Optimizing delivery of multivalent targeting constructs for detection of secondary tumors.

Abstract

Targeting drugs or imaging molecules to specific cells by conjugating them to antibodies or ligands for cell surface receptors may allow earlier detection of pathology, better localization for intervention, and fewer side effects. Delivery of these molecules to the target is complicated by construct size, which cannot cross typical endothelial barriers such as the vascular wall, and lack of a priori knowledge of the location of secondary tumor sites to which the construct is targeted. Here we develop mathematical models for diffusive and convection-enhanced delivery of a trivalent construct. Results show that delivery of the construct to the tissue does not yield acceptable contrast or specificity; therefore, unbound construct must be removed from the area of interest by allowing diffusion out of the area or a follow-up injection of fluid containing no construct (e.g., saline). The need for this additional step requires weeks to months for diffusive delivery to yield acceptable contrast, but convection-enhanced delivery may be able to achieve acceptable contrast within several days. Thus, convection-enhanced delivery of multivalent constructs may provide a mechanism to locate secondary tumor sites without prior knowledge of their location which would greatly enhance the ability to detect and treat cancer.