Lim Jae Cheong, Cho Eun Ha, Kim Jin Joo, Choi Sang Mu, Lee So Young, Nam Sung Soo, Park Ul Jae, Park Soo Hyun
Radioisotope Research Division, Department of Research Reactor Utilization, Korea Atomic Energy Research Institute, Daejeon 305-353, Republic of Korea; Bio-therapy Human Resources Center, Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea.
Radioisotope Research Division, Department of Research Reactor Utilization, Korea Atomic Energy Research Institute, Daejeon 305-353, Republic of Korea.
Nucl Med Biol. 2015 Mar;42(3):234-41. doi: 10.1016/j.nucmedbio.2014.10.008. Epub 2014 Oct 22.
The gastrin-releasing peptide receptor (GRPR) has been shown to be overexpressed in many human tumors, including prostate, colon, gastric, breast, pancreatic, and small cell lung cancers. Because bombesin (BBS) binds to GRPR with high affinity, BBS derivatives have been labeled with various radionuclides and have been demonstrated to be successful candidates for peptide receptor radiotherapy (PRRT). The present study describes the in vitro and in vivo preclinical characteristics of (177)Lu-DOTA-Lys(glucose)-4 aminobenzoic acid-BBS7-14 ((177)Lu-DOTA-gluBBN) to prepare radiolabeled candidates for the treatment of GRPR-expressing prostate tumors.
(177)Lu-DOTA-gluBBN was prepared as previously published [1]. Human prostate PC-3 tumor cells were used to determine the binding (Kd) retention and efflux of (177)Lu-DOTA-gluBBN. Pharmacokinetic, imaging, and radiotherapy studies were performed in PC-3 xenografted mice.
The Kd value of (177)Lu-DOTA-gluBBN was 0.63 nM, with a maximum binding capacity (Bmax) of 669.7 fmol/10(6) cells (4.04×10(5) GRPR/cell). During a 2-hr incubation, 90.1±0.4% of the cell-associated radio-peptide was internalized, and 56.3±7.1% of the internalized radio-peptide was externalized in vitro. High amounts of the radio-peptide were rapidly accumulated in a PC-3 tumor in vivo, and the % ID/g of the tumor was 12.42±2.15 1 hr p.i. The radio-peptide was quickly cleared from the blood, yielding tumor-to-blood ratios of 39.22±17.36 at 1 hr p.i. and 330.67±131.23 at 24hr p.i. In addition, (177)Lu-DOTA-gluBBN was clearly visualized in PC-3 tumors 1 hr p.i. and significantly inhibited the tumor growth (P<0.05). Treatment-related toxicity in the pancreas and kidneys was not observed, except for slight glomerulopathy.
The pharmacokinetic, imaging, and therapy studies suggest that this (177)Lu-DOTA-gluBBN has promising characteristics for application in nuclear medicine, namely, for the diagnosis and treatment of GRPR-overexpressing prostate tumors.
胃泌素释放肽受体（GRPR）已被证明在许多人类肿瘤中过度表达，包括前列腺癌、结肠癌、胃癌、乳腺癌、胰腺癌和小细胞肺癌。由于蛙皮素（BBS）与GRPR具有高亲和力结合，BBS衍生物已用各种放射性核素标记，并已被证明是肽受体放射治疗（PRRT）的成功候选者。本研究描述了（177）Lu-DOTA-赖氨酸（葡萄糖）-4-氨基苯甲酸-BBS7-14（（177）Lu-DOTA-谷氨酸BBN）的体外和体内临床前特征，以制备用于治疗GRPR表达前列腺肿瘤的放射性标记候选物。
（177）Lu-DOTA-谷氨酸BBN的制备如先前发表的[1]。用人前列腺PC-3肿瘤细胞测定（177）Lu-DOTA-谷氨酸BBN的结合（Kd）保留和流出。在PC-3异种移植小鼠中进行药代动力学、成像和放射治疗研究。
（177）Lu-DOTA-谷氨酸BBN的Kd值为0.63 nM，最大结合容量（Bmax）为669.7 fmol/10（6）个细胞（4.04×10（5）GRPR/细胞）。在2小时孵育期间，90.1±0.4%的细胞相关放射性肽被内化，56.3±7.1%的内化放射性肽在体外被外化。大量放射性肽在体内迅速积聚在PC-3肿瘤中，注射后1小时肿瘤的%ID/g为12.42±2.15。放射性肽迅速从血液中清除，注射后1小时肿瘤与血液的比率为39.22±17.36，注射后24小时为330.67±131.23。此外，注射后1小时在PC-3肿瘤中可清晰观察到（177）Lu-DOTA-谷氨酸BBN，并显著抑制肿瘤生长（P<0.05）。除轻微肾小球病外，未观察到胰腺和肾脏的治疗相关毒性。
药代动力学、成像和治疗研究表明，这种（177）Lu-DOTA-谷氨酸BBN在核医学应用中具有有前景的特征，即用于诊断和治疗GRPR过度表达的前列腺肿瘤。
