具有肿瘤靶向的多西他赛pH敏感脂质体的可控制备及敏感机制研究

The PH-sensitive liposome drug delivery system has been widely developed for cancer therapy over the past few years. Our recent study suggesting that when entrapped different drugs in liposomes, which were prepared with the same materials and the same composition ratio, it will reveal various PH sensitivity. What's worse, the processing schedule is unstable and difficult to control. Therefore, it's necessary to found out the mechanism related to the PH-sensitive of liposomes. Isothermal titration calorimetry Technology (ITC) will be applied to investigating the relationship between each material, and exploring the structure-effects connection. Additionally, the phase-transfer behavior and microscopic structure alteration of liposomes in diverse PH buffer will be studied by advanced technology, such as SAXS, TEM, DSC et. We expect to found out the PH-sensitive mechanism basing on the research above, and supply the regulation for material choosing and processing optimization, finally making it possible for controlled preparation of docetaxel liposomes. Further, the liposomes which prepared under the guidance will be estimated by Anti-tumor effect in vivo and in vitro, ensuring its practicability. The research combined the practising of pharmaceutics with the theory and advanced technology of physical chemistry to explore the PH-sensitive mechanism of liposomes, the design is reasonable and novel, which will provide a promising way to study and develop anticancer drug with merits of high effects and low toxicity.

近年来，pH敏感性脂质体已成为抗癌药物传递系统的研究热点。我们前期研究发现在材料及组成相同的条件下,制备的pH敏感脂质体对于不同药物，其pH敏感点有较大差异，且制备过程中工艺不稳定。解决上述问题，需要清楚掌握pH敏感脂质的敏感机制。我们拟通过等温滴定量热技术对脂质体各组分之间的相互作用进行研究，探索其在脂质体结构变化中的构效关系，并在此基础上采用先进测量技术从纳米尺度上研究脂质体在不同pH条件下的相转移行为，提出pH敏感脂质体的敏感机制；用所获机制指导制剂材料的筛选和工艺优化，实现对多西他赛pH敏感脂质体的可控制备；最后通过体内、外抗肿瘤实验对脂质体的有效性进行评价。本课题来自制剂学实践，用先进的物理化学理论及技术研究生命过程中的化学过程，并用所获规律指导制剂材料的筛选和工艺优化。课题思路新颖，将为研究和开发高效低毒的抗癌药物新剂型提供重要的实验和理论依据。

近年来，pH敏感性脂质体已成为抗癌药物传递系统的研究热点。我们前期研究发现在材料及组成相同的条件下，制备的pH敏感脂质体对于不同药物，其pH敏感点有较大差异，且制备过程中工艺不稳定。解决上述问题，需要清楚掌握pH敏感脂质的敏感机制。我们选取油酸、亚油酸（LA）、胆固醇琥珀酸单脂（CHEMS）作为pH敏感材料制备了不同的pH敏感脂质体，测定了脂质体在不同pH环境下的电导率,获得了脂质体的pH敏感点为pH=5，恰与肿瘤组织微环境的pH值相近；通过NANO DSC技术对脂质体各组分之间的相互作用进行研究，探索其在脂质体结构变化中的构效关系；采用先进测量技术从纳米尺度上研究了脂质体在不同pH条件下的形态变化，提出了pH敏感脂质体的敏感机制。依据所提出的敏感机制，根据药物释放所需的pH环境，有目的性的选择合适的pH敏感材料及组成，成功制备了多种载多西他赛pH敏感脂质体，实现了可控制备。且所制得的脂质体理化性质稳定，体外释药实验结果也表明脂质体具有良好的pH敏感性。另外，在实际应用上我们又通过脂质体与凝胶的组合，探索了脂质体在不同给药方式上的可行性。最后成功建立了面向肿瘤细胞靶向的脂质体的体内、外有效性评价方法，结果显示所制备的pH敏感脂质体皆表现出良好的肿瘤靶向性。实验结果说明所制脂质体可作为有效的抗癌药物载体，并能提高其在特定组织的靶向效率，降低其毒副作用。课题所得结论将为研究和开发高效低毒的抗癌药物新剂型提供重要的实验和理论依据。