超分子弱相互作用构筑纳米肿瘤诊疗试剂

发布时间：2018-06-30 08:08

本文选题：纳米粒子 + 聚合物　；参考：《吉林大学》2017年博士论文

【摘要】：恶性肿瘤也被称为癌症,具有治愈困难,易于转移和复发的特点,再加上传统手术、放射疗法、化学疗法等毒副作用,使得癌症的致死率非常高,因而癌症也被称为威胁人类健康的第一杀手。避开传统癌症诊疗方法的弊端,将纳米技术应用于癌症的诊疗,发展新型诊疗方法学,成为癌症治疗的又一线曙光。我的工作围绕着对超分子弱相互作用的理解,构筑具有肿瘤诊疗性能的纳米复合试剂。在第二章中,我们以15-20nm的球形金纳米粒子作为构筑基元,通过偶极吸引诱导一维链状组装体的产生,组装结构保持了金球的稳定性,并增强了在近红外光区的消光能力,在808nm处的消光系数随着组装体链长的增加而增强。为了进一步提高胶体稳定性,我还在组装体外包覆聚吡咯壳层,壳层的引入进一步增强了光热转化性能,并将复合物的光热转化效率提高到接近70%。体外的细胞实验表明,复合材料在激光照射下能够有效杀灭癌细胞,动物实验结果表明金链复合物在808nm激光照射下能够有效抑制肿瘤生长。为了防止治疗后的肿瘤复发,我们进一步将光热治疗与化疗结合将铜离子配合物负载于壳聚糖中,制备成纳米粒子。复合物纳米粒子的肿瘤抑制能力来源于光热治疗和化疗性能,其中光热治疗是通过调节铜离子周围的配体场,从而改变铜离子配合物在近红外光区的光热转化性能;化疗来源于铜离子的毒性,通过壳聚糖在体内缓慢降解逐渐释放铜离子达到化疗效果。动物实验数据表明单独的化疗肿瘤抑制率为93.1%,结合光热治疗后,热化疗能够完全消除肿瘤,并且在后续两个月的观察中没有出现肿瘤复发。为了进一步提高纳米试剂的安全性,在第三章中,我们将铜离子和铁离子通过配位作用掺杂在聚苯胺纳米梭中,制备了磁共振成像肿瘤诊断和热化疗性能的多功能试剂。过渡金属离子掺杂在四个方面对聚苯胺性能带来了提升:1.改变聚苯胺共轭能级,增强近红外光区消光;2.纳米梭表面正电性,与癌细胞产生快速粘附,有利于肿瘤滞留;3.掺杂的铜离子在巯基小分子刺激下释放,形成化疗;4.铜离子和铁离子3d轨道中存在不成对电子,可以增强纳米梭在磁共振成像T1中的造影能力。所以将纳米梭通过静脉注射到小鼠体内,结果显示静脉注射的纳米梭能够清晰标记肿瘤区域和边界,并且可以通过化疗抑制肿瘤生长,单独的化疗肿瘤抑制率为46.2%,结合光热治疗后,一次热化疗即可将肿瘤完全消除,并且两个月内未观测到复发。在第四章中,我们进一步利用聚苯胺纳米梭表面的正电性,对超分子弱相互作用于肿瘤摄取的关系进行研究。在体外,静电吸引可以使纳米梭快速粘附在细胞表面,特别是对Hela细胞。进一步在活体肿瘤模型中,静电吸引主动增强肿瘤对纳米梭的滞留,纳米梭在肿瘤区域的富集程度取决于纳米梭与癌细胞间静电吸引强度。因而,静电吸引较强的Hela肿瘤对纳米梭的富集率高达8.1%ID/g,而静电作用较弱的KB肿瘤只有3.2%ID/g;在同一只小鼠的双瘤模型中,KB和Hela肿瘤的富集率分别为2.8和7.9%ID/g。我还对比了PEG和SDS修饰后的铜离子掺杂聚苯胺纳米粒子,修饰后的纳米粒子具有对免疫系统增强的隐身效应,有利于肿瘤吞噬,但基于EPR效应的被动靶向结果仍然较静电吸引驱动的非特异性肿瘤主动靶向的效果差。另外,由于纳米梭没有通过表面修饰来增强对免疫系统的隐身效应,进入小鼠体后会在肝部大量富集,并快速代谢,保证纳米梭在使用时的安全性。
[Abstract]:Malignant tumor, also known as cancer, has the characteristics of cure difficulties, easy transfer and recurrence, combined with traditional surgery, radiation therapy, chemical therapy and other toxic side effects, which make cancer fatal, so cancer is also known as the first killer of human health. Avoid the drawbacks of traditional cancer diagnosis and treatment methods, and apply nanotechnology to the application of nanotechnology. In the second chapter, in the second chapter, we use the spherical gold nanoscale as the building element to induce one dimension through the dipole attraction. The assembly structure keeps the stability of the gold ball and strengthens the extinction ability in the near infrared light area. The extinction coefficient at 808nm increases with the increase of the length of the assembly chain. In order to further improve the colloid stability, I also assemble the polypyrrole shell in vitro. The introduction of the shell further enhanced the light and heat transfer. Experimental results show that the composite material can effectively kill the cancer cells under the laser irradiation. The results of animal experiments show that the gold chain complex can effectively inhibit the tumor growth under the 808nm laser irradiation. We will further prevent the recurrence of the tumor after the treatment, and we will further improve the tumor growth. Photothermal therapy and chemotherapy combine copper ion complexes with chitosan to prepare nanoparticles. The tumor inhibition ability of the composite nanoparticles is derived from photothermal therapy and chemotherapeutic performance, in which photothermal treatment changes the photothermal transformation of copper ion complexes in the near infrared light region by regulating the