温敏智能纳米探针的构建及其在药物控制释放中的应用

The combination of multiple drugs with different molecular targets has been proved to be an efficient strategy against multidrug resistance, which is a major factor in the failure of many forms of cancer chemotherapy. In this proposal, smart nanoprobes with tunable surfaces will be designed with temperature-sensitive polymers (TSPs), gold nanostructures, and nanogels to spatial-temporally modulate target delivery and control drug release in order to achieve real-time monitoring and synergistic treatment of cancer disease. First, smart fluorescent nanoprobes (SFNPs) will be prepared on the basis of the reversible response of TSPs to temperature by optimizing the conjugation density of the fluorescence dye. Then, the functionalized SFNPs will be employed as gatekeepers to construct smart nanocarriers (SNCs) with tunable surfaces by virtue of the specific interaction between phenylboronic acid and diols, the reversible phase transition of polymers, and the photothermal conversion of gold nanorods. Furthermore, by using different gold nanostructures, two SNCs respectively responsive to 675 nm and 808 nm laser will be prepared to construct the smart nanogels (SNGs) for hierarchically controlled release of doxorubicin and disulfiram. As designed, by adjusting the power of the near infrared laser, the surface composition of the nanocarriers will be finely controlled so as to achieve photothermal-guided target recognition and controlled drug release simultaneously. Meanwhile, due to their fast response and high sensitivity, the temperature variations during the treatment are dynamically monitored by recording the fluorescence of the SFNPs, which is favorable to modulate the drug release behaviors and optimize the administration methods, thus maximizing the therapy efficacy and minimizing side effects in synergistic treatment of multi-drug resistant tumor. In general, we hope that our multifunctional smart nanoprobes will advance the development of technology in cancer diagnosis and treatment.

多种药物协同治疗是抑制肿瘤耐药性的有效手段，本项目拟利用温敏聚合物、金纳米颗粒、凝胶等材料，设计表面性质可调的智能纳米探针，通过近红外激光精准操控和实时监测探针的靶向识别和药物释放，实现耐药性肿瘤的协同治疗。利用温度响应可逆的聚合物和聚集荧光增强的染料，通过优化染料修饰密度制备温敏荧光探针；以荧光探针为纳米门，借助苯硼酸／单糖的特异性识别、温敏探针的可逆相变及纳米金棒的光热转化设计多重温度响应的智能药物载体；调控金纳米颗粒的结构以调控载体的激光响应波长，构建多重激光响应的药物缓释凝胶，控制药物阿霉素和双硫仑的分层次释放。本项目旨在通过光热控制载体表面温度，进而精准调节载体表面性质，分步控制载体的靶向识别与药物释放；同时，借助响应快速、灵敏的荧光探针，实时监测药物释放和细胞内温度变化，精准地控制药物释放行为，以期优化给药方案，提高肿瘤的治疗效果，降低副作用，为癌症诊疗一体化提供新的思路。

纳米药物载体表面性质决定其在生物体内的分布、代谢、疗效和副作用，但表面单一的组成难以实现复杂生命体内肿瘤的精准靶向和有效治疗。环境响应的智能纳米载体能够在肿瘤处被动富集，并被刺激信号激活靶向功能，在时空多维度可控地释放药物分子，这有助于优化给药方案，增强治疗效果，减轻组织损伤。因此，开发新型环境响应的智能材料，并提高其在生物体内的可操控性，对于癌症的精准治疗具有重要的科学意义。本项目设计和合成了一系列环境响应的智能材料，用于纳米材料表面和组成的精准调控，从而实现肿瘤的精准靶向和药物的精准递送。1）为提高纳米载体的靶向精度，基于自然界中存在的胍基/磷酸三重氢键构建了pH/温度/GSH三重响应的聚合物分子拉链，并用于智能纳米载体表面性质调控，在活体水平实现纳米粒子表面性质精准操控，延长了载体在血液中的循环时间，增强了肿瘤部位的被动富集，进而实现近红外光激活的细胞选择性吸收，有效地抑制了肿瘤的生长，降低了副作用，为肿瘤的精准治疗提供了新的工具。2）受限于结构复杂性和反应活性差异，传统的环境响应元件难以实现灵活组装，我们首次提出基于“自降解化学”设计结构类似、反应活性相同的环境响应分子砌块库，并构建可降解聚合物，通过静电诱导的疏水组装制备具有不同逻辑运算能力的纳米药物载体，在细胞和活体水平通过生物逻辑运算实现药物的精准释放。3）多药联用是肿瘤治疗的有效手段，但不同药物的理化性质和靶点不同，难以实现共同递送和精准释放。我们通过生物信息学的大数据分析，获得肿瘤细胞内特异性表达的标志物，利用环境响应分子砌块库构建可编程纳米药物载体，进行生物逻辑运算，实现多种药物的分层释放，极大提高了肿瘤的靶向效果，为肿瘤治疗提供新的策略。本项目为智能生物材料的构建提供了新的可编程工具，有助于推动生物材料、组织工程、纳米医学等领域的发展和临床转化，具有重要的科学意义和经济价值。