PSCA适配子-tBID-Fe3O4双功能MR分子探针对前列腺癌及其骨转移靶向诊疗作用的研究

Prostate cancer (PCa) is one of the most common genitourinary system tumor which threaten the health of Chinese men. At present, there is still no specific method in early, accurate diagnosis and targeted therapy in Pca and osseous metastasis. Establishment of early specific diagnosis and targeted treatment strategy simultaneously and integratedly is an important scientific problem in the field of PCa diagnosis and treatment. In the former study (financially supported by youth project), we have successfully constucted a PSCA specific MR molecular probe which can diagnose PCa targetedly in vivo. As a continual research, we aim to construct a difunctional MR molecular probe with small molecular weight, rapid penetration, low immunogenicity, stability, high specificity, and high affinity named PSCA Aptamer-tBID-Fe3O4, which can diagnose and treat PCa targetedly and simultaneously. After that, PCa and osseous metastasic gene in situ expression should be non-invasively, real-time and repeatedly imaged using the MR molecular probe. At the same time, it will be compared with X-ray, CT and fMRI PET-like. Furthermore, molecular and functional MRI will be used in evaluating therapeutic effect in PCa osseous metastasis. Thus, the study may establish a new technique foundation of non-invasive, early specific, precise diagnosis and targeted treatment, real-time monitor therapeutic effect and in vivo drug screening strategy simultaneously and integratedly in PCa and osseous metastasis by molecular and functional MRI.

前列腺癌(Prostate Cancer, PCa)严重威胁我国男性健康。目前对PCa及其骨转移的准确诊断和治疗均无特异手段，因此特异性诊断与靶向性治疗同步一体化策略的建立是PCa诊治领域重要的科学问题。本课题拟在前期青年项目已率先构建PSCA特异性PCa诊断探针并成功用于体内外MR成像实验的研究基础上，采用针对PSCA的适配子、课题组制备的具有自主知识产权的Fe3O4纳米颗粒和tBID蛋白，研制分子量小、穿透力强、稳定性好、低免疫源性、高特异性、高亲和力的PCa诊治双功能分子探针PSCA适配子-tBID-Fe3O4，并对在体PCa及其骨转移基因原位表达进行实时、可重复MR分子成像，同时与X线、CT和类PET成像对比，评价探针特异性诊断和靶向性治疗效果，为医学影像学在分子基因与功能水平对PCa及其骨转移无创、特异、准确诊断、靶向治疗和实时疗效监测同步一体化奠定全新的技术方法基础。

前列腺癌严重威胁我国男性健康，早期特异性诊断与靶向性治疗同步一体化策略的建立是前列腺癌诊治领域重要的科学问题。本课题拟制备能与前列腺癌特异性结合的核酸适配子；经化学修饰，构建具有强生物屏障穿透性、生物稳定性和特异性的双功能分子探针；该探针具有理想的生物分布特性和药物代谢动力学特性，可在磁共振成像，特异性诊断前列腺癌癌；同时促进肿瘤细胞凋亡，抑制其生长，对前列腺癌进行治疗。4年来主要完成以下研究：1. 构建、表达和纯化治疗组件促凋亡蛋白tBID，用于实现分子探针的治疗功能；2. 制备高质量生物相容性纳米颗粒nanoflower，为分子探针提供信号组件和载体；3. 筛选出与前列腺癌高表达的膜蛋白EpCAM特异性结合的核酸适配子 Ep1和Ep2，为分子探针提供亲和组件；4. 构建并检测前列腺癌特异性双功能分子探针Ep1-nanoflower-tBID，对前列腺癌细胞有特异性结合与靶向性杀伤功能；5. 探针能够特异性降低前列腺癌T2WI信号，有望特异性诊断前列腺癌，但是对前列腺癌在体治疗效果不够理想。本课题成功构建前列腺癌特异性双功能分子探针Ep1-nanoflower-tBID，为前列腺癌诊疗一体化提供新思路。