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环二肽自组装:结构调控及其在肿瘤治疗中的应用
杨梦瑶
Subtype硕士
Thesis Advisor闫学海
2019-07-01
Degree Grantor中国科学院大学
Degree Discipline生物化工
Keyword环二肽,自组装,纳米结构,染料分子,肿瘤治疗
Abstract

环二肽(CDPs)作为许多活性天然产物的骨架,由于其独特的生物和药理活性,如抗肿瘤、抗菌、免疫调节等引起了人们的广泛关注。作为最小的环肽化合物,CDPs不仅具有短肽分子良好的生物相容性、低免疫原性等优点,刚性的结构还使得CDPs可以有效克服线型肽易酶解的缺点。但另一方面,CDPs优异的结构刚性和形成氢键的能力又导致许多具有生物活性的CDPs在生物医学应用中存在水溶性差、易结晶、生物利用度低等问题。近年来,无载体单组分纳米药物已成为一种有望克服这一难题的选择。然而,由于CDPs结构的特殊性,与线型肽相比,CDPs纳米结构的可控制备仍然存在一定的挑战。鉴于CDPs自身的氢键、疏水作用和π-π堆积等相互作用力以及染料分子的大π共轭结构与环二肽分子存在一定相互作用。为此,我们通过对CDPs分子间作用力进行调控以及借助染料分子实现了可控纳米结构的制备以解决CDPs面临的挑战,进而提高CDPs的生物利用度及其应用范围。具体的研究包括:(1)发展了一种基于CDPs(cyclo-(Leu-Phe) (CLF))的多功能水凝胶。CLF基水凝胶不仅具有均匀纳米纤维缠绕的三维网络支架结构,在20-60℃的范围内都可以保持良好的凝胶性质。CLF分子不同于线型二肽,它具有很强的柔韧性,不仅可以凝胶化纯水,还可以凝胶化PBS、DMEM和酶溶液,其力学性能也得到了较好的改善。研究发现凝胶化性能优越的主要原因是CLF分子间固有的氢键相互作用,同时疏水效应也有助于CLF分子对水的聚集。由CLF制备的水凝胶具有良好的稳定性、可调节的流变特性以及在极端条件下的高稳定性,这为开发用于生物医学和工程应用的先进软材料提供了新的思路。(2)基于两亲性染料分子介导的CDPs疏水自组装,通过调控分子间氢键、π-π堆积等弱相互作用,获得了在水溶液中分散性良好的环二肽纳米带。两亲性染料分子不仅为环二肽纳米带的制备提供了强疏水相互作用,还提供了足够的静电斥力来稳定制备的组装体。环二肽纳米带的形貌、大小可控,可以通过调控动力学参数得到不同长度的纳米纤维及纳米带。同时,纳米带的结构促进了细胞对环二肽的摄取,有利于实现环二肽的抗肿瘤活性。此外,由于采用了功能性的染料分子,CDPs组装体具有多种功能模式。例如ICG分子具有光热性质,可以进行光声成像实现了诊疗一体。本论文主要通过调控分子间的弱相互作用,制备了多种类型的环二肽纳米结构,有效解决了环二肽水溶性差、易结晶的问题。更为重要的是,环二肽纳米结构的调控不仅拓宽了肽基材料的应用范围,还实现了环二肽分子的有效递送,进而提高了环二肽的生物利用度并取得良好的抗肿瘤效果。;As the backbone of most natural active products, cyclic dipeptides (CDPs) have attracted extensive attention due to their unique biological and pharmacological activities, such as anti-tumor, anti-bacterial, immune regulation and so on. As the smallest cyclic peptide compound, CDPs not only have the advantages of short peptide molecules like good biocompatibility, low immunogenicity and so on, but also circumvent the limitations of chain peptides of rapid enzymatic degradation under physiological conditions. However, it is also because CDPs molecules have excellent structural rigidity and superior ability to form hydrogen bonds that serious problems such as poorly soluble and easy to crystallize, resulting in very low bioavailability exist. In recent years, single component drug without carrier has become a promising option to overcome this problem. However, due to the particularity of CDPs structure, compared with linear structure, the controllable preparation of CDPs nanostructures is still a huge challenge. In view of the hydrogen bonds and hydrophobic action of CDPs and the interaction of the large conjugated structures of dye molecules with CDPs, different nanostructures can be prepared by self-assembly of CDPs and dye-mediated self-assembly. The research content mainly includes the following two parts:(1) A cyclic dipeptide (Cyclo-(Leu-Phe), CLF) has been developed as a versatile hydrogelator capable of self-assembly for formation of supramolecular fibrous hydrogels. The resulting hydrogels have a three-dimensional fiber network scaffold, and it can keep good gel properties in the range of 20 to 60℃. Different from the linear dipeptide, CLF is very flexible, not only for gelating pure water, but also for gelating PBS, DMEM and enzymetic solutions. We have found that the superior gelation capability is mainly derived from the inherent intermolecular hydrogen bonding interactions between CLF peptides. The hydrophobic effect may assist the molecular aggregation against water. The resulting hydrogels show excellent stability, adjustable rheological properties and high survivability against extreme conditions, which provides opportunities to develop advanced soft materials for biomedical and engineering applications.(2) The CDPs nanoribbon with good dispersibility in aqueous solution was obtained by dye-mediated hydrophobic self-assembly, further combined with intermolecular hydrogen bond and π-π stacking. Amphiphilic dye molecules not only provide strong hydrophobic interaction for the formation of cyclic dipeptide nanoribbon, but also provide enough electrostatic repulsion to stabilize the formed assembly. The shape and size of CDPs nanoribbon can be controlled, and different lengths of nanofibers and nanoribbon could be obtained by adjusting kinetic parameters. At the same time, the structure of nanoribbon promotes the uptake of CDPs, which is beneficial to the antitumor activity of CDPs. In addition, due to the use of functional dye molecules, CDPs assemblies have multiple functional modes. For example, ICG molecules have photothermal properties and can be used for photoacoustic imaging to achieve integrated diagnosis and treatment.Therefore, CDPs Nanostructures were prepared based on the regulation of weak intermolecular interactions, which solved the problem of poor water solubility and easy crystallization of CDPs. Most importantly, it not only broadened the application of peptide-based materials, but also realized the effective delivery of CDPs, thus improving the bioavailability of cyclic dipeptides and achieving good anti-tumor effect. 

Language中文
Document Type学位论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/40616
Collection中国科学院过程工程研究所
Recommended Citation
GB/T 7714
杨梦瑶. 环二肽自组装:结构调控及其在肿瘤治疗中的应用[D]. 中国科学院大学,2019.
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