Lopez-Rodriguez V, Gaspar-Carcamo R E, Pedraza-Lopez M, Rojas-Calderon E L, Arteaga de Murphy C, Ferro-Flores G, Avila-Rodriguez M A
Unidad PET, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., Mexico.
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D.F., Mexico.
Nucl Med Biol. 2015 Feb;42(2):109-14. doi: 10.1016/j.nucmedbio.2014.09.010. Epub 2014 Oct 5.
Integrin αvβ3 plays an important role in angiogenesis and is over-expressed in tumoral endothelial cells and some other tumor cells. RGD (Arg-Gly-Asn) peptides labeled with (68)Ga (t1/2=68min) have showed good characteristics for imaging of αvβ3 expression using positron emission tomography (PET). Gallium-66 has been proposed as a PET imaging alternative to (68)Ga and given the unique high energy of its emitted positrons (Emax 4.15MeV) it may also be useful for therapy. The aim of this research is to prepare [(66)Ga]DOTA-E-[c(RGDfK)]2 and evaluate in mice its potential as a new theranostic radiopharmaceutical.
High specific activity (66)Ga was produced via the (66)Zn(p,n) reaction, and the labelling method of DOTA-E-[c(RGDfK)]2 with (66)Ga was optimized. Radiochemical purity was determined by TLC, and in vitro stability and protein binding were determined. Serial microPET imaging and biodistribution studies were carried out in nude mice bearing C6 xenografts. Radiation absorbed dose estimates were based on the biodistribution studies, where tumor and organs of interest were collected at 0.5, 1, 3, 5 and 24h post-injection of [(66)Ga]DOTA-E-[c(RGDfK)]2.
Our results have shown that [(66)Ga]DOTA-E-[c(RGDfK)]2 can be prepared with high radiochemical purity (>97%), specific activity (36-67GBq/μmol), in vitro stability, and moderate protein binding. MicroPET imaging up to 24 post-injection showed contrasting tumors reflecting αvβ3-targeted tracer accumulation. Biodistribution studies and dosimetry estimations showed a stable tumor uptake, rapid blood clearance, and favorable tumor-to-tissue ratios.
The peptide conjugated DOTA-E-[c(RGDfK)]2 labeled with (66)Ga may be attractive as a theranostic agent for tumors over-expressing αvβ3 integrins.
整合素αvβ3在血管生成中起重要作用，在肿瘤内皮细胞和其他一些肿瘤细胞中过度表达。用（68）Ga（半衰期=68分钟）标记的RGD（精氨酸-甘氨酸-天冬酰胺）肽在使用正电子发射断层扫描（PET）对αvβ3表达进行成像方面显示出良好的特性。镓-66已被提议作为（68）Ga的PET成像替代物，鉴于其发射正电子的独特高能量（最大能量4.15MeV），它也可能用于治疗。本研究的目的是制备[(66)Ga]DOTA-E-[c(RGDfK)]2，并在小鼠中评估其作为一种新型治疗诊断放射性药物的潜力。
通过（66）Zn（p，n）反应产生高比活度的（66）Ga，并优化了DOTA-E-[c(RGDfK)]2与（66）Ga的标记方法。通过薄层层析法测定放射化学纯度，并测定体外稳定性和蛋白质结合率。对携带C6异种移植瘤的裸鼠进行了连续的微型PET成像和生物分布研究。辐射吸收剂量估计基于生物分布研究，在注射[(66)Ga]DOTA-E-[c(RGDfK)]2后0.5、1、3、5和24小时收集肿瘤和感兴趣的器官。
我们的结果表明，[(66)Ga]DOTA-E-[c(RGDfK)]2可以以高放射化学纯度（>97%）、比活度（36-67GBq/μmol）、体外稳定性和适度的蛋白质结合率制备。注射后长达24小时的微型PET成像显示出对比鲜明的肿瘤，反映了αvβ3靶向示踪剂的积累。生物分布研究和剂量学估计显示肿瘤摄取稳定、血液清除迅速且肿瘤与组织的比值良好。
用（66）Ga标记的肽偶联物DOTA-E-[c(RGDfK)]2作为一种针对过度表达αvβ3整合素的肿瘤的治疗诊断剂可能具有吸引力。