ligand field around copper ions. Yes, chemotherapy was derived from the toxicity of copper ions and gradually released copper ions through the slow degradation of chitosan in the body to achieve the effect of chemotherapy. Animal experimental data showed that the tumor inhibition rate of a single chemotherapeutic tumor was 93.1%. After photothermal therapy, chemotherapy could completely eliminate the tumor, and no recurrence was found in the follow-up for the next two months. In order to further improve the safety of nanoscale, in the third chapter, we doped the copper and iron ions in the polyaniline nanossifon by coordination, and prepared the multi-functional reagents for the diagnosis of tumor and the performance of the thermo chemotherapy. The transition metal ions doped in four sides brought about the enhancement of polyaniline performance: 1. to change polyphenylene. Amines conjugated energy levels, enhance the extinction of near infrared light area; 2. nanoscale spindle surface positively charged with cancer cells, which is beneficial to the retention of cancer cells; 3. doped copper ions are released under the small molecule stimulation of sulfhydryl groups to form chemotherapy; 4. copper ions and iron ion 3D orbit are not paired electrons, which can enhance the fabrication of nanoscale in magnetic resonance imaging (MRI). Therefore, the nanossio was injected into the mice by intravenous injection. The results showed that the intravenous nanoscale could clearly mark the tumor area and boundary, and could inhibit the tumor growth by chemotherapy. The tumor inhibition rate of the individual chemotherapy was 46.2%. After photothermal therapy, the tumor could be completely eliminated by one heat chemotherapy, and two In the fourth chapter, in the fourth chapter, we further used the positive power of the polyaniline nanoscale surface to study the relationship between the supramolecular weak interaction in the tumor uptake. In vitro, the electrostatic attraction can make the nanossies adhere to the cell surface rapidly, especially on the Hela cells. The enrichment of nanossie in tumor area depends on the electrostatic attraction between nanossie and cancer cells. Therefore, the enrichment rate of the Hela tumor with strong electrostatic attraction is up to 8.1%ID/g, while the KB tumor with weak electrostatic action is only 3.2%ID/g; in the double tumor model of the same mouse, KB The enrichment rates of the Hela and Hela tumor were respectively 7.9%ID/g. and I also compared the copper ion doped polyaniline nanoparticles modified by PEG and SDS. The modified nanoparticles have the stealth effect on the immune system, which is beneficial to the tumor, but the passive target based on the EPR effect is still more than the non specific tumor driven by the electrostatic attraction. The effect of active targeting is poor. In addition, because the nanossibon has not been modified by surface modification to enhance the stealth effect on the immune system, after entering the mouse body, it will accumulate in the liver and metabolize quickly, so as to ensure the safety of the nanoscale in use.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：TQ421.7

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