瓶刷形纳米药物传输系统的构建和研究

Recently, increasing interest and active effort have been devoted to nanoscale carriers for biomedical use, especially, delivering antitumor agents.Due to the specific "leaky" structure of tumor vasculature, nanocarriers in circulatory system are passively trapped and retained in tumor site, addressed as enhanced permeation and retention (EPR) effect. To fully exploit the potential of nano drug delivery systems, other strategies, including bioconjugating target ligands and constructing stimulated responsive linkers onto "passive targeting" nanocarriers. Thus, the basic physicochemical properties and in vivo performance of "passive targeting" nanocarriers largely shaped their in vivo fate and antitumor efficacy. So far, All of the clinically approved nano drug and most of the academic research on nano drug delivery systems are focus on "self-assembling" nano carriers. However, the lack of control of self-assembling process may led to a batch of nonuniform nanocarriers with high polydesperisity, which is not a precise model for the development of basic theory in the field and also confuses the understanding of scientific results. In this program, combining new tumor targeting therapy strategies with the advance of synthetic materials science, we designed and developed a serials of synthetic bottle-brush nanocarriers. Ring-Opening Metathesis Polymerization (ROMP), Reversible Addition-Fragmentation chain Transfer polymerization (RAFT) and "Click Chemistry" were employed to prepare bottle-brush nano drugs with uniform size, low polydisperisity, well-defined structure, adjustable surface properties and high drug loading ratio. Firstly, we will synthesis well-defined bottle-brush polymers with different backbone length, brush thickness, surface composition. After that, we will measure their antifouling properties, in vivo circulation time, cell uptake to select the superior polymers as nanocarriers. These nanocarriers will be conjugated with silyl ester based pH stimulated responsive linker and tumor penetrating ligand -- iRGD. According to experimental results, we may find out how could nanocarriers' structure affect their in vivo fate, the relationship between iRGD labeled nanocarriers and tumor penetration, as well as the drug release propertise and the structure of sily ester linker. All these scientific fruits will contribute to rational design of new nano drug delivery systems, also, our bottle-brush nanocarriers will provide a safe, beneficial and high efficient nano drug delivery platform.

纳米抗肿瘤药物传输系统是当今科学界的研究热点，为了提高化疗的效率，有必要开发研究高性能的抗肿瘤药物传输系统，因此本项目结合肿瘤治疗的新理念和材料科学的新方法，使用控制性聚合技术合成一系列瓶刷形纳米高分子材料。通过开环易位聚合，可逆加成-断裂链转移自由基聚合和"点击化学"制备尺寸均一、形貌可控、表面化学性质可控、高载药量、结构精确的纳米给药系统。克服了传统自组装纳米药物系统多分散、不均一和修饰性能较差的弱点。考察不同尺寸和表面组成的瓶刷形高分子的抗血浆蛋白粘附能力、体内循环时间、巨噬细胞吞噬等指标的差异,筛选最佳尺寸和表面结构的材料作为纳米载体，用于主动靶向和肿瘤渗透的研究。揭示瓶刷形给药系统在体内外的转运过程的内在机理，探讨pH敏感硅酯作为刺激响应连接臂对于抗肿瘤药物释放的影响，为理性设计药物传输系统提供科学依据，为抗肿瘤药物提供安全和高效的纳米载体平台。

实现精确可控的高分子结构是高分子材料和工程学中一项重要的工作。本项目基于降冰片烯和可降解磷酯系统，集中开发了基于格拉布催化剂的烯烃易位聚合方法，包括了开环易位（ROMP），无环二烯烃易位（ADMET）和原子转移自由基聚合（ATRP），通过开发一锅法等简易合成方法制备了磷酸酯和2-（二甲胺基）乙基甲基丙烯酸甲酯制备接枝型的瓶刷高分子，带有巯基侧链官能团的降冰片烯及其超支化结构，并于用无机-有机复合物的构建；制备了具有点击化学特性的降冰片烯高分子；串联使用ROMP和ADMET技术制备了新型瓶刷形高分子材料；使用ADMET技术制备了不对称线性-树状的聚磷酯结构，制备了具有可生物降解的四臂星形结构；串联ROMP和ADMET技术制备了线性-超支化的大分子结构；使用表面引发-ROMP技术将降冰片烯固定在基板表面并实现单分子检测。除此之外，我们还研究了部分聚降冰片烯，聚磷酯瓶刷形结构的纳米粒子性能以及在生物医学中的应用。该项目共发表9篇SCI论文。