αVβ3 Integrin-Targeted Radionuclide Therapy with 64Cu-cyclam-RAFT-c(-RGDfK-)4
αVβ3 Integrin-Targeted Radionuclide Therapy with 64Cu-cyclam-RAFT-c(-RGDfK-)4
复制标题
DOI：
10.1158/1535-7163.mct-16-0040
复制
发表时间：
2016-09-01
影响因子：
5.7
通讯作者：
Saga, Tsuneo
中科院分区：
文献类型：
--
作者：
Jin, Zhao-Hui;Furukawa, Takako;Saga, Tsuneo
跨膜细胞粘附受体α（V）β（3）整联蛋白（alpha（V）beta（3））已被鉴定为癌症成像和治疗的重要分子靶标。我们已经开发了基于四聚环RGD（Arg-Gly-Asp）肽的放射性示踪剂Cu-64-cyclam-RAFT-c（-RGDfK-）（4），其通过PET成功捕获aVb 3阳性肿瘤和血管生成。在这里，我们随后使用已建立的α（V）β（3）阳性肿瘤小鼠模型评估其治疗潜力和副作用。皮下移植U87 MG胶质母细胞瘤的小鼠接受37和74 MBq的Cu-64-cyclam-RAFT-c（-RGDfK-）（4）（37 MBq/nmol）、肽对照或溶剂溶液单次给药，并进行肿瘤生长评估。根据体重、常规血液学和肝肾功能评估荷瘤和无瘤小鼠的副作用。分别在注射后3小时和不同时间点（2分钟-24小时）测定肽剂量递增（0.25-10 nmol）和治疗剂量为2 nmol的Cu-64-cyclam-RAFT-c（-RGDfK-）（4）的生物分布，并据此估计辐射吸收剂量。结果显示，Cu-64-cyclam-RAFT-c（-RGDfK-）（4）剂量依赖性地减缓肿瘤生长。平均肿瘤剂量分别为1.28和1.81戈伊，来自37和74 MBq的Cu-64-cyclam-RAFT-c（-RGDfK-）（4）。肽剂量研究显示，64 Cu-cyclam-RAFT-c（-RGDfK-）（4）的肿瘤摄取在剂量>= 1 nmol时剂量依赖性地降低，表明α（V）β（3）在施用的治疗剂量（1和2 nmol）下饱和。对荷瘤和无瘤小鼠数据的综合分析显示，37-74 MBq Cu-64-cyclam-RAFT-c（-RGDfK-）未引起显著毒性（4）。我们的研究证明了Cu-64-cyclam-RAFT-c（-RGDfK-）4用于α（V）β（3）靶向放射性核素治疗的疗效和安全性。（64）Cucyclam-RAFT-c（-RGDfK-）（4）将是用于癌症成像和治疗的有前景的治疗诊断药物。(C)2016年AACR。
The transmembrane cell adhesion receptor alpha(V)beta(3) integrin (alpha(V)beta(3)) has been identified as an important molecular target for cancer imaging and therapy. We have developed a tetra-meric cyclic RGD (Arg-Gly-Asp) peptide-based radiotracer Cu-64-cyclam-RAFT-c(-RGDfK-)(4), which successfully captured aVb3-positive tumors and angiogenesis by PET. Here, we subsequently evaluated its therapeutic potential and side effects using an established alpha(V)beta(3)-positive tumor mouse model. Mice with subcutaneous U87MG glioblastoma xenografts received single administrations of 37 and 74 MBq of Cu-64-cyclam-RAFT-c(-RGDfK-)(4) (37 MBq/nmol), peptide control, or vehicle solution and underwent tumor growth evaluation. Side effects were assessed in tumor-bearing and tumor-free mice in terms of body weight, routine hematology, and hepatorenal functions. Biodistribution of Cu-64-cyclam-RAFT-c(-RGDfK-)(4) with ascending peptide doses (0.25-10 nmol) and with the therapeutic dose of 2 nmol were determined at 3 hours and at various time points (2 minutes-24 hours) postinjection, respectively, based on which radiation-absorbed doses were estimated. The results revealed that Cu-64-cyclam-RAFT-c(-RGDfK-)(4) dose dependently slowed down the tumor growth. The mean tumor doses were 1.28 and 1.81 Gy from 37 and 74 MBq of Cu-64-cyclam-RAFT-c (-RGDfK-)(4), respectively. Peptide dose study showed that the tumor uptake of 64Cu-cyclam-RAFT-c(-RGDfK-)(4) dose dependently decreased at doses >= 1 nmol, indicating a saturation of alpha(V)beta(3) with the administered therapeutic doses (1 and 2 nmol). Combined analysis of the data from tumor-bearing and tumor-free mice revealed no significant toxicity caused by 37-74 MBq of Cu-64-cyclam-RAFT-c(-RGDfK-)(4). Our study demonstrates the therapeutic efficacy and safety of Cu-64-cyclam-RAFT-c (-RGDfK-)4 for alpha(V)beta(3)-targeted radionuclide therapy. (64)Cucyclam-RAFT-c(-RGDfK-)(4) would be a promising theranostic drug for cancer imaging and therapy. (C) 2016 AACR.