Abstract:

Drug targeting to specific cells relies upon conjugating a drug to a ligand for a receptor, which is over-expressed by the target cell population. This study present the presentation of a mathematical model derived using the principles of mass action that predicts the binding specificity of multivalent drug-ligand constructs. In this study it is demonstrated, mathematically and experimentally that multivalent constructs will exhibit increased specificity (the ratio of the number of total bound constructs on target versus untargeted cells) beyond intrinsic specificity determined by the ratio of the number of receptors and we elucidate critical parameters for the rational design of such molecules.

This study present the synthesis of a multivalent biomacromolecule intended to target glioma cells via binding to the alpha-six-beta-one integrin. The construct was created by linking three dodecapeptides, reported to bind the targeted integrin, with poly(ethylene glycol) linkers. The construct is intended to be delivered locally, and it demonstrates a more homogenous and swift perfusion profile in comparison with quantum dots. The binding specificity of the construct was investigated using glioblastoma and normal human astrocyte cells. The results reveal quantitative differences, in binding between glioma and astrocyte cells, with a moderate increase in binding avidity due to multivalency (0.79 micromolar for the trivalent construct versus 4.28 micromolar for the dodecapeptide). Binding specificity of these constructs follows the predicted mathematical trend, demonstrating a sharp increase in specificity, 3 fold above the specificity of monovalent construct, at concentrations lower than its affinity (0.6 micromolar).

Overall, these multivalent biomacromolecular constructs demonstrate good targeting properties: swift and homogenous perfusion profiles in tissue analogs, increased avidity and specificity with respect of concentration variation.