单分子聚合物纳米颗粒的精密合成及其纳米医学输送性能研究

Attributing to their easy functionalization, stimuli-responsibility, biocompatibility, and biodegradability, polymer nanoparticles have demonstrated huge application in medical therapeutics. They are used as vehicles to deliver chemistry drugs and functional biologics to targets for chemotherapy, gene therapy, immunotherapy and protein/peptide therapy, which will bring completely new era of medicine. It is known that size, shape, and surface properties of the particles greatly influence the pharmacologic behaviors of therapeutics. Recently, it is demonstrated that the small size (10-50 nm) and shape (rodlike) are very important for particle trafficking in some tumors with dense tissue and lymph system. They become critical factors to enhance tissue targeting and penetrating in tumor and immuotherapy. However, there lacks a powerful materials scaffold by which particular precise structures, including the size, the shape, and the surface, may be tailored rational. This project will study precision synthesis of biofunctional polymer bottlebrushes as new kind of uni-molecular nanoobjects. By using controlled polymerization and click chemistry, the molecular nanoobjects with well-defined particular diameter (10-50 nm), shape (sphere vs. rod) and length (rod), surface properties as well as biomedical functions will be prepared. They will be used as model particles to study structure factors dependent behavior in nanomedical delivery system. Hypovasicular tumors will be used as models to evaluate the penetrating of present molecular nanoobjects with precisely controlled structures. Moreover, core/shell molecular nanoobjects with excellent penetration and retention as well as target release in hypovasicular tumor will be studied for delivering siRNA.

在纳米医学研究中，运输治疗功能分子复合纳米颗粒的结构因素对颗粒在体内血液和肿瘤组织中的输送行为影响非常大。近几年发现小尺寸（10-50 nm范围）颗粒更易进入乏血供肿瘤组织，非球形颗粒（如柱形）代谢和输送性能显著不同于球形颗粒，这些问题成为肿瘤治疗和免疫治疗中提高组织靶向的关键。但目前缺乏可从分子层次上对聚合物纳米颗粒实现精密合成的研究平台，用于阐述小尺寸和形状对颗粒输送行为规律影响的研究。本项目将通过可控聚合和高效点击化学合成聚合物分子刷，作为单分子纳米颗粒用于纳米医学输送系统研究；将实现其从尺寸、形状、表面、刚柔性，以及生物功能等多方面的精密控制，研究这类新颖纳米颗粒在体内输送、在乏血供肿瘤组织扩散及细胞作用行为。设计合成能够输送siRNA单分子纳米输送材料，并具有生物相容性和肿瘤细胞环境响应性降解释放的性质，在乏血供肿瘤模型中验证其性能。

纳米颗粒的尺寸和形状对其体内输送行为的行为影响非常大，是纳米医学研究的核心问题。文献中对纳米材料尺寸的研究已经获得了系统的认识，而对非球形颗粒（如柱形）的输送性能研究显著不足。从纳米材料选择上，尚缺乏从分子层次可实现精密合成的研究平台，用于阐述尺寸和形状对颗粒纳米医学行为影响的研究。本项目通过可控聚合和高效点击化学合成聚合物分子刷，作为单分子纳米颗粒用于纳米医学输送系统研究。实现其从尺寸、形状、表面、刚柔性等多方面结构的精密控制，研究这类纳米颗粒在小鼠体内、在肿瘤组织扩散及细胞作用行为。项目按计划进展顺利，取得的重要结论如下：.1）.实现了聚合物分子刷生物长径比、侧链结构、可降解性等多方面的可控合成；揭示了核壳侧链结构对聚合物分子刷负载模型药物分子的显著影响，侧链为多接枝亲水链壳的聚合物刷具有更高的负载量和更高的溶液稳定性；.2）.揭示了纳米颗粒长径比对细胞内吞、小动物体内分布、肿瘤模型的影响，发现适当长径具有最佳的行为。优化长径负载光热试剂的纳米颗粒可以更有效在肿瘤富集并破坏肿瘤；.3）.在类风湿关节炎模型中，揭示了聚合物刷主链主链长度、侧链体积、电荷密度等结构对被动靶向炎症关节腔的影响。主链聚合物度越大、侧链体积越大，聚合物颗粒在关节腔聚集越多，并且颗粒阳离子性质可有效清除关节腔的高浓度游离核酸，从而表现出更好的抑制免疫炎症反应；.4）.在靶向淋巴结的输送体系中，发现聚合物分子刷长径比越大，从皮下注射部位到达淋巴结的越慢，但达到淋巴结后在滞留时间更长。负载了分子佐剂的聚合物分子刷，发现适当长径比的聚合物刷具有更好的激活TLR9功能，在免疫慢性乙肝动物中，表现出更佳优异的免疫治疗行为。