The long term objective of this project is to prepare a protein-based drug carrier that can be used in drug targeting to solid tumors. Macromolecules are shown to accumulate in leaky blood vessels surrounding rapidly growing tumor tissue. However, the movement of these molecules from where they are retained to actual tumor cells is extremely slow, due to unfavorable convection, or solvent drag, around the tumor site. In contrast, small molecules (<10 kDa)can utilize diffusion dictated by concentration gradient to access the site of action. The overall goals of the proposed study are to: (1) synthesize water-soluble biotinylated derivative of paclitaxel, (2) identify high-affinity paclitaxel-binding proteins via the mRNA display system, (3) further select those that will release paclitaxel when pH is lowered to 6.5 or temperature is elevated to 42?C, (4) covalently couple these proteins to a dendrimer to increase the overall MW, and (5) finally characterize the assembly in terms of paclitaxel binding and release.
|Watson, Venita Gresham; Motsinger-Reif, Alison; Hardison, Nicholas E et al. (2011) Identification and replication of loci involved in camptothecin-induced cytotoxicity using CEPH pedigrees. PLoS One 6:e17561|
|Watson, Venita Gresham; Hardison, Nicholas E; Harris, Tyndall et al. (2011) Genomic profiling in CEPH cell lines distinguishes between the camptothecins and indenoisoquinolines. Mol Cancer Ther 10:1839-45|
|Gresham, Venita; McLeod, Howard L (2009) Genomics: applications in mechanism elucidation. Adv Drug Deliv Rev 61:369-74|