The role of molecular conformation on tumor uptake of polymeric contrast agents

Rationale and Objective: We wanted to test the hypothesis that linear extended polymers are able to translocate across compromised endothelia to a much higher degree than polymers that are in a coiled configuration. The basis for this hypothesis is the concept of polymer reptation, a process allowing linear polymers to move around fixed obstacles and through small pores. Materials and Methods: The conjugation of polylysine with DTPA was varied from 55% to 95% of lysine moieties for a fixed polymer degree of polymerization. The variable conjugation constructs were assessed in their ability to enhance tumor signals in an animal model. The blood circulation time was also assessed, as was the proton relaxivity of the constructs. Results: The relaxivity values of the variable conjugation constructs indicated that the conformation of the highly conjugated polymers was consistent with an extended conformation. Images of the highly conjugated constructs with cryoelectron microscopy showed structures also consistent with an extended peptide chain conformation. These constructs gave tumor signal enhancements 10 times larger than observed for constructs of lower conjugation at the same injection dose. Conclusions: The conformation of polymer agents is of decisive importance in the imaging efficacy of tumors. Polylysine conjugates of Gd-DTPA, at conjugation levels of 90% or higher, assume an extended linear conformation, which enables them to translocate across tumor endothelium more effectively than less highly conjugated polymers.