新型双靶点近红外二区荧光多肽探针的构建及其在前列腺癌显像研究

Prostate Cancer (PCa) boasts the features of heterogeneity，however, the limited diagnostic information provided by current mono-targeted probes can result in the poor diagnostic accuracy. Therefore, it is significant to develop high-performance and dual-targeted imaging probes to enhance the accuracy in tumor diagnosis and improve the prognosis of the patients. Based on our previous research, the molecular platform strained cyclooctyne (BCN) conjugated with a series of second near-infrared window (NIR-II) fluorophores (CH1055, Q4, S4), then thiol modified AE105 and JMV594 were assembled into the BCN via base-catalyzed thiol-cyclooctyne chemistry, and we aim to design and synthesize a series of novel dual-targeted NIR-II peptide based probes which are able to specifically interact with both uPAR and GRPR on PCa. By using chemical biology and molecular imaging techniques, the targeted specificity and imaging properties of these probes are investigated in vitro and vivo, aiming to achieve probes with excellent imaging characteristics such as high specificity, high tumor uptake and high contrast in small-animal models. High-performance and dual-targeted probes can accurately describe the complex microenvironment of tumor, increase the total number of tumor binding sites, improve the signal to noise ratio, thus providing a new method for PCa precise diagnosis and tumor staging.

前列腺癌呈现明显异质性特征，目前单靶点探针由于自身的局限性，使得诊断精准度受限。因此，开发高性能双靶点分子探针对于实现前列腺癌病灶组织的精确诊断和改善患者的生存质量具有重要的研究意义。本项目将不同发射波长的近红外二区荧光分子连接到环辛炔分子平台后，借助碱催化的巯基-环辛炔化学反应，将巯基修饰的靶向多肽AE105和JMV594可控导入到该分子平台，从而构建一系列能够同时靶向尿激酶型纤溶酶原激活剂受体(uPAR)和胃泌素释放肽受体(GRPR)的双靶点近红外二区荧光多肽探针。随后利用化学生物学和分子影像技术，致力于从体外，组织和活体水平研究其靶向特异性和显像效果，期望开发活体上具有高特异性、高肿瘤摄取及高信噪比显像效果的双靶点多肽探针。本项目设计的高性能双靶点荧光多肽探针更能准确地反映复杂的肿瘤微环境，能够增加肿瘤结合位点总数、提高信噪比，为前列腺癌的精确诊断和肿瘤分型提供新的研究手段和方法。

癌症会呈现明显的异质性，现有的单功能型荧光探针由于自身的局限性，使得诊断精准度受限。因此，开发多功能型荧光探针对于实现癌症的精准诊断和改善患者的生存质量具有重要的研究意义。本项目以设计筛选高生物组织穿透能力和高灵敏度的近红外二区（发射波长>1000 nm）荧光分子为核心，交叉集成化学生物学、纳米医学及分子影像的前沿技术，构建了一系列多功能型近红外二区荧光探针，实现了癌症诊治的多个突破，包括采取自主研发的巯基-炔基化学工具高效可控的构建了首例可以靶向前列腺癌及脑胶质瘤的双靶点和双模态近红外二区荧光多肽探针，并利用其局部成像的高信噪比（～4.77），成功应用于小鼠体内移植肿瘤的荧光成像引导手术切除；此外，我们也率先研制了兼顾近红外二区荧光/光声多模态成像及化疗和热疗的诊疗探针，实现了通过荧光成像对前列腺癌、乳腺癌、肝癌和脑胶质瘤等重大疾病的疗效评估。这些研究进一步拓展了近红外二区荧光活体成像探针和相应诊疗探针的研发，从而为重大疾病的活体分析研究提供新方法。