Multiscale Modeling of the Nanocarrier-Cell Ahesion Interface in Targeted Drug Delivery

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1236514PI: RadhakrishnanTargeted drug delivery is an emerging application of nanotechnology. It involves designing pharmaceuticals by packaging them into nanocarriers and targeting them for intravenous delivery directly to the diseased tissue. Benefits of this approach include optimal drug dosage in-terms of the drug reaching diseased tissue (enhanced therapeutic efficacy) and a concomitant decrease in drug reaching normal tissue (reduced toxicity). Success is directly dependent on the design and synthesis of carrier particles that have specific features such as particle size/shape and surface coverage with binding molecules specific to the biomarkers (target receptors) of diseases being treated. Optimal design leads to the desired, and necessary, initial event, namely, selective binding and arrest of the carrier particle to endothelial cells in blood vessels within the diseased tissue, followed by carrier internalization into the cells post arrest. Using computational modeling and engineering principles, the project will investigate experimental and design parameters such as receptor density on nanocarriers, nanocarrier size & shape, and binding response to blood flow in order to optimize the targeting the nanocarriers to specific (diseased) cells. The model will integrate multiple length and time scales involving blood flow, nanocarrier arrest, cell membrane mobility, and biomolecular receptor-ligand interactions, all of which contribute to the physical environment for nanocarrier binding, and collectively define the efficacy of nanocarrier arrest on the target cell. The model will delineate nanocarrier binding and arrest influenced by hydrodynamic forces resulting from blood flow, expression-levels of specific (target) receptors on the endothelial cell surface, their lateral diffusion on the membrane, the presence or absence of a glycocalyx, and cell membrane mobility. The model will be validated against quantitative cellular and animal experiments and will be employed to make predictions for optimal design of nanocarriers.Success of targeted drug delivery protocols relies in part on the development of rational technologies designing nanocarrier pharmaceuticals and clinical methods for injecting such functionalized, targeted drug carriers into the blood stream close to the disease tissue. The results of the project will lead directly to a design platform for targeted nanocarriers to endothelial cells, which line blood vessels. The versatility of the modeling combined with experimental approaches will then enable their utility in context specific pharmacological applications, e.g., designing carriers for specific/different disease states, preventive (prophylactic) versus therapeutic targeting, targeting in arteries versus veins, and exercising control on toxicity. Project results will directly facilitate the optimal engineering design, as well as impact the clinical translation of such drug delivery systems for targeted disease treatment.