Development of a Tumor-Targeting MR Contrast Agent Using the High-Affinity Folate Receptor

Abstract

Macromolecular contrast agents enhance tumors by means of active or passive targeting. Active targeting requires surface receptors. Many tumors of epithelial origin express the high-affinity folate receptor (hFR), including ovarian tumors. The objective of this research was to enhance tumors that express hFR using macromolecular contrast agents conjugated to folic acid. The authors prepared a folate-conjugated dendrimer polychelate by attaching folic acid to a fourth-generation ammonia-core polyamidoamine dendrimer. The remaining amines were reacted with 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriamine pentaacetic acid. Relaxivity measurements (r1 and r2) and MRI were conducted at 4.7 T. The dendrimer r2 exceeded that of Gd-HP-DO3A by 8.2 times at 4.7 T. It increased the tumor percentage contrast enhancement, 24 hours after injection, of T2-weighted images by 33%. 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.