磁共振筛查联合共聚焦激光显微内镜引导光动力精准治疗胰腺原位癌实验研究

Monitoring of pancreatic ductal adenocarcinoma (PDAC) in high-risk population to achieve ultra-early diagnosis and accurate treatment of pancreatic carcinoma in situ is effective to improve the prognosis of PDAC. Concerning above issues, we designed an integrative programme for screening, diagnosis and therapy of pancreatic carcinoma in situ in this proposal on the basis of the previous series of studies. We first established a chemical-induced rat model for pancreatic carcinogenesis and confirmed that the abnormal high-expression of integrin α6β4 and cathepsin E in both PDAC and precancerous lesions, gradually increased in the process of pancreatic carcinogenesis. Then, we developed the smart contrast agent and theranostic drug which have synergistic effect of “integrin α6β4 active targeting” and “cathepsin E induced magnetic resononce signal and fluorescence enhancement along with drug release”.We use the smart contrast agent for ultra-early detection of pancreatic carcinoma in situ by magnetic resonance imaging consecutively and dynamically, followed by the photodynamic therapy guided by confocal laser endomicroscopy with the smart theranostic drug. This integrative programme for magnetic resonance imaging screening combined with photodynamic therapy guided by confocal laser endomicroscopy for pancreatic carcinoma in situ holds promise to explore a new strategy for the clinical prevention and treatment of PDAC and provides scientific basis for monitoring the high risk population of PDAC and developing systems for ultra-early theranostics of pancreatic carcinoma in situ.

监测胰腺癌高危人群，实现对胰腺原位癌的超早期诊断及精准治疗，将有效改善胰腺癌的预后。基于上述问题，本项目在前期系列研究的基础上，进一步设计了胰腺原位癌筛查并诊疗一体化方案：首先建立化学诱导大鼠胰腺癌发生过程模型，并证实胰腺癌及其癌前病变内整合素α6β4及组织蛋白酶E随病程进展逐渐异常高表达；再构建具有“整合素α6β4主动靶向”和“组织蛋白酶E诱导磁共振及荧光信号增强伴光敏前药释放”协同效应的智能化磁共振造影剂和诊疗药物；继之结合智能化磁共振造影剂，通过磁共振连续动态成像监测胰腺癌发生过程，及时发现胰腺原位癌；随即结合智能化诊疗药物，对胰腺原位癌病灶进行共聚焦激光显微内镜引导下的光动力治疗。本项目提出的磁共振监测并共聚焦激光显微内镜引导光动力治疗胰腺原位癌的诊疗策略，将为临床胰腺癌防治开辟一条新的道路，并为胰腺癌高危人群的监测及胰腺原位癌超早期诊疗一体化体系的构建提供科学依据。

胰腺癌恶性程度很高，对胰腺癌高危人群进行监测，实现胰腺原位癌的超早期诊断，并及时干预，必将有利于改善胰腺癌的预后。本课题构建了胰腺原位癌超早期诊疗一体化方案：胰腺癌发生过程中磁共振随访监测，发现胰腺原位癌后，由共聚焦激光显微内镜明确诊断，并在其引导下光动力精准治疗。主要研究内容：1、磁共振造影剂和诊疗药物的研制、表征及体外细胞实验，2、DMBA诱导大鼠胰腺癌发生过程中磁共振/共聚焦激光显微内镜成像，3、共聚焦激光显微内镜引导下光动力治疗，4、肿瘤微环境pH诱导、尺寸转化、深度递送诊疗药物的研制。本项研究的开展为临床胰腺癌高危人群的筛查及胰腺原位癌的超早期诊疗一体化体系的构建提供了科学依据，为胰腺癌防治开辟了一条新的道路。