靶向治疗诱导肺癌自噬凋亡小分子PET显像研究

The major treatments for lung cancer of intermediate or advanced stage are chemotherapy, radiation therapy and molecule targeted therapy. However, primary or secondary resistance to anti-cancer drugs often occurs, treatment-related changes and the duration of effects vary greatly, and treatment effects are not necessarily consistent with prognosis.Although using PET imaging to qualitatively and quantitatively evaluate tumor cell metabolism is strongly advantageous, 18F-FDG imaging has its limitation of relying on glycolysis of cancer cells. Hence, there is a great need for the development of a new molecular imaging agent as supplement. This study aims to develop a novel small-molecule poly-peptide imaging agent called 18F-FP-Cinnamycin so as to improve the pharmacokinetic profile, based on the established targeting imaging agents of phosphatidylserine and phosphatidylethanolamine (PE) which have been used to assess programmed cell death(PCD).We intend to investigate the in vitro and in vivo biological activity and mechanism of action of this novel imaging agent, to establish PE small-molecule targeting imaging model through experiments such as cell culture, drug-based induction of cell death, animal models of lung cancer and targeted therapy, the induction of PCD in animal model. It is hoped that the results of this study could help solve some problems in PET imaging specific for anti-cancer treatment-related PCD, improve the accuracy and timeliness in evaluation of treatment effects and prognosis. Hopefully, the study could enable us to monitor the sensitivity or resistance to anti-cancer therapy in an early, non-invasive and dynamic way and provide reliable evidence for early clinical intervention.

中晚期肺癌主要采用放化疗及分子靶向治疗，药物治疗常出现原发性或获得性耐药，治疗后肿瘤变化程度及疗效维持时间各异，疗效与预后并不一致。使用PET显像对肿瘤细胞代谢进行定性和定量评估极具优势，常用显像剂18F-FDG依赖于癌细胞糖酵解有局限性，亟需研发新型分子显像剂作为补充手段。本课题在已研制的靶向磷脂酰丝氨酸和磷脂酰乙醇胺(PE)细胞程序性死亡（PCD）小分子显像剂的基础上，为改善药代动力学特性，研发新型小分子多肽类显像剂18F-FP-肉桂霉素。经细胞培养、药物诱导细胞死亡，建立荷肺癌及靶向治疗动物模型，诱导肺癌细胞PCD，研究其体内外生物活性和作用机理，确立靶向PE小分子PET显像新模式，解决药物治疗致癌细胞PCD特异性PET显像监测的某些难题，提高疗效评价及预后判断的准确性和时效性；以期能早期、无创、动态地监测药物治疗的敏感性或耐药性，为临床早期干预提供可靠依据。

项目背景：中晚期肺癌的药物治疗主要是导致癌细胞凋亡，治疗过程中会出现耐药，准确、动态的疗效评估尤为重要，细胞凋亡分子成像极具应用价值。磷脂酰乙醇胺（PE）是细胞死亡时由细胞膜磷脂内侧翻向外侧的靶点，耐久霉素和肉桂霉素能与之特异性结合，且具有分子量小、稳定性好、与靶点结合力强等优点。主要研究内容：用18F标记肉桂霉素和耐久霉素，制备新型显像剂，并对其进行生物学评估，活体成像评价其对肿瘤靶向药物疗效的检测效果，为其临床应用奠定实验基础。重要结果及关键数据： [18F]AlF-NOTA-PEG3-D合成步骤耗时30~45min，放射化学纯度大于98%，放化产率为20.3±6.6%。该显像剂具有较高的体内外稳定性。与对照组相比，经喜树碱处理的凋亡细胞对[18F]AlF-NOTA-PEG3-D的摄取值增高了3倍（p＜0.05）；生物分布实验表明[18F]AlF-NOTA-PEG3-D主要通过泌尿系统排泄，并在肾脏滞留，在肝脏摄取较少。PET/CT显像结果表明：在裸鼠HCC827肿瘤治疗模型中，使用[18F]AlF-NOTA-PEG3-D两次不同时间显像，治疗组裸鼠肿瘤摄取值最后一次显像较前一次升高（p＜0.001），而对照组裸鼠肿瘤摄取值无明显改变（p＞0.05）。而[18F]-FDG PET/CT显像结果表明：在裸鼠肿瘤治疗模型中治疗组肿瘤摄取值最后一次显像较前一次下降（p＜0.001），而对照组肿瘤摄取值无明显改变（p＞0.05）。[18F]AlF-NOTA-PEG3-CM合成步骤耗时35~45min，放射化学纯度大于95%，放化产率为27.5±4.1%。该显像剂具有较高的体内外稳定性。与对照组相比，经喜树碱处理的凋亡细胞对[18F]AlF-NOTA-PEG3-CM的摄取值增高了316倍（p＜0.05）；生物分布实验表明，[18F]AlF-NOTA-PEG3 -CM主要通过泌尿系统排泄，在肝脏摄取较多。PET/CT显像结果表明：在裸鼠PC9肿瘤治疗模型中，使用[18F]AlF-NOTA-PEG3-CM显像，治疗组裸鼠肿瘤摄取值最后一次显像较前一次升高（p＜0.001），而对照组肿瘤摄取值无明显改变（p＞0.05）。科学意义：成功制备靶向结合PE的显像剂，并探索药代动力学特性，检测肺癌靶向治疗的疗效，为临床转化提供实验资料。

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