以穿心莲为代表的中药有效部位肿瘤靶向聚合物胶束研究

Large dose and fewer effective components are two main obstacles for the modernlization of TCM. So,it is very urgent to enrich the effective components and formulate them into targeting drug delivery system. As our target, Andrographis paniculata ,of which the effective parts (mainly diterpene lactones) were enriched by supramolecular technology and had proven anti-tumor effect in our previous work, are extensively studied in this project.Firstly, optimizations of AEP enriching process are performed.Secondly, assumed as a model drug, AEP are encapsulized in different micelles made from pH-sensitive PEO-PPO-PEO and mPEG-PLA by various methods.On the basis of in vivo and vitro experiment,the relationships are discussed between type,molecular-weight, hydrophobic-hydrophilic ratio of micellar materials,particle size，drug-loading , composition of AEP and anti-tumor effect. Then, nanoscale drug delivery systems with tumor-targeting property for multi-components of TCM are well developed. A systematic study on the tumor targeting capicity, tissue permeability and overcoming tumor mutidrug resistance ability shed light on how the AEP-loaded polymeric micelles enhancing the anti-tumor efficacy.As our overall goal of this project, by exploring polymeric micelles in anti-tumor formulation of TCM effective parts, theoretical and technical surpports will be provided in developing more efficient nanocscale drug delivery for TCM.

中药有效成分含量低、服用量大制约了中药现代制剂的发展。采用现代科技手段富集中药有效成分，构建靶向给药系统是提高中药质量、改善疗效的关键。课题组采用超分子技术富集得到穿心莲二萜内酯类有效部位AEP，其体内抗肿瘤作用显著。本课题拟进一步优化AEP制备工艺，以AEP为模型药物，选用pH敏感聚合物和聚氧乙烯-聚氧丙烯-聚氧乙烯、聚乙二醇单甲醚-聚乳酸等胶束材料，通过不同制备方法包载药物，结合胶束的体内、外抗肿瘤试验，建立胶束材料的类型、分子量和疏水/亲水比、粒径及有效部位主要成分的配比、载药量等与抗肿瘤之间的关系，从而构建多组分中药的肿瘤靶向纳米给药系统。通过胶束体内肿瘤靶向性、对肿瘤组织渗透效应研究和胶束逆转肿瘤多药耐药性的研究，阐明载药聚合物胶束的抗肿瘤增效机制，探索聚合物胶束在抗肿瘤中药有效部位给药系统中的应用，为构建用于肿瘤治疗的中药有效部位纳米给药系统提供理论依据。

中药有效成分含量低、服用量大制约了中药现代制剂的发展。采用现代科技手段富集中药有效成分，构建靶向给药系统是提高中药质量、改善疗效的关键。. 采用超分子技术富集穿心莲中二萜内酯类有效成分，并优化工艺，制得穿心莲有效部位（AEP），其中穿心莲内酯（A）、脱水穿心莲内酯（DDA）与14-去氧穿心莲内酯（DA）的总含量超过50%。.以聚乙二醇（mPEG）为亲水段，分别以聚乳酸（PLA）和茄尼醇-马来酸酐酯（SOLM）为疏水段，合成mPEG2000-PLA（1000-8000）和mPEG2000-SOLM，采用红外光谱、核磁共振、凝胶渗透色谱等方法验证材料合成及性质。.采用上述材料制备载AEP胶束，星点设计-效应面法优化处方工艺。采用同样方法包载单体成分A、DA和DDA，结果表明，与单体相比（如A），穿心莲有效部位载药胶束可提高载药量和包封率。采用粉末X-射线衍射法和DSC法评价胶束载药性质，结果表明，药物分散包载于胶束内核。.在不同介质中考察载药胶束的稳定性。mPEG2000-PLA1000-AEP和mPEG2000-SOLM-AEP均具有良好抗盐解离、蛋白质吸附和阴离子取代的能力。胶束在含20%细胞裂解液的溶液中被细胞裂解液降解。.以不同离子强度、pH缓冲液为释放介质，采用透析法考察mPEG2000-PLA1000-AEP和mPEG2000-SOLM-AEP的释药特性，表明药物释放不受介质离子强度和pH影响，胶束中A、DA和DDA的释放具有均一性，释放过程符合一级动力学方程。胶束可提高A和DDA的溶解度，具有增溶效应。.MTT法考察胶束对4T-1和MCF-7细胞的作用。结果表明，两种材料均对细胞生长无抑制作用；AEP和mPEG2000-PLA1000-AEP胶束对4T-1细胞的IC50值分别为66.34μg/mL和39.11μg/mL(24h)；AEP和mPEG2000-SOLM-AEP胶束对MCF-7细胞的IC50值分别为28.9 μg/mL和 15.47μg/mL(48h)。以上研究结果表明，聚合物胶束可有效包载中药有效部位，改善药物性质，提高抗肿瘤效果。