68Ga-NOTA-Duramycin 新型凋亡显像剂的合成及用于早期评价肿瘤疗效的实验研究

Early monitoring tumour response to treatment is of great importance in oncology, are still largely assessed from imaging measurements of reductions in tumour size. However, this can take several weeks to become manifest and in some cases may not occur at all, despite a positive response to treatment .This technique also has many limits in the evaluation of response to molecular therapy .It is high time to establish new approach for the early evaluation of response to treatment..Increased tumour apoptosis early during the course of treatment in preclinical and clinical studies, has been shown to be a good prognostic indicator of outcome.Substantial evidences reveal that apoptosis is not only the biomarker of tumor response but also the molecular target of therapy..In onset of apoptosis, PE is exposed onto the cell surface as the redistribution of phospholipids across the bilayer is facilitated，it can be served as early hallmarker of apoptosis.Duramycin is a 19 amino peptide with stable and rigid three dimentional structure,which binds the headgroup of PE with high affinity, it is defferent from present apoptosis ligands which are usually large molecular protein including annexin V and synaptotagmin C2A domain.Due to low molecualr wight,unique physico-chemicalstructure,it might be a better apoptosis ligand..The aim of this study is to syntehsize 68Ga-NOTA-duramycin as a novel molecular probe for the detection of apoptosis and monitor response to different treatment including radiochemotherapy and antiangenesis in VX2 and nude mice tumor models.18F-FDG and 99mTc-3P-RGD2 imaging were also performed to reflect tumor glucose metabolism and angiogenesis .Our preliminary study demonstrated it had rapid blood clearence and better biodistribution.Furthermore,PE is more abundant in the mammalian celluar membrane than PS,giving stronger signals,these merits may hold promise for the early evaluation of tumor therapy outcome..In summary,this study will pave the way for the utilization of apoptosis imaging in early evaluation of response to treatment and translation from bench to bedside， it will further promote the personalized therapy of oncology,further study is warranted.

早期评价疗效是肿瘤临床诊疗急需解决的问题，临床依赖影像学测量肿瘤大小改变来评价疗效，但在早期评价，尤其在分子靶向治疗方面受到更多限制，需寻找早期评价疗效的新技术。.细胞凋亡是肿瘤疗效评价的分子标志，研究表明：凋亡显像可早期评价肿瘤疗效。但现有凋亡配体多是大分子蛋白，较复杂的标记方法及免疫原性限制其临床应用。.本课题设计68Ga-NOTA-Duramycin有如下优势①磷脂酰乙醇胺是凋亡早期标志，且胞膜含量比磷脂酰丝氨酸更丰富②Duramycin（MW =2013Da）独特化学结构使其成为理想的凋亡配体③68Ga标记方法简单，易制成药盒，可发挥PET分辨率高、定量分析的特点④前期研究证实：其靶向性好，生物分布理想，图像质量好。.68Ga-NOTA-duramycin PET分析放化疗及抗新生血管治疗诱导肿瘤发生凋亡的能力，建立早期评价肿瘤疗效的新策略，推动分子影像临床转化及肿瘤个体化治疗。

早期评价疗效已成为肿瘤临床诊疗急需解决的问题，临床依赖影像学检查测量肿瘤大小改变来评价疗效，但常无法实现早期评价，在评价靶向治疗方面受到更多限制，急需寻找早期评价疗效的新技术。.细胞凋亡是肿瘤疗效评价的分子标志，凋亡显像用于早期评价肿瘤疗效已成为研究热点。现有凋亡配体多是大分子蛋白，相对复杂的标记方法及免疫原性限制其应用。外翻的磷脂酰乙醇胺（PE）也是细胞凋亡早期标志，且胞膜含量远高于磷脂酰丝氨酸。Duramycin（MW =2013Da）可与PE高特异性结合，独特化学结构使其成为理想的凋亡分子配体。.课题组经过研究证实：68Ga-NOTA-Duramycin生物分布理想，血液清除快，靶向性好，在肿瘤疗效评价方面更有优势。本课题以68Ga-NOTA-duramycin PET定量分析肿瘤细胞凋亡水平，结合18F-FDG、新生血管成像，为建立早期评价肿瘤疗效新策略奠定基础。

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