基于官能团化瓜环制备的超分子纳米结构用于药物递送的研究

Development of multi-functional nano drug-carriers is of practical value for precision medicine. Due to the dynamic, reversible association, and facile modification through host-guest interactions, supramolecular nano-assemblies have natural advantages in the design and construction of multi-functional nano drug-carriers. As promising macrocycles, cucurbit[n]urils (CB[n]s) have recently emerged in biomedical sciences on account of their high selectivity and strong binding affinity towards a variety of guest molecules. With our several years of experiences in exploration of CB[n]’s potential applications in biomedical sciences, as well as our recent efforts in functionalizing CB[n]s, we have designed two types of CB[n] based supramolecular nano drug-carriers on the basis of recent development of macrocycles (particularly, CB[n]s). On the one hand, Biotin-PEGylated CB[7] derived from monohydroxylated CB[7] will be prepared and be built into amphiphilic complexes upon binding with phenylalanyl-doxorubicin (Phe-DOX) through host-guest complexation between CB[7] and Phe moiety, which may further self-assemble into nanoparticles with targeting functionality (through biotin) and pH responsiveness (through the labile bond of Phe-Dox). On the other hand, we intend to crosslink amino-terminated CB[6] (derived from perhydroxylated CB[6]) and brominated pillar[5]arene (PA[5]) in order to make nanocapsules with hetero-macrocycles (both CB[6] and PA[5]) on the surface. Upon loading with model drugs, the nanocapsules will be further endowed with targeting and imaging functionalities, through the selective guest-insertion into CB[6] and PA[5], respectively. Both types of nanoparticles will be fully characterized, and their biocompatibility, targeted drug delivery, as well as molecular imaging will be evaluated on in vitro cellular models. Our research efforts will certainly expand functionalized CB[n] as building blocks for functional biomaterials, and further promote the use of macrocycles in biomedical research for practical applications in future.

超分子自组装体因其动态可逆，且可通过客体分子进行非共价键修饰，在构建多功能纳米药物载体方面具有非常强大的天然优势。本课题组利用多年来在瓜环生物医药方面的研究经验以及近年来对官能团化瓜环的探索，结合国内外大环分子研究最新进展，设计了两种基于瓜环衍生物的超分子纳米药物载体。一种利用单羟基CB[7]的Biotin-PEG衍生物与苯丙氨酰多柔比星（DOX）主客体组装形成两亲性化合物，进而在水溶液中自组装成载药的pH 敏感性靶向纳米粒子。另一种利用全羟基CB[6]的端氨基衍生物与溴代柱芳烃[5]交联形成载药的纳米胶囊，并在表面进行选择性靶向Biotin及成像FITC修饰，并全面评价两种纳米粒的生物相容性，靶向载释药以及分子成像。本研究从瓜环衍生化的角度可以拓展开发基于瓜环的新型功能材料构筑基元，并利用此种基元构筑新型多功能纳米药物载体，极大推进大环分子在生物医药领域的应用研究。

多功能纳米药物的开发对实现疾病的精准高效治疗具有重要意义。基于大环的超分子自组装体在构建多功能纳米药物载体方面具有天然的优势。一方面大环主客体作用的动态可逆性使得纳米药物载体具有竞争客体响应性；另一方面主客体包结的特异性可以很容易实现纳米结构多种功能修饰。瓜环（CB[n]）分子具有优异的客体分子选择性及包结稳定性，在构建多功能纳米药物载体方面极具潜力。在项目执行期间，我们以两种经典的官能团化瓜环CB[6]衍生物和CB[7]衍生物作为构筑基元，成功构筑了一系列多功能超分子纳米药物递送系统。首次开发了一种直接利用CB[6]羟基化衍生物构筑纳米胶囊的简便方法，并以此构筑了响应型CB[6]超分子纳米胶囊；系统研究了CB[7]衍生物的合成及超分子纳米载体的构建，拓展了利用CB[7]主客体作用进行纳米载体功能基团修饰的简便方法；开拓了CB[7]衍生物在细胞膜修饰的应用，首次提出了“超分子细胞”的概念，利用CB[7]主客体作用开发了一种简便的、生物正交的超分子细胞搭便车式给药策略。项目开辟了瓜环及其衍生物的应用新途径，拓展了基于瓜环衍生物构建超分子纳米载体的新方法，所开发的多功能纳米药物具有一定的应用前景。