基于多肽的诊断治疗一体化纳米材料的制备及其生物医学研究

Cancer has become a leading factor for threatening to human lives, thus, it is necessary to find an effective therapeutic method to diagnose and therapy cancer. Current cancer therapies are largely limited by biological barriers, non-specific drug delivery, drug resistence of cancer, and lack of an effective method for treatment monitoring. In order to overcome these carriers, series of theranostics materials that combines the modalities of diagnostic imaging and therapy will be synthesized. Two classes of theranostic materials will be prepared based on cell penetrating peptide R8, histidine-rich peptide, MMP-2 activable peptide PLGLAG, and DOX. BHQ2 and AuNP will be respectively used as fluorescence quenching probe to quench the fluorescence of DOX. After these theranostic materials arriving at tumor site, the PLGLAG peptide can be hydrolyzed by the overexpressed MMP-2 protease, leading to the pronounced fluorescence of DOX recovered from quenching to exciting state. And then R8 and Hn can continue carrier DNA to cell and express gene. Hence, the theranostic system is able to induce the cancer imaging and drug/gene synergistic therapy simultaneously.

癌症已经成为当今威胁人类生命的一个主要因素，因此，需要一种能有效地诊断和治疗癌症的医疗方法。目前由于生物体内的屏障、药物的非特异性传递、抗药耐药性以及缺乏有效的治疗监测手段等问题，癌症治疗受到了很大的限制。为了克服以上问题，拟设计和制备基于多肽的成像诊断及药物和基因协同治疗的诊断治疗一体化体系。以具有穿膜功能的八聚精氨酸(R8)和内涵体逃逸功能的组氨酸序列（Hn）作为基因载体，以基质金属蛋白酶敏感肽PLGLAG为靶向基团，以抗癌药物阿霉素作为荧光成像基团，分别以BHQ2和金纳米粒子作为阿霉素荧光淬灭剂，构建BHQ2-GPLGLAGR8HnG-DOX和AcCHnR8PLGLAG-DOX/AuNP两类诊疗体系。选取体外性能良好的诊疗材料，将表面过度表达基质金属蛋白酶的肿瘤细胞接种到裸鼠体内培养肿瘤模型，以p53抑癌基因作为治疗基因，重点研究诊疗材料的体内成像及药物和基因协同治疗癌症的效果。

完成了多个功能材料的设计、合成和材料的表征，包括细胞靶向肽、核定位信号肽、内涵体缓冲肽等多肽序列。研究了这些功能材料的自组装行为和生物相容性等性能。这些功能性材料主要作为药物/基因传递、肿瘤成像和治疗、肿瘤多模态联合治疗的传递系统，用于肿瘤、白内障等各种疾病的治疗及预防。多肽功能材料作为基因载体，研究了多肽载体的细胞靶向能力、双重外部刺激响应下的DNA释放情况，以及在小鼠体内的基因表达效果。多肽功能材料作为多模式联合治疗系统，小鼠体内实验动物实验评价了其抗肿瘤活性，测定了肿瘤体积和重量，荷瘤动物存活率和生存时间等。结果表明这些联合治疗体系具有良好肿瘤抑制的效果，有潜在的临床应用前景。