藤黄素GA与核素188Re标记IL-11受体介导的靶向分子探针的构建与抗癌机理研究

Problems of target specificity and stability in vivo are still exist on research of drug delivery systems now, the key solution of these is to find a non-invasive, specific, and targeting the appropriate carrier and target of tumor cells. Our recent study found that interleukin-11 analogues ring nonapeptide has targeted specific binding to interleukin-11 receptor (IL-11R), which was highly expressed in prostate cancer and bone metastases. However, it has no binding effect in normal tissues such as liver and lung. In this study, we would first synthesis ring nonapepti and the targeted probe of ring nonapeptide which was labeled by Chinese anti-cancer medicine Garcinia acid (GA) and 188Re, and then determine the best labeling conditions and investigate the stability, affinity and biological activity; secondly, we would perform the intervention study in vitro and in vivo using the labeled probe in breast cancer, endometrial adenocarcinoma and ovarian malignancy cancer and bone metastasis, which have high expression levels of IL-11R, then explore the anti-cancer effects and possible radiation sensitizer, synergy and attenuation mediated by IL-11R using molecular imaging technology, pathology and molecular biology from the molecular, cellular, tissue and animal levels, and meanwhile investigate the mechanism. This study will provide a scientific basis for the molecular targeted therapy of malignancy and bone metastases.

目前研究药物递送系统仍然存在靶向特异性和体内稳定性等问题，解决关键是寻找具有无创、特异、靶向的合适载体和肿瘤细胞作用靶点。先期研究发现白介素11类似物环九肽对前列腺癌及骨转移灶高表达的白介素11受体（IL-11R）具有靶向特异结合性，而对肝肺、胃肠等正常组织脏器无结合。本项目拟自主合成环九肽，构建抗癌中药藤黄酸（GA）、核素188Re标记环九肽分子靶向探针，确定最佳标记条件，进行稳定性、亲和力及生物活性检测；应用标记探针对富含IL-11R的乳腺癌、子宫内膜腺癌和卵巢癌恶性肿瘤及骨转移进行体内外干预，采用分子影像技术、病理学及分子生物学检测手段，从分子、细胞、组织及动物水平探讨IL-11R介导的分子探针产生抗癌效应和可能发生的辐射增敏、增效减毒作用，阐明其分子机制，为恶性肿瘤及骨转移的分子靶向治疗提供科学依据。

目前研究药物递送系统仍然存在靶向特异性和体内稳定性等问题，解决关键是寻找具有无创、特异、靶向的合适载体和肿瘤细胞作用靶点。先期研究所发现白介素11类似物环九肽对前列腺癌及骨转移灶高表达的白介素11受体（IL-11R）具有靶向特异结合性，而对肝肺、胃肠等正常组织脏器无结合。本研究则通过环九肽介导靶向肿瘤，耦联化疗药物藤黄素及放射性核素，提高肿瘤杀伤作用的同时降低对机体的毒副作用。研究中对环九肽进行了核素131I、18F、99Tc及188Re的标记，其中131I标记的环九肽血浆稳定性不高，而18F、99Tc和188Re标记则均具有一定的稳定性，分别适用于显像及治疗。而环九肽与藤黄素的成功耦联也提升了藤黄素的安全性。通过在乳腺癌及卵巢癌细胞系及荷瘤鼠模型上比较对照组与化疗组、放疗组、靶向化疗组、放化疗联用组及靶向联用组，单独化疗组具有显著肝脏毒性，小鼠出现不同程度的肝硬化，而靶向组则显著改善；通过比较瘤块大小，靶向联用组的治疗效果显著优于其余组。本研究研发了一种兼显像与治疗，集高效与安全于一体的复合药物，通过明确药物的动力学及毒理学等，有利于为将来临床提供肿瘤杀伤的利器，具有广阔应用前景。