No abstract

These data demonstrate that folate-conjugated magnetic resonance imaging contrast agents represent a promising new approach to tumor targeting.

This new agent accumulates in tumors expressing hFR. These results do not differentiate between active and passive targeting mechanisms. Receptor-negative tumors suggest a mechanism other than a nonspecific blood pool effect.

The need to develop target-specific MRI contrast agents to aid in disease characterization remains highly essential. In this study, we present a generation four polyamidoamine (PAMAM) folate-dendrimer that specifically targets the high affinity folate receptor (hFR) overexpressed on more than 80% of ovarian tumors. In vitro, mouse erythroleukemia cells expressing the hFR bind the radiolabeled folate-dendrimer chelate resulting in over 2700% increase in binding compared with untreated cells. The binding was inhibited by free folic acid to levels observed on folate-receptor-negative cells. In vivo, ovarian tumor xenografts resulted in a 33% contrast enhancement, following the folate-dendrimer chelate administration, that was significantly different compared with results obtained with a non-specific, extracellular fluid space agent, Gd-HP-DO3A. In addition, this contrast enhancement was absent in saline-treated animals, folate-receptor-negative tumors, and was inhibited by free folic acid. Results suggest that a macromolecular, dendrimeric MRI agent with high molecular relaxivities (1646 mM(-1) s(-1)) can be used in specifically targeting the hFR on tumor cells and ovarian tumors.

Biodistribution studies confirm previous MRI findings and show that the accumulation of the folate-dendrimer requires the expression of the hFR.