基于多功能自组装聚合物纳米胶束的抗癌药物口服传递系统的构建及其性能研究

One difficulty for oral chemotherapy is the absorption hurdle, the second is extensive in vivo distribution of the drug, leading to poor efficacy. Moreover, new drug delivery system development is facing more and more drug and carrier, carrier and body interactions and extensive time, manpower and material resources are required. Taking these bottlenecks shooting as the aim, based on the pre-built polymeric micelles with promoted oral absorption and passive targeting properties, this project intends to build adaptive high-throughput model for drug delivery system screening on the basis of a combination of materials science, computational chemistry, pharmaceutics, molecular biology and other disciplines, and to verify the suitability of the proposed model by investigating its application in three representative model drugs, and elucidate from cellular and whole animal level the correlation of drug properties, the nature of polymeric carrier and the change of system energy with drug loading, in vivo uptake and absorption, and clarify the related mechanism. In summary, this project aims to provide experimental and theoretical basis for the design of efficient oral drug delivery system for poorly soluble anticancer drugs in an economic way. Construction and evaluation of high-throughput screening model of polymeric micelle system have not been reported so far. The scientific novelty of the project is good, with stronger research background, research conditions are met. Some preliminary studies have been carried out, and feasibility of the project design has been confirmed.

抗癌药口服制剂研究难点之一是吸收困难，二是体内分布广泛而导致疗效不佳，新型给药系统研究又面临更多药物与载体、机体相互作用而比以往的药物研发需要投入更多的时间、人力及物力。本项目拟针对上述瓶颈问题，在前期构建的具有促进吸收及被动靶向于一体的口服聚合物纳米胶束基础上，结合材料学、计算化学、制剂学、分子生物学等学科研究方法，构建给药系统适应性高通量筛选模型，并验证所建模型在3种代表性模型药物中应用的适宜性，从细胞水平和整体动物水平探讨药物性质、聚合物载体性质、体系能量变化与药物负载、体内摄取、吸收之间关系，阐明该传递系统的作用机理和规律，旨为高效、经济的难溶性抗肿瘤药物口服给药系统设计与调控提供实验和理论依据。该聚合物胶束系统高通量筛选模型的构建与评价，国内外均未见报道。本项目科学性新颖性好，研究力量较强，科研条件具备，有关工作基础扎实，已进行了部分前期研究，已证实可行性良好。

抗癌药口服制剂研究难点之一是吸收困难，二是体内分布广泛而导致疗效不佳，新型给药系统研究又面临更多药物与载体、机体相互作用而比以往的药物研发需要投入更多的时间、人力及物力。本项目针对上述瓶颈问题，构建了聚合物胶束递药系统设计可行性预测模型，分别采用计算机分子模拟和基团贡献法通过计算溶解度参数可预测药物和聚合物的相容性，并通过理论预测和实验验证建立了药物载体相容性的理论预测模型，同时通过体外、体内实验研究证明了模型预测的可靠性。该项目研究表明，应用基团贡献法，通过模型B预测药物载体之间的相容性可作为高通量筛选模型，之后可通过计算机分子模拟进一步深入研究药物载体的相容性，在此基础上开展的实验研究可大大提高研究的成功率和效率。该研究成果可为药物聚合物胶束体系的高效构建提供重要的理论基础。同时，该研究证明了应用聚合物胶束作为抗癌药物口服载体，其生物利用度和安全性显著高于静注，并有较好的缓释效果。 .该聚合物胶束系统高通量筛选模型的构建与评价，为开展基于计算预测指导下的药剂学研究作了较好的探索。