. This work to characterize quantitatively and predict computationally the binding mechanics and dynamics for nanocarrier binding to endothelial cells will lead to improvements in therapeutics for many diseases. ? ? ?
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