核素标记新型NGR靶向抗癌肽的肿瘤诊疗研究

Tumor threatens human health seriously, and most conventional cancer treatment display poor targeting and toxic side effects. To synthesize a single pharmaceutical formulation improving tumor targeting and reducing toxicity at the same time has become a hot issue of cancer molecular research. Anti-cancer peptides can selectively bind with tumor cell, lead to tumor cell membrane lysis without receptor mediated and induce cell apoptosis quickly. It also has several advantages such as good water solubility, high plasma stability and avoiding multidrug resistance. Our previous research has synthesized several tumor targeting NGR peptides and performed molecular imaging successfully. Therefore, the project is based on NGR motif as the platform, and flexible groups are used for attaching anticancer peptide for preparation of a novel tumor targeting anti-cancer peptide D-NKL. Then NKL was labeled with radionuclide 68Ga and 90Y respectively for in vitro activity assay and medical molecular imaging research. The project will integrate tumor targeting NGR and tumor selective anti-cancer peptide to organically increase tumor specificity and local uptake effectively, while synchronously possess biological treatment of targeting anticancer peptide and radiation therapy of radionuclide to efficient killing tumor cells, improve tumor targeting specificity significantly, and reduce side effects of conventional therapy to achieve better therapeutic effect meanwhile. It will provide new direction to design novel multifunctional polypeptide probe and new ideas for the precise integration of tumors treatment.

肿瘤严重威胁着人类健康，但是常规治疗方式大多靶向性差且毒副作用较大，如何使用单一药物制剂在提高靶向性的同时降低毒副作用成为肿瘤分子研究领域亟需解决的热点问题。抗癌肽能选择性结合肿瘤细胞发生非受体介导的膜溶解，快速诱导肿瘤细胞凋亡，具有水溶性好、血浆稳定性高和避免耐药等优点。我们前期合成了多种肿瘤靶向性NGR探针并成功进行了分子成像，在此基础上本项目拟以NGR基序为设计平台，采用柔性基团连接抗癌肽制备新型肿瘤靶向性抗癌肽NKL，分别标记核素68Ga和90Y并进行体外活性检测和分子影像诊疗研究。本项目能有机融合肿瘤靶向性NGR和肿瘤选择性抗癌肽，有效提高靶向特异性和肿瘤局部药物浓度，联合抗癌肽生物治疗和核素内放射治疗发挥协同作用，高效杀伤肿瘤细胞，显著降低传统治疗方法的毒副作用，达到良好的治疗效果。本项目的实施将为设计新型多功能多肽探针提供新方向，为肿瘤的精准性诊疗一体化研究提供新思路。

肿瘤严重威胁着人类健康，但是常规治疗方式大多靶向性差且毒副作用较大，抗癌肽能选择性结合肿瘤细胞发生非受体介导的膜溶解，快速诱导肿瘤细胞凋亡，具有水溶性好、血浆稳定性高和避免耐药等优点。本项目以肿瘤靶向肽NGR为设计平台，成功利用柔性基团连接具有肿瘤选择性的D型水溶性抗癌肽，制备出一系列新型的肿瘤靶向性抗癌肽（如NKL,RKL等）并陆续标记核素68Ga和Cy5.5，经过体外试验和体内试验证实，探针能够成功用于近红外荧光光学成像。68Ga-DOTA-NKL具备良好的理化特性，在体内外对CD13阳性的肿瘤细胞及组织具有良好的靶向作用，有望成为PET/CT显像探针。NKL和RKL探针的近红外荧光光学成像靶本比值高、特异性高，可在皮下肿瘤模型和原位肿瘤模型进行高对比度特异性显像，特别是进行模拟脑胶质瘤根治术的术中导航时，显像效果好，能够清晰显示脑胶质瘤与周围正常脑组织的边界。综上所述，本项目有效拓展了新型抗癌肽的普适性和特异性，对肿瘤进行成像、分期，用于肿瘤根治术中对肿瘤进行定位，辅助切除肿瘤。为肿瘤靶向探针研究提供新的方法，利用靶向多肽和抗癌肽各自的优势开发能进行放射性核素或光学标记的前体探针具有良好的肿瘤诊疗应用前景，为肿瘤诊疗一体化研究和个体化诊疗提供新的方向。