Abstract:

Targeting drugs to specific cells by conjugating the drug to a ligand for a cell surface receptor has the potential to yield earlier detection of pathology; better localization for intervention; and, fewer side effects from drug therapies. Cancer drugs can be targeted by conjugating ligand(s) specific for an over-expressed receptor with carrier entities such as polymers, thereby creating multivalent constructs and enabling more specific targeting of tumor cells relative to non-tumor cells. In the brain, systemic drug delivery is often not effective due to the blood-brain barrier, so direct injection to the tissue is required. A mathematical model of diffusive and convective transport of multivalent constructs within tissue was developed, including the biophysics of binding to tumor and non-tumor cells, to optimize construct targeting to tumor cells in brain tissue. Predictive modeling indicates that in order to optimize attainable contrast between tumor and non-tumor tissue, a convective wash must be included subsequent to delivery to remove unbound construct.

To demonstrate proof-of-concept, novel multivalent cell targeting conjugates were synthesized and characterized, and experiments were done in vitro to determine their binding ability to glioblastoma and normal healthy astrocyte (NHA) cells. To validate the results of the model, 3-D cell-gel co-cultures were created to test the delivery scheme predictions. Construct binding to tumor cells only relative to non-tumor cells, and increased visualization of tumor cells relative to background after a wash period were accomplished. Through the integration and collaboration of the multidisciplinary fields of engineering, mathematics, chemistry, and biology, a novel approach to predict, identify, and implement a solution to a challenging problem was achieved.