177Lu-labeled monomeric, dimeric and multimeric RGD peptides for the therapy of tumors expressing a(?)ß(3) integrins
177Lu-labeled monomeric, dimeric and multimeric RGD peptides for the therapy of tumors expressing a(?)ß(3) integrins
复制标题
DOI：
10.1002/jlcr.2910
复制
发表时间：
2012-04-01
影响因子：
1.8
通讯作者：
Isaac-Olive, Keila
中科院分区：
文献类型：
--
作者：
Luna-Gutierrez, Myrna;Ferro-Flores, Guillermina;Isaac-Olive, Keila
肽与金纳米颗粒（AuNPs）的缀合产生具有靶特异性分子识别的生物相容性和稳定的多聚体系统。已报道基于环Arg-Gly-Asp（RGD）序列的肽作为α β 3整联蛋白的高亲和力试剂。本研究的目的是制备177 Lu标记的金纳米颗粒与c（RGDfK）C（cyclo（Arg-Gly-Asp-Phe-Lys）Cys）缀合的多聚体系统，并比较177 Lu标记的单体和二聚体RGD肽对小鼠a β 3整合素阳性U87 MG肿瘤的辐射吸收剂量。合成DOTA-GGC（1，4，7，10-四氮杂环十二烷-N-N '，N，N-四乙酸-Gly-Gly-Cys）和c（RGDfK）C肽，并通过巯基的自发反应将其缀合至AuNP。透射电子显微镜、紫外可见光谱、X射线光电子能谱、拉曼光谱和远红外光谱等技术表明，金纳米粒子被肽功能化。为了获得177 Lu-AuNP-c（RGDfK）C，首先制备177 Lu-DOTA-GGC放射性肽并加入AuNP溶液中，然后加入c（RGDfK）C（25 μ l，5 μ m），在18 ℃下保持15分钟。通过将177 LuCl 3（370 MBq）加入到用50 μ l pH 5的1 M乙酸盐缓冲液稀释的5 μ l（1 mg/ml）DOTA衍生物中制备177 Lu-DOTA-GGC、177 Lu-DOTA-cRGDfK和177 Lu-DOTA-E-c（RGDfK）2。将混合物在90 ° C下在块状加热器中孵育30分钟。通过超滤和HPLC分析测定放射化学纯度。在具有U87 MG诱导的肿瘤的无胸腺小鼠中完成生物动力学研究。所有177 Lu-RGD衍生物的放射化学纯度为96 +/-2%。递送至U87 MG肿瘤的每注射活性的177 Lu吸收剂量为0.357 +/- 0.052Gy/MBq（多聚体）、0.252 +/- 0.027Gy/MBq（二聚体）和0.102 +/- 0.018Gy/MBq（单体）。177 Lu标记的二聚体和多聚体RGD肽表现出适合表达α β 3整联蛋白的肿瘤的靶向放射性核素治疗的特性。版权所有（c）2012约翰威利父子有限公司
The conjugation of peptides to gold nanoparticles (AuNPs) produces biocompatible and stable multimeric systems with target-specific molecular recognition. Peptides based on the cyclic Arg-Gly-Asp (RGD) sequence have been reported as high-affinity agents for the a()beta(3) integrin. The aim of this research was to prepare a multimeric system of 177Lu-labeled gold nanoparticles conjugated to c(RGDfK)C (cyclo(Arg-Gly-Asp-Phe-Lys)Cys) and to compare the radiation-absorbed dose with that of 177Lu-labeled monomeric and dimeric RGD peptides to a()beta(3) integrin-positive U87MG tumors in mice. DOTA-GGC (1,4,7,10-tetraazacyclododecane-N-N',N,N-tetraacetic acid-Gly-Gly-Cys) and c(RGDfK)C peptides were synthesized and conjugated to AuNPs by a spontaneous reaction of the thiol groups. Transmission electron microscopy, ultravioletvisible, X-ray photoelectron spectroscopy, Raman and far-infrared spectroscopy techniques demonstrated that AuNPs were functionalized with the peptides. For the 177Lu-AuNP-c(RGDfK)C to be obtained, the 177Lu-DOTA-GGC radiopeptide was first prepared and added to a solution of AuNPs followed by c(RGDfK)C (25 mu l, 5 mu m) at 18 degrees C for 15min. 177Lu-DOTA-GGC, 177Lu-DOTA-cRGDfK and 177Lu-DOTA-E-c(RGDfK)2 were prepared by adding 177LuCl3 (370MBq) to 5 mu l (1mg/ml) of the DOTA derivative diluted with 50 mu l of 1 m acetate buffer pH 5. The mixture was incubated at 90 degrees C in a block heater for 30min. Radiochemical purity was determined by ultrafiltration and HPLC analyses. Biokinetic studies were accomplished in athymic mice with U87MG-induced tumors. The radiochemical purity for all 177Lu-RGD derivatives was 96 +/- 2%. 177Lu-absorbed doses per injected activity delivered to U87MG tumors were 0.357 +/- 0.052Gy/MBq (multimer), 0.252 +/- 0.027Gy/MBq (dimer) and 0.102 +/- 0.018Gy/MBq (monomer). 177Lu-labeled dimeric and multimeric RGD peptides demonstrated properties suitable for targeted radionuclide therapy of tumors expressing a()beta(3) integrins. Copyright (c) 2012 John Wiley & Sons, Ltd.