Tumor-selective radiopharmaceutical targeting via receptor-mediated endocytosis of gallium-67-deferoxamine-folate.
Tumor-selective radiopharmaceutical targeting via receptor-mediated endocytosis of gallium-67-deferoxamine-folate.
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发表时间：
1996-06
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通讯作者：
Carla J. Mathias;Susan Wang;Robert J. Lee;David J. Waters;Philip S. Low;Mark A. Green
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作者：
Carla J. Mathias;Susan Wang;Robert J. Lee;David J. Waters;Philip S. Low;Mark A. Green
研究了维生素叶酸的受体介导的内吞摄取途径作为肿瘤选择性放射性药物递送的靶点。这种传递机制的分子靶点是一种膜相关叶酸结合蛋白（FBP），它被多种恶性细胞系过度表达。方法采用裸鼠肿瘤模型，观察67 Ga标记的去铁胺-叶酸偶联物（67 Ga-DF-folate）体内靶向肿瘤细胞的能力。将约4 × 10（6）个叶酸受体阳性KB（人鼻咽癌）细胞皮下接种到无胸腺小鼠体内，15天后产生约0.20 g肿瘤，此时通过静脉注射给予67 Ga-DF-叶酸、67 Ga-去铁胺（67 Ga-DF）或67 Ga-柠檬酸盐。结果67 Ga-DF-叶酸缀合物在体内显示出显著的肿瘤特异性沉积，在注射后4小时肿瘤中具有注射剂量的1.0 +/-0.3%（%ID）（等于5.2 +/-1.5%ID/g肿瘤; n = 3只小鼠）。注射后4小时的相应肿瘤与背景比值为：肿瘤/血液= 409 +/- 195;肿瘤/肌肉= 124 +/- 47;肿瘤/肝脏= 11 +/- 3;肿瘤/肾脏= 2.6+/-0.9。通过共注射2.4+/-1.0 mg游离叶酸盐有效地阻断了67 Ga-DF-叶酸盐缀合物的肿瘤摄取。在对照实验中，67 Ga-柠檬酸盐显示出肿瘤摄取为注射剂量的2.2 +/- 0.4%（10.9 +/-0.2% ID/g肿瘤），但靶-背景对比度非常差（肿瘤/血液= 0.84 +/-0.19;肿瘤/肌肉= 5.4 +/-0.7;肿瘤/肝脏= 2.3 +/-0.2;肿瘤/肾脏= 2.4 +/-0.3）。未缀合的67 Ga-去铁胺显示无肿瘤亲和力。结论受体介导的叶酸偶联物的内吞作用可能为放射性药物选择性地进入肿瘤提供了一种合适的机制，用于诊断成像和/或放射治疗。
UNLABELLED The receptor-mediated endocytosis uptake pathway for the vitamin folate was investigated as a target for tumor-selective radiopharmaceutical delivery. The molecular target for this delivery mechanism is a membrane-associated folate binding protein (FBP) that is overexpressed by a variety of malignant cell lines. METHODS The ability of a 67Ga-labeled deferoxamine-folate conjugate (67Ga-DF-folate) to target tumor cells in vivo was examined using an athymic mouse tumor model. Subcutaneous inoculation of approximately 4 X 10(6) folate-receptor-positive KB (human nasopharyngeal carcinoma) cells into athymic mice yielded approximately 0.20 g tumors in 15 days, at which time either 67Ga-DF-folate, 67Ga-deferoxamine (67Ga-DF) or 67Ga-citrate was administered by intravenous injection. RESULTS The 67Ga-DF-folate conjugate showed marked tumor-specific deposition in vivo, with 1.0 +/- 0.3% of the injected dose (%ID) in tumor at 4 hr postinjection (equating to 5.2 +/- 1.5 %ID/g tumor; n = 3 mice). Corresponding tumor-to-background ratios at 4 hr postinjection were: tumor/blood = 409 +/- 195; tumor/muscle = 124 +/- 47; tumor/liver = 11 +/- 3; and tumor/kidney = 2.6+/-0.9. Tumor uptake of 67Ga-DF-folate conjugate was effectively blocked by co-injection of 2.4+/-1.0 mg free folate. In control experiments, 67Ga-citrate exhibited tumor uptake of 2.2 +/- 0.4% of the injected dose (10.9 +/- 0.2 %ID/g tumor), but very poor target-to-background contrast (tumor/blood = 0.84 +/- 0.19; tumor/muscle = 5.4 +/- 0.7; tumor/liver = 2.3 +/- 0.2; and tumor/kidney = 2.4 +/- 0.3). Unconjugated 67Ga-deferoxamine showed no tumor affinity. CONCLUSION Receptor-mediated endocytosis of radiolabeled folate-conjugates may offer a suitable mechanism for selectively delivering radiopharmaceuticals to tumors for diagnostic imaging and/or radiation therapy.