自组装药物传递系统的理性设计和实验验证

The concept, self-assembled drug delivery systems (SADDS), was suggested by Jin. SADDS is defined the highly water-dispersing regular molecular self-assemblies of amphiphilic prodrugs that are the conjugates of drugs and helper molecules. SADDSs have the advantages of high drug loads, well stability, targeting, and controlled-release. We have worked on the research of SADDSs for more than 10 years and obtain many achievements and experiences. In this study, the design of the amphiphilic prodrugs, the rule of self-assembly, and the biological interaction of self-assemblies are focused on. The result will provide the theoretic and methodological support for the novel drug delivery system. The optimal amphiphilic prodrug structures will be obtained based on computer-aided design and experimental experience. Model drugs include small hydrophobic or hydrophilic molecules, large molecules (e.g., siRNA, microRNA, and peptides). Models will be constructed by computer chemistry and molecular dynamic software to simulate the self-assembly process of prodrug molecules, resulting in the rational design of prodrugs. The optimal molecules will be synthesized based on organic chemistry. The self-assemblies will be prepared based on nanotechnology. The biological interaction between the self-assemblies and biologics will be explored on the various levels involving proteins, cell membranes, cells, tissues, and animals. The interaction can also be simulated on the workstation. In the whole study, computer method, chemical technique and biological method are always combined and comprehensively used. The results of the study great support the construction of SADDS theory.

自组装药物传递系统（SADDS）由申请者提出，指药物和辅分子共价结合形成的两亲性前药在水溶液中自组装形成高度分散的有序分子聚集体，具有高载药、稳定、靶向、控释的特点。SADDS已经在多个药物模型上取得成果和经验。目前关键问题是两亲性前药分子的理性设计和自组装模拟。本项目着重研究两亲性前药的设计、自组装规律考察和自组装体生物相互作用，为这种新型给药技术提供理论支撑和方法学。通过理论计算和实践经验设计优化两亲性前药结构（涉及小分子疏水或亲水药物、大分子药物如siRNA、microRNA、多肽）；用计算机化学原理和分子动力学软件建模，模拟分子自组装过程；采用有机化学技术合成前药，用纳米技术制备自组装体；考察自组装体和细胞膜、蛋白、细胞、组织、动物的相互作用，并在工作站计算平台上模拟。在研究过程中，计算机方法、化学技术、生物学方法始终交叉运用，为建立SADDS 理论体系打下基础。

大部分药物，特别是水溶性药物的纳米制剂一直存在包封率低、药物易渗漏、最终到达靶部位药量小等问题。自组装药物传递系统（SADDS）彻底摒弃传统纳米制剂的设计缺陷，直接将辅分子与药物共价结合形成两亲性前药，该前药可在水中自组装形成纳米自组装体，具有高载药、稳定、不渗漏、最终到达靶部位药量大的优势。本项目对多种两亲性前药进行了分子自组装的计算机模拟，考察了前药分子结构和分子自组装的关系；合成了多种前药分子，对其理化性质、自组装体制备和性质、自组装体的稳定性、生物相互作用、药效药理进行了详细考察。通过计算机手段的介入，获得了前药分子结构和分子自组装的关系规律，为用于自组装药物传递系统（SADDS）的前药设计打下基础。通过物理、化学、生物学方面的研究，获得了多个载药量大、靶向性强、药效强、副作用小的两亲性前药及其自组装体。具体包括设计并合成了多个两亲性前药及其自组装体，如胆固醇基膦酰吉西他滨和胆固醇基磷酰齐多夫定等。用耗散动力学模式和粗粒化模型，用分子动力学模拟方法和Materials Studio软件模拟前药分子水中自组装，模拟自组装体形态和实际自组装体相近，证明分子自组装模拟在自组装药物传递系统研究上可行性和指导意义。对前药分子的理化性质进行详细考察，发现碳链越长，柔韧性下降，分子难以组装成流动性好可弯曲的双分子层，非常短碳链衍生物极性头相对大，倾向形成胶束或溶于水。主要采用注入法制备了前药的自组装体，其中短碳链前药分子可形成球状囊泡，较稳定，但长碳链前药分子的聚集体似乎缺少有序性，易聚集。不同生物环境对前药降解速度不同。建立了各种动物疾病模型，前药自组装体基本体现了高效抗病毒和抗肿瘤效果，同时进行了细胞水平作用机理的考察、药代动力学证明了自组装体的器官和肿瘤组织的靶向性。上述研究结果为自组装药物传递系统理论体系和技术平台的建设完善打下了坚实基础，大大推动了分子药剂学的发展，可产生多个能应用于临床的创新性新药。