Hoffman Timothy J, Gali Hariprasad, Smith C Jeffrey, Sieckman Gary L, Hayes Donald L, Owen Nellie K, Volkert Wynn A
Research Service, Harry S. Truman Memorial VA Hospital, Columbia, Missouri, USA.
J Nucl Med. 2003 May;44(5):823-31.
Gastrin-releasing peptide (GRP) receptors have been shown to be expressed with high densities on several types of cancer cells including prostate, breast, small cell lung, and pancreas cancers. Bombesin (BBN) has been known to bind to GRP receptors with high affinity and specificity. The aim of these studies was to develop new (111)In-labeled BBN analogs having high tumor uptake and optimal pharmacokinetics for specific targeting of human prostate cancers.
A novel series of dodecanetetraacetic acid (DOTA)-X-BBN[7-14]NH(2) (X = 0, beta-Ala, 5-Ava, 8-Aoc, or 11-Aun) conjugates and their In(III)/(111)In complexes exhibiting high GRP-receptor-binding affinities were synthesized and characterized.
In vitro competitive binding assays, using PC-3 androgen-independent human prostate cancer cells, demonstrated values of <2.5 nmol/L for inhibitory concentration of 50% for analogs with beta-Ala, 5-Ava, and 8-Aoc spacers. In vivo biodistribution studies of the (111)In-DOTA-X-BBN[7-14]NH(2) conjugates performed on CF-1 mice at 1 h after injection have revealed that the uptake of radioactivity in the pancreas, a GRP-receptor-expressing tissue, increased as a function of hydrocarbon spacer length (i.e., from 0.20 +/- 0.04 percentage injected dose [%ID] per gram for the analog with no spacer to a maximum of 26.97 +/- 3.97 %ID/g for the analog with 8-Aoc spacer). The radioactivity was cleared efficiently from the blood pool by excretion mainly through the renal/urinary pathway (e.g., 71.6 +/- 1.8 %ID at 1 h after injection for 8-Aoc spacer analog). In vivo pharmacokinetic studies of the (111)In-DOTA-8-Aoc-BBN[7-14]NH(2) conjugate conducted on PC-3 human prostate cancer-derived xenografts in SCID mice showed a specific uptake of radioactivity in tumor, with 3.63 +/- 1.11 %ID/g observed at 1 h after injection. High tumor-to-blood and tumor-to-muscle ratios of approximately 6:1 and 45:1, respectively, were achieved at 1 h after injection. Relative to the radioactivity observed in the tumor at 1 h after injection, 43%, 19%, and 9% of the radioactivity was retained at, respectively, 24, 48, and 72 h after injection.
These studies showed that radiometallated DOTA-X-BBN[7-14]NH(2) constructs with hydrocarbon spacers ranging from 5 to 8 carbon atoms are feasible candidates for further development as diagnostic and therapeutic radiopharmaceuticals for patients with GRP-positive cancers.
胃泌素释放肽（GRP）受体已被证明在几种类型的癌细胞上高密度表达，包括前列腺癌、乳腺癌、小细胞肺癌和胰腺癌。蛙皮素（BBN）已被证实以高亲和力和特异性与GRP受体结合。这些研究的目的是开发新的具有高肿瘤摄取率和最佳药代动力学的（111）In标记的BBN类似物，用于特异性靶向人类前列腺癌。
合成并表征了一系列新型的十二烷四乙酸（DOTA）-X-BBN[7-14]NH₂（X = 0、β-丙氨酸、5-氨基戊酸、8-氨基辛酸或11-氨基十一酸）缀合物及其表现出高GRP受体结合亲和力的In(III)/(111)In络合物。
使用PC-3雄激素非依赖性人前列腺癌细胞进行的体外竞争性结合试验表明，具有β-丙氨酸、5-氨基戊酸和8-氨基辛酸间隔基团的类似物的50%抑制浓度值<2.5 nmol/L。在注射后1小时对CF-1小鼠进行的（111）In-DOTA-X-BBN[7-14]NH₂缀合物的体内生物分布研究表明，作为GRP受体表达组织的胰腺中的放射性摄取随着烃间隔基团长度的增加而增加（即，从无间隔基团的类似物的每克0.20±0.04注射剂量百分比[%ID]增加到具有8-氨基辛酸间隔基团的类似物的最大26.97±3.97 %ID/g）。放射性主要通过肾/尿途径从血池中有效清除（例如，具有8-氨基辛酸间隔基团类似物在注射后1小时为71.6±1.8 %ID）。在SCID小鼠中对PC-3人前列腺癌衍生的异种移植瘤进行的（111）In-DOTA-8-氨基辛酸-BBN[7-14]NH₂缀合物的体内药代动力学研究表明，肿瘤中放射性有特异性摄取，注射后1小时观察到为3.63±1.11 %ID/g。注射后1小时分别实现了约6:1和45:1的高肿瘤与血液和肿瘤与肌肉比值。相对于注射后1小时在肿瘤中观察到的放射性，分别在注射后24、48和72小时保留了43%、19%和9%的放射性。
这些研究表明，具有5至8个碳原子烃间隔基团的放射性金属化DOTA-X-BBN[7-14]NH₂构建体是作为GRP阳性癌症患者的诊断和治疗放射性药物进一步开发可行性候选物。
