Müller Cristina, Schibli Roger, Krenning Eric P, de Jong Marion
Department of Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
J Nucl Med. 2008 Apr;49(4):623-9. doi: 10.2967/jnumed.107.047704. Epub 2008 Mar 14.
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 99mTc-radiofolates in mice. The aim of this study was to corroborate the effect of pemetrexed with the clinically tested 111In-DTPA-folate (DTPA is diethylenetriaminepentaacetic acid) in a human ovarian cancer xenografted mouse model.
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 111In-DTPA-folate (0.7 MBq/mouse, 0.35 mug) with or without preinjection of pemetrexed (PMX, 400 microg) 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 microg).
In biodistribution studies the tumor uptake of 111In-DTPA-folate (IGROV-1: 9.79 +/- 3.21 %ID/g [percentage injected dose per gram]; SKOV-3: 7.57 +/- 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 ( approximately 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 111In-DTPA-folate, whereas the tumor uptake was retained. Thus, the tumor-to-kidney ratio was significantly increased to approximately 0.50. SPECT/CT images confirmed the superior tumor-to-background ratio in mice injected with PMX. These findings were particularly evident in mice with SKOV-3 metastases that could be visualized only when 111In-DTPA-folate was administered in combination with PMX.
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.
基于叶酸的放射性药物可作为成像剂，并用于叶酸受体（FR）阳性恶性组织（如卵巢癌）的潜在放射治疗。然而，肾脏中大量的FR表达会导致放射性物质在肾脏中出现不必要的滞留。最近，我们发现预先注射一种抗叶酸药物可显著提高有机金属99mTc-放射性叶酸在小鼠体内的肿瘤选择性。本研究的目的是在人卵巢癌异种移植小鼠模型中，用临床测试的111In-DTPA-叶酸（DTPA是二乙三胺五乙酸）证实培美曲塞的作用。
在携带皮下FR阳性卵巢肿瘤（IGROV-1和SKOV-3）或转移瘤（腹腔注射SKOV-3细胞后）的雌性无胸腺裸鼠中进行体内研究。在注射111In-DTPA-叶酸（0.7 MBq/小鼠，0.35 μg）前1小时，无论是否预先注射培美曲塞（PMX，400 μg），在给药后1、4和24小时进行生物分布研究。在注射放射性示踪剂（30 - 50 MBq/小鼠，4.5 - 10 μg）后4和24小时，用高分辨率、高灵敏度的SPECT/CT相机采集图像。
在生物分布研究中，111In-DTPA-叶酸的肿瘤摄取量（IGROV-1：注射后4小时为9.79±3.21 %ID/g[每克注射剂量的百分比]；SKOV-3：7.57±0.61 %ID/g）较高，且在研究期间保持稳定。然而，在肾脏中发现有大量放射性物质滞留（注射后4小时为85 - 105 %ID/g），导致肿瘤与肾脏的比值极低（约为0.10），情况不利。预先注射PMX导致在注射111In-DTPA-叶酸后的所有时间点，肾脏摄取量显著降低（为对照值的20% - 30%，P < 0.03），而肿瘤摄取量保持不变。因此，肿瘤与肾脏的比值显著提高至约0.50。SPECT/CT图像证实，在注射PMX的小鼠中，肿瘤与背景的比值更高。这些发现在患有SKOV-3转移瘤的小鼠中尤为明显，只有当111In-DTPA-叶酸与PMX联合给药时，转移瘤才能被可视化。
PMX的应用显著降低了肾脏中不必要的放射性物质积累，而肿瘤摄取不受影响。这些观察结果表明，PMX对放射性叶酸在肾脏中摄取的降低作用具有普遍有效性。我们的发现将为基于叶酸的放射治疗的发展指明方向。
