自修复近红外荧光与pH超敏感聚多肽纳米粒的合成及在药物可视化导向控释中的应用

It is very important to treat the cancer at its early stage via nano-theranostics, and the imaging technologies with high sensitiveness are of especial important for the imaging-guided diagnosis and therapy. The key points include increasing the stability and the enhancement of the signal. Near infrared (NIR) fluorescence has attracted much attention for its large penetrative depth for tissues. Here, in this proposal, we will try to prepare polypeptide-based polymeric materials as the nano-carriers, the self-healing NIR fluorescence molecules as the probe, and the pH responsive properties as the mechanism for fluorescence off/on and enhancement. A series of amphiphilic block polypeptides with various tertiary amino groups at the side chains will be designed and synthesized for the polymers owning a pH-responsive assembly-disassembly behavior. Self-healing NIR fluorescence probes can be synthesized by conjugation of quencher of triplet state to decrease the blinking and photobleaching. Next, the NIR probes are conjugated by chemical linking to the target or non-target copolymers, and the materials should own an ultra-pH sensitive dark/light fluorescence ratio. The polymeric nanoparticles are then used as the theranostic drug to detect the special target of tumor or cancer cells. After the imaging of the targets, the encapsulated drug or photosensitizers can be trigged for kill the cancer cell. The research will be very helpful for developing new polymeric system for cancer theranostics.

肿瘤的早期诊断与治疗对于遏制癌症的发展至关重要，可视化的诊断与治疗均离不开高灵敏的成像技术，近红外探针因其高的组织穿透性而备受关注，在纳米诊疗过程中，提高荧光信号的稳定性与信号增强至关重要。本项目拟以生物相容性和可降解的聚多肽为高分子主体骨架，以具备自修复功能的荧光分子为探针，以pH超敏感响应为荧光开关与增强机理，设计并合成多种叔胺基侧基修饰的两亲性多嵌段共聚物，使其具备窄pH范围与特征pH值响应的聚集与分散响应特性，设计与合成高量子效率的近红外探针分子、并通过链接三线态淬灭剂降低闪烁与光漂白，实现荧光的自修复功能，并使之与靶向/非靶向共聚物进行共价键合，使其在共聚物纳米粒聚集/分散转变过程中实现pH超敏感的高荧光开关比，实现其对肿瘤细胞特定部位的高灵敏探测，并结合抗癌药物或者光动力治疗实现更简单与高效的癌症诊疗功能，并为新的智能纳米诊疗体系提供重要基础信息。

合成了系列带活性官能团的近红外Cy7和BODIPY型分子，并通过三线态淬灭技术，实现了具有自修复功能的近红外荧光分子，研究了其自修复荧光特性和分子受激后单重激发态-三重激发态-单线态氧之间的能量转移规律及调控方式，按照不同需要调控其荧光强度、稳定性和单线态氧产率，在荧光成像和光动力治疗方面达成平衡；通过结合开环聚合、自由基聚合、Click反应等手段合成出了多种智能响应的嵌段共聚物，并与合成的染料或光敏剂结合，得到复合功能的聚多肽纳米载药体系。得到了超pHe敏感的高分子纳米粒，对肿瘤微环境成高倍率的荧光成像，可用于早期的癌症诊断与治理一体化；同时还发展了pH响应型的两亲聚多肽，可高效同时负载BODIPY和DOX，表现出了优良的近红外光可视化的联合光动力-化疗；在合成高单线态BODIPY近红外敏感的光敏剂的基础上，合成了半乳糖靶向靶向聚多肽基纳米粒，实现了超低近红外光能量下的可视化光动力治疗，对降低治疗过程中的毒副作用效果明显。合成了多种PEG及POGEMA保护的功能聚合物纳米粒子，并系统研究了其作为药物载体的行为（包括双pH响应）；设计并合成了以胱氨酸聚合物纳米凝胶为主体的新型纳米材料，实现了还原响应特性，体外与体内实验表明该体系实现了肿瘤的纳米药物示踪与治疗一体化，达到了近红外引导的可视化光动力治疗的效果，疗效明显。在项目的支持下发表了41篇高水平的研究论文，培养了6名博士生。