Pemetrexed Improves Tumor Selectivity of ¹¹¹In-DTPA-Folate in Mice with Folate Receptor–Positive Ovarian Cancer

Abstract

Folate-based radiopharmaceuticals can be used as imaging agents and for potential radiotherapy of folate receptor (FR)-positive malignant tissue (e.g., ovarian carcinomas). However, substantial FR expression in the kidneys results in undesired renal retention of radioactivity. Recently, we found that the preinjection of an antifolate significantly improved tumor selectivity of organometallic 99m Tc-radiofolates in mice. The aim of this study was to corroborate the effect of pemetrexed with the clinically tested 111 In-DTPA-folate (DTPA is diethylenetriaminepentaacetic acid) in a human ovarian cancer xenografted mouse model. Methods: In vivo studies were performed in female athymic nude mice bearing subcutaneous FR-positive ovarian tumors (IGROV-1 and SKOV-3) or metastases (after intraperitoneal SKOV-3 cell inoculation). Biodistribution studies were performed 1, 4, and 24 h after administration of 111 In-DTPA-folate (0.7 MBq/mouse, 0.35 mg) with or without preinjection of pemetrexed (PMX, 400 mg) 1 h before the radiofolate. Images were acquired with a high-resolution, high-sensitivity SPECT/CT camera, 4 and 24 h after injection of the radiotracer (30-50 MBq/ mouse, 4.5-10 mg). Results: In biodistribution studies the tumor uptake of 111 In-DTPA-folate (IGROV-1: 9.79 6 3.21 %ID/g [percentage injected dose per gram]; SKOV-3: 7.57 6 0.61 %ID/g, 4 h after injection) was high and retained over the time of investigation. However, considerable retention of radioactivity was found in kidneys (85-105 %ID/g, 4 h after injection), resulting in unfavorably low tumor-to-kidney ratios (;0.10). Preinjection of PMX resulted in a significant reduction of renal uptake (20%-30% of control values, P , 0.03) at all time points after injection of 111 In-DTPA-folate, whereas the tumor uptake was retained. Thus, the tumor-to-kidney ratio was significantly increased to ;0.50. SPECT/CT images confirmed the superior tumor-tobackground ratio in mice injected with PMX. These findings were particularly evident in mice with SKOV-3 metastases that could be visualized only when 111 In-DTPA-folate was administered in combination with PMX. Conclusion: The application of PMX resulted in a significant reduction of undesired radioactivity accumulation in kidneys, whereas the tumor uptake remained unaffected. These observations suggest a general validity of the reducing effect of PMX on the uptake of radiofolates in kidneys. Our findings will lead the way toward the development of folate-based radiotherapy.

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

“…The biodistribution profiles of acetazolamide derivatives compares favourably with the ones previously reported for other ligands [23][24][25][26]. In particular, we were pleased to see that %ID/g values in the tumor were higher than the corresponding values in the kidney (the main organ for drug clearance), even as early as one hour after intravenous administration of the product [18].…”

“…Unlike antibodies (which can easily be raised against the majority of target proteins of interest), it is not always easy to generate high-affinity small molecule ligands to tumor-associated antigens. However, excellent tumor-targeting results have been reported for folate analogues targeting folate-receptor positive tumors [23,24], substituted urea derivatives targeting prostate-specific membrane antigen [25], somatostatin antagonists targeting the somatostatin receptor [26] and for carbonic anhydrase IX (CAIX) ligands [16][17][18]27].…”

177Lu-EC0800 Combined with the Antifolate Pemetrexed: Preclinical Pilot Study of Folate Receptor Targeted Radionuclide Tumor Therapy

“…As a consequence there is an inherent risk of damage to the kidneys by particle radiation. However, we have shown in several preclinical studies that administration of the antifolate pemetrexed (PMX) resulted in a tremendous reduction of the radiofolate's retention in the kidneys whereas accumulation in tumor xenografts remained unaffected (11)(12)(13). The exact mechanism of this interaction is still not completely clear.…”

“…IGROV-1 cells are human ovarian cancer cells that express the folate receptor at a somewhat lower level than KB cells (12,31,36). The human prostate cancer cell line PC-3 does not express the folate receptor and was used as a negative control.…”

A New 18F-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor–Positive Tumors

“…Recently, Müller et al reported a favorable effect of the antifolate pemetrexed on kidney and tumor uptake (17,18); thus, the high radioactivity accumulation and the potential risk of damage to the kidneys may no longer be an issue.…”