程序化响应肿瘤微环境的不对称肽类树状大分子多药递送系统用于肿瘤的化疗/光热疗

The combination of chemo- and photothermal-therapy is an efficient method for tumor clinical treatment. For combination therapy, it’s necessary to design a vehicle for realizing the co-delivery of different drugs. Janus peptide dendrimers are easily multifunctional modificated and could load drugs in diversified manners. In this project, tumor microenvironment programmed-responsive co-delivery system for the combination of chemo- and photothermal-therapy (PTT) will be designed, while Janus dendrimer modified with arginine in its single-terminal is chosen as a carrier. Chemotherapy drug will be covalently coupled with Janus dendrimer via enzyme sensitive linker, whlie photosensitizer prodrug will be loaded through phisical interaction. To achieve effective drug delivery to the target site, the delivery system should overcome multiple physiological barriers. After intravenous injection, the nanoparticles should be stable and the loading drugs could be protected by PEG during circulation. After accumulation into tumor, the first level sensitive response caused by extracellular low pH would be activated. Meanwhile, unnecessary PEG shell fell off from nanoparticles, which could lead to the reduction of size. The nanoparticles with smaller size would enhance the ability of penetration into tumor tissues. At the same time, the exposion of positive surface charge would promote cellular uptake. The second level sensitive response caused by intracellular overexpressed cathespin B would be activated after cellular internalization, then, the free drug could be released rapidly in its original structure. At the same moment, the third level sensitive response would be activated by reactive oxygen species (ROS). Following the fluorescence molecule released from prodrug of photosensitizer, fluorescent signal could be turned from “off” into “on”, that guide the accurate treatment of PTT. In summary, we aim to enhance antitumor efficiency through combination of chemotherapy and photothermal therapy while multifunctional programmed-responsive Janus peptide dendrimers are chosen as drug delivery carriers. The overall structural design of Janus dendrimer vehicle in this project may provide useful strategies for design and preparation for peptide dendritic polymers as safe and efficient drug delivery systems.

化疗/光热治疗的联用是临床肿瘤治疗的有效手段，采用载体共递送药物是实施联合治疗的重要策略。基于不对称肽类树状分子具有载药多样性且易功能化等优势，本项目拟设计多功能不对称肽类树状分子作为化药和光敏剂共递送的载体，用于肿瘤的化疗/热疗。化药通过酶敏感连接臂与树状分子偶联，光敏剂则制备成前药物理包载在载体中。该递送系统可程序化响应肿瘤微环境。静注后基于载体中的PEG增加血液长循环，通过被动靶向富集于弱酸性肿瘤组织，发生第一级响应，载体由负电逆转成正电，PEG层脱落，载体粒径变小，增强对组织深层渗透，正电性载体促进细胞摄取。在胞内发生第二级响应，胞内组织蛋白酶B快速降解化药连接臂，释放化药。同时胞内发生第三级响应，光敏剂前药在胞内ROS作用下释放出光敏剂及荧光分子，检测荧光信号对肿瘤实施精准的光热治疗，增强抗肿瘤效果。本研究为单一载体构筑高效的多药递送系统提供了依据，为联合用药提供了载体技术平台。

肿瘤的复杂性及异质性是肿瘤难以治愈的关键原因。化疗是肿瘤治疗必不可少的疗法，而光热治疗等新型疗法的兴起也为肿瘤治疗提供了更多的可能性。化疗/光热治疗的联用是临床肿瘤治疗的有效手段，采用载体共递送药物是实施联合治疗的重要策略。基于两亲性肽类树状分子具有载药多样性且易功能化等优势，本项目拟设计了几类多功能肽类树状分子分别作为药物载体，用于肿瘤的化疗、及化疗/热疗联合治疗研究。具体研究内容包括：（1）通过不对称肽类树状大分子及酶敏感响应短肽的设计，利用高效的点击反应构建了一种两亲性肽类树状大分子前药。该体系提高了易失活药物吉西他滨的稳定性，增强了药物的抗肿瘤效果和生物安全性，为拓展药物吉西他滨的应用前景和适应症提供了潜在的策略。（2）通过设计不同代数的两亲性肽类树状大分子，构建了一类基于低代数的两亲性肽类树状大分子自组装体系。探索了该体系的药物递送效率和药物在三维培养肿瘤球形模型中的渗透和分布情况及体外抗肿瘤效果，较深入地探索了药物深层递送的潜力和相应的机制。有效地利用低代数的两亲性肽类树状大分子实现了药物的肿瘤深层递送，显著提高了对耐DOX细胞系（MCF-7R）的抗肿瘤效果。（3）基于前期的探索基础，进一步优化两亲性肽类树状大分子载体，构建了一类逐级响应的两亲性肽类树状大分子用于化疗/光热治疗协同治疗。将化疗药物和光敏试剂分别通过两种方式（共价连接和物理包载）构建在该同一递送系统中，使其具有依次释放不同药物的能力，利用成像指导下实现对肿瘤的精准光热治疗，并期望通过模式互补实现协同治疗，增强抗肿瘤效果。本研究将为增加药物的药效、拓展药物的应用范围、药物的深层渗透提供一定的思路，为利用单一载体构筑高效的多药递送系统提供了依据，为联合用药提供了载体技术平台。