Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates

Folic-acid-based radioconjugates have been developed for nuclear imaging of folate receptor (FR)-positive tumors; however, high renal uptake was unfavorable in view of a therapeutic application. Previously, it was shown that pre-injection of pemetrexed (PMX) increased the tumor-to-kidney ratio of radiofolates several-fold. In this study, PMX was combined with the currently best performing radiofolate ([Lu-177] cm13), which is outfitted with an albumin-binding entity. Biodistribution studies were carried out in mice bearing KB or IGROV-1 tumor xenografts, both FR-positive tumor types. SPECT/CT was performed with control mice injected with [Lu-177] folate only and with mice that received PMX in addition. Control mice showed high uptake of radioactivity in KB and IGROV-1 tumor xenografts, but retention in the kidneys was also high, resulting in tumor-to-kidney ratios of similar to 0.85 (4 hp.i.) and similar to 0.60 (24 h p. i.) or similar to 1.17 (4 h p. i.) and similar to 1.11 (24 h p. i.) respectively. Pre-injection of PMX improved the tumor-to-kidney ratio to values of similar to 1.13 (4 h p. i.) and similar to 0.92 (24 h p. i.) or similar to 1.79 (4 h p. i.) and similar to 1.59 (24 h p. i.), respectively, due to reduced uptake in the kidneys. It was found that a second injection of PMX-3 h or 7 h after administration of the radiofolate-improved the tumor-to-kidney ratio further to similar to 1.03 and similar to 0.99 or similar to 1.78 and similar to 1.62 at 24 h p. i. in KB and IGROV-1 tumor-bearing mice, respectively. SPECT/CT scans readily visualized the tumor xenografts, whereas accumulation of radioactivity in the kidneys was reduced in mice that received PMX. In this study, it was shown that PMX had a positive impact in terms of reducing the kidney uptake of albumin-binding radiofolates; hence, the administration of PMX resulted in similar to 1.3-1.7-fold higher tumor-to-kidney ratios. This is, however, a rather moderate effect in comparison to the previously shown effect of PMX on conventional radiofolates (without albumin binder), which led to 5-6-fold increased tumor-to-kidney ratios. An explanation for this result may be the different pharmacokinetic profiles of PMX and long-circulating radiofolates, respectively. Despite the promising potential of this concept, it is believed that a clinical translation would be challenging, particularly when PMX had to be injected more than once.