基于CXCR4与pHLIP双重靶向的核素诊疗一体化探针在脑胶质瘤中的研究

Glioma is a common of the central nervous system, prognosis of primary malignant tumor. It is difficult to completely removed by surgery, and poor treatment effect caused by the high recurrence rate and low survival rate is a difficult problem to be solved. Glioma cells have high expression of CXCR4 receptor, at the same time around the existence of acidic microenvironment. This study will fuse NFB-T140 (CXCR4 specificity ligand) and Var3 (insert peptide pHLIP low pH) as NTV3 peptide, a developed new type of dual targeting polypeptide, fusion of two kinds of targeted mechanism advantages, on the one hand, strengthen the targeting effect of glioma cells; On the other hand, make up the defects of lack of CXCR4 internalization, to achieve higher tumor/background ratio. We propose NTV3 labeled by gallium 68 for tumor PET/CT research, NTV3 labeled by lutecium 177 as the treatment nuclide, carries on the research of tumor destruction, achieve finally illuminate inside the glioma targeting nuclide diagnosis and treatment, and expect to get enhanced synergy effect, achieve targeted for molecular imaging in the diagnosis of glioma, enhanced curative effect, improved safety, and can be targeted monitoring purposes.

脑胶质瘤是中枢神经系统一种常见的、预后差的原发性恶性肿瘤。该肿瘤手术难以完全切除且综合治疗效果差，复发率高、生存率低，因此，特异诊断和精准治疗是亟待解决的难题，分子靶向诊疗是解决这一难题的重要手段。本研究利用胶质瘤细胞高表达CXCR4受体、同时周边存在酸性微环境这两个特性，将NFB-T140（CXCR4特异性配体）与Var3（低pH值插入肽，pHLIP）融合为NTV3多肽，研制新型双靶向探针，融合两种靶向机制优势，一方面加强对胶质瘤细胞的靶向作用；另一方面弥补CXCR4内化不足的缺陷，达到更高的瘤/本比。本研究拟采用68Ga标记双靶向探针NTV3，进行动物模型及临床病例正电子显像研究，评价其靶向性；采用177Lu作为治疗核素标记NTV3，在体外及动物模型进行肿瘤杀伤研究，评价其治疗效果。最终达到对胶质瘤的核素靶向内照射诊疗，并预期得到协同的增强效果，提高靶向性、改进安全性及可监控性的目的。

脑胶质瘤是中枢神经系统一种常见的、预后差的原发性恶性肿瘤。该肿瘤手术难以完全切 除且综合治疗效果差，复发率高、生存率低，因此，特异诊断和精准治疗是亟待解决的难题，分子靶向诊疗是解决这一难题的重要手段。本研究利用胶质瘤细胞高表达CXCR4受体、同时周边存在酸性微环境这两个特性，将NFB-T140（CXCR4特异性配体）与Var3（低pH值插入肽，pHL IP）融合为NTV3多肽，研制了新型双靶向探针，融合两种靶向机制优势，一方面加强对胶质瘤细 胞的靶向作用；另一方面弥补CXCR4内化不足的缺陷，达到更高的瘤/本比。本研究尝试了多种策略，合成了NFB-T140-Var一体化探针，采用了68Ga 标记双靶向探针NTV，标记率达到90%以上，并进行了动物模型的正电子显像研究，评价了其靶向性，较传统显像剂降低了本底，提高瘤/本比值；该一体化探针能够促进 CXCR4 的内化作用，改善 pHLIP 的特异性，提高胶质瘤精准显像效果，为拓展肿瘤残余灶、复发灶的靶向诊疗奠定了基础。