离子互补型纳米自组装短肽与水难溶性药物的相互作用和控释研究

Ionic-complementary self-assembling peptides possess the potential of drug carrier for their amphiphilic property and being able to promptly self-assemble into hydrogels under physiological conditions. Their inherent properties can be regulated by changing their amino acid residues. Three novel self-assembling peptides with different hydrophobic lateral chains will be designed and synthetized on the basis of RAD16-I. The interactions between these peptides and model hydrophobic compound, pyrene, will be investigated through electron microscope, fluorospectrophotometry and atomic force microscope, respectively. Moreover, most efforts will be focused on the performance as well as the related mechanism of these peptides to stabilize emodin in aqueous system. Then, the colloidal suspensions of emodin with these peptides will be prepared in water under mechanical stirring and in-situ hydrogels will be established by adding proper amounts of the suspensions into phosphate buffers or liquid cell culture media. Following that, the controlled release of emodin in the hydrogels as well as antibacterial and antitumor effects will be investigated in vitro, respectively. Lastly, the antitumor effects of emodin in some selected hydrogels will also be investigated in vivo. These work will contribute to ascertain the mechanism through which self assembling peptides stabilize hydrophobic drugs. This will be of great value to study self assembling peptides and to develop new formulations of hydrophobic drugs. The practice of developing self assembling peptides as hydrophobic drug carriers will be greatly promoted by the colloidal suspension-in situ hydrogel system established in this research.

离子互补型纳米自组装短肽具有两亲性，并可在生理条件下形成水凝胶，其内在特性可通过氨基酸残基替换而加以调控，因而具备作为药物载体材料的潜力。拟通过系统替换RAD16-I中的疏水氨基酸，设计合成侧链疏水性不同的系列短肽，先以电镜、荧光分光光度法、原子力显微镜等研究系列短肽与模式疏水化合物芘的相互作用；探讨短肽对大黄素在水性体系中的稳定和增溶机制；考察短肽和大黄素形成胶体混悬液以及水凝胶的情形并加以表征；比较侧链疏水性不同的纳米自组装短肽所形成的水凝胶中大黄素的体外控释和体内、外抗菌、抗肿瘤作用差异。该研究将有助于明确离子互补型纳米自组装短肽稳定疏水性药物的机制，这对促进自组装短肽药物载体材料开发和疏水性药物剂型改良均有重要的理论和实践指导价值。

疏水性药物的给药系统一直是药学研究中的挑战性课题。离子互补型纳米自组装短肽具有两亲性，并可在生理条件下形成水凝胶，因而具备作为疏水性药物载体材料的潜力。本课题研究了自组装短肽RAD16-I、RVDV16-I与疏水性药物大黄素的相互作用以及其稳定疏水性药物的性能和初步机制；初步构建和表征自组装短肽与大黄素的胶体混悬液-原位凝胶系统并研究了水凝胶中大黄素的体外控释及体外抗菌与体外及体内（C57小鼠肝癌Hepa1-6细胞、肺癌LLC细胞移植瘤）抗肿瘤作用。在相互作用和给药系统部分还以芘、芦荟大黄素、黄芩苷、芒果苷等对大黄素的研究进行了对比或验证。结果表明，离子互补型纳米自组装肽与疏水性化合物或药物的相互作用以疏水相互作用为主导，自组装短肽通过其适当的两亲性和自组装特性稳定疏水性化合物或药物；研究中涉及到的疏水性药物或化合物均可与自组装短肽在水溶液中于机械搅拌下形成粒度在数百纳米的胶体混悬液，该混悬液均可在生理的pH或/和离子强度条件下原位形成凝胶；该给药系统明显改进了大黄素体外和体内给药的可行性，水凝胶对其中药物的释放表现出一定的缓控释特性，并从某种程度上改进了药物固有的抗菌或抗肿瘤作用；虽然RVDV16-I体现了比RAD16-I更强的与疏水性药物或化合物间的相互作用，但在给药系统构建、缓控释方面并无明确优势，提示自组装短肽结构中某种程度的疏水亲水平衡性是成功构建疏水性药物的自组装短肽混悬液-原位凝胶给药系统的关键，其具体内在机制有待进一步研究。该研究有助于明确离子互补型纳米自组装短肽稳定疏水性药物的机制，对促进自组装短肽药物载体材料开发和疏水性药物剂型改良均有重要的理论和实践指导价值。