Recent advances in the fields of polymer science, bioengineering, and genomics present an exciting opportunity for a synergistic and strategic approach to developing specific cancer therapies. The multi-disciplinary team of investigators assembled here brings the important contributions from each field together to create a novel and potentially powerful general strategy for targeting therapeutic molecules to cells overexpressing two cell surface receptors. The hypothesis tested is that multivalent ligands (many ligands bound to one polymer) can increase specificity of that construct for a target cell type by at least one order-of magnitude, while decreasing the required concentration of unbound ligand by at least one order-of magnitude. Further, it is hypothesized that, if one of the ligand types binds to an integrin, it will decrease cell adhesion strength thus preventing tumor cell migration. Combined with genomic testing to determine which cell surface receptors are highly expressed in specific pathological cell types, this two-ligand type strategy has potential to target almost any cellular pathology in which the expression of at least two cell surface receptors is up-regulated; and the specific aims in this study are intended to demonstrate proof-of principle for a model system based on this approach. Ligands for a receptor target determined by global gene expression data will be synthesized or isolated from recombinant production. These will be bound in combination to a co-polymer with side chains each containing one of two chemically reactive groups. A mathematical model of these multivalent ligands binding to cells will be developed, and the accuracy of the model will be tested by comparing to in vitro affinity and specificity experiments. The model's predictions will be implemented by systematically varying the number of each ligand type on the polymer construct to optimize specificity for cancer cells versus normal brain cells. Finally, in vitro cell culture assays for cell adhesion, cell migration, and apoptosis will determine the therapeutic potential of these constructs.
| Stukel, Jill M; Li, Ronald C; Maynard, Heather D et al. (2010) Two-step synthesis of multivalent cancer-targeting constructs. Biomacromolecules 11:160-7 |
| Rosca, Elena V; Gillies, Robert J; Caplan, Michael R (2009) Glioblastoma targeting via integrins is concentration dependent. Biotechnol Bioeng 104:408-17 |
| Shewmake, Thomas A; Solis, Francisco J; Gillies, Robert J et al. (2008) Effects of linker length and flexibility on multivalent targeting. Biomacromolecules 9:3057-64 |
| Stukel, Jill M; Heys, Jeffrey J; Caplan, Michael R (2008) Optimizing delivery of multivalent targeting constructs for detection of secondary tumors. Ann Biomed Eng 36:1291-304 |
| Stukel, Jill M; Parks, Jason; Caplan, Michael R et al. (2008) Temporal and spatial control of neural effects following intracerebral microinfusion. J Drug Target 16:198-205 |
| Rosca, Elena V; Stukel, Jill M; Gillies, Robert J et al. (2007) Specificity and mobility of biomacromolecular, multivalent constructs for cellular targeting. Biomacromolecules 8:3830-5 |
| Satterfield, Brent C; Kulesh, David A; Norwood, David A et al. (2007) Tentacle Probes: differentiation of difficult single-nucleotide polymorphisms and deletions by presence or absence of a signal in real-time PCR. Clin Chem 53:2042-50 |
| Hwang, Jungyeon; Li, Ronald C; Maynard, Heather D (2007) Well-defined polymers with activated ester and protected aldehyde side chains for bio-functionalization. J Control Release 122:279-86 |
