Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance P
Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance P
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DOI：
10.1158/1078-0432.ccr-05-2820
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发表时间：
2006-06-15
影响因子：
11.5
通讯作者：
Merlo, Adrian
中科院分区：
文献类型：
--
作者：
Kneifel, Stefan;Cordier, Dominik;Merlo, Adrian
目的：恶性胶质脑肿瘤持续过度表达神经激肽1型受体。在经典的基于粒子的近距离放射治疗中，插入一个到几个刚性I-125粒子，主要用于治疗小的低级别胶质瘤。快速增殖的高级别胶质瘤的复杂几何形状需要靶向肿瘤相关表面结构的扩散系统以使肿瘤（包括其边缘）饱和。我们通过将螯合剂1，4，7，10-四氮杂环十二烷-1-谷氨酸-4，7，10-三乙酸与P物质的Arg（1）偶联，产生分子量为1，806 Da和IC 50为0.88 +/- 0.34 nmol/L的放射性药物。用胶质母细胞瘤细胞系进行细胞生物学研究。本文对58例肿瘤活检标本进行了神经激肽1型受体（NK 1 R）放射自显影，以Y-90标记为主。为了减少关键部位肿瘤中的“交叉火力效应”，使用（177）Lut和Bi-213代替。在一项初步研究中，我们评估了i.t.用放射性标记的1，4，7，10-四氮杂环十二烷-1-谷氨酸-4，7，10-三乙酸P物质注射14例胶质母细胞瘤和6例WHO 2 ~ 3级胶质瘤患者。发现肽载体的内化是特异性的。在临床上，放射性药物根据肿瘤几何形状分布。仅在1例患者中观察到一过性毒性为症状性放射性水肿（观察期，7-66个月）。在20例患者中的13例中观察到疾病稳定和/或神经功能状态改善。二次切除术广泛的放射性坏死，改善demarcation.Conclusions：有针对性的放射治疗使用扩散肽载体的恶性胶质瘤，这将进一步评估作为一种新辅助治疗方法的局部控制的创新策略。
Purpose: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid I-125 seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins.Experimental Design: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid- 4,7,1 0-triacetic acid to Arg(1) of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC50 of 0.88 +/- 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies, For labeling, Y-90 was mostly used. To reduce the "cross-fire effect" in critically located tumors, (177)Lut and Bi-213 were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3.Results: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation.Conclusions: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.