基于短肽配位自组装的纳米药物及其在肿瘤治疗中的应用

发布时间：2018-10-18 17:06

【摘要】：肿瘤治疗是当今医学界所面临的重大难题之一,其主要原因是在治疗过程中产生的巨大的毒副作用以及多药耐药性等。具有选择性好、创伤小、无耐药性等优势的光动力治疗是解决上述问题的潜在选择之一,另外,中药的多位点、多阶段的抗肿瘤机制使其在肿瘤治疗中具有高效低毒的特性而赋予其广阔的应用前景。然而,这些治疗方法存在着不同程度的问题从而限制了其临床的普遍应用和发展。例如,光动力治疗的核心元素光敏剂存在水溶性差、无靶向性的问题,在中药姜黄素化疗中,姜黄素存在生理条件易降解、生物利用度低的问题。因此,如何通过合理的设计,发挥纳米技术在药物递送方面的优势,构建理想的纳米载体和剂型,发展具有高效负载、肿瘤特异性富集和可控释放的纳米药物是解决这些问题的关键。受自然界中金属蛋白的启发,基于短肽与Zn2+的配位作用、疏水作用等弱相互作用实现纳米尺度的组装,制备出具备良好应用前景的静脉注射制剂,用于抗肿瘤治疗,其具体研究成果包括:(1)以Fmoc-His或Z-His-Phe与Zn2+为组装基元,基于羧基、咪唑基与Zn2+的配位作用以及疏水作用、π-π堆叠等弱相互作用实现纳米颗粒的可控自组装,纳米粒子尺寸均一,进一步利用Zn2+与光敏剂Ce6的配位作用,通过共组装实现高的负载率,NPs-Ce6在类细胞溶酶体的微环境中具有pH和氧化还原双重刺激响应性,迅速解组装,实现细胞内的药物释放,在体内外水平都比无载体光敏剂分子表现出增强的肿瘤靶向性和抗肿瘤效果。(2)以Zn2+与Fmoc-His和姜黄素的共配位作用为驱动力,进一步通过疏水作用、π-π堆叠等弱相互作用实现了新型的共组装体设计的突破,共组装体粒径分布均一且可以通过改变溶剂的种类实现尺寸的调控。通过一系列光谱表征了其共配位的分子结构,主要以1:1:1形式存在,共组装纳米颗粒实现了高的负载率且保证了姜黄素在生理条件下的稳定性,与对照组姜黄素单体相比,在细胞水平及体内水平上都表现出增强的肿瘤靶向性和抗肿瘤效果。因此,短肽和Zn2+调控药物共组装设计的纳米颗粒在药物有效递送、提高生物利用度和降低毒副作用等方面都具有显著的效果,有效地解决了光敏剂和中药姜黄素等药物在抗肿瘤光动力治疗和化疗中的问题。
[Abstract]:Cancer therapy is one of the most difficult problems in the medical field nowadays. The main reasons are the huge side effects and multidrug resistance in the course of treatment. Photodynamic therapy with advantages of good selectivity, little trauma and no resistance to drug resistance is one of the potential options to solve the above problems. In addition, there are many sites in traditional Chinese medicine. Multi-stage anti-tumor mechanism makes it have the characteristics of high efficiency and low toxicity in tumor therapy and gives it a broad application prospect. However, these treatments have varying degrees of problems, thus limiting their clinical application and development. For example, Guang Min, the core element of photodynamic therapy, has poor water solubility and no targeting. In curcumin chemotherapy, curcumin is easy to degrade under physiological conditions and low bioavailability. Therefore, how to make use of the advantages of nanotechnology in drug delivery through rational design, construct ideal nano-carrier and dosage form, and develop high-efficient loading, Tumor specific enrichment and controlled release of nanopharmaceuticals are key to solve these problems. Inspired by the metalloprotein in nature, based on the weak interaction of short peptide and Zn2, the nanoscale assembly was realized, and the intravenous injection preparation with good application prospect was prepared for antitumor therapy. The specific research results include: (1) based on the coordination and hydrophobic interaction of carboxyl, imidazolyl and Zn2, 蟺-蟺 stacking, the controllable self-assembly of nanoparticles is achieved by using Fmoc-His or Z-His-Phe and Zn2 as assembly units, and the size of nanoparticles is uniform. Further more, by using the coordination of Zn2 and Guang Min Ce6, the high loading rate was achieved by co-assembly. NPs-Ce6 had the double stimulative response of pH and redox in the microenvironment of lysosomal like cells, and was rapidly unassembled to realize the release of drugs in cells. In vitro and in vivo, both of them showed enhanced tumor targeting and antitumor effect compared with vector free Guang Min molecules. (2) the cocoordination of Zn2 with Fmoc-His and curcumin was the driving force. Through hydrophobic interaction, 蟺-蟺 stacking and other weak interactions, a breakthrough in the design of a new type of co-assembly is achieved. The particle size distribution of the co-assembly is uniform and the size of the co-assembly can be adjusted by changing the type of solvent. The molecular structure of the co-coordination was characterized by a series of spectra, mainly in the form of 1:1:1. The co-assembled nanoparticles achieved high loading rate and guaranteed the stability of curcumin under physiological conditions, compared with curcumin monomer in control group. Enhanced tumor targeting and anti-tumor effects were demonstrated at both cellular and in vivo levels. Therefore, the nanocrystalline nanoparticles designed by Zn2 and short peptides have remarkable effects in drug delivery, bioavailability and toxicity reduction. It has effectively solved the problems of Guang Min and curcumin in anti-tumor photodynamic therapy and chemotherapy.
【学位授予单位】：中国科学院大学(中国科学院过程工程研究所)
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R730.5

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