可视化光热治疗用微纳米近红外吸收剂的研究

发布时间：2019-06-02 01:55

【摘要】：光热治疗是近年来发展的一种微创肿瘤治疗技术，通过激光将肿瘤局部温度升高来杀死肿瘤细胞，能够实现定点杀伤，大大降低了全身系统毒性，因此光热治疗被看作是非常有潜力替代手术的治疗肿瘤的技术之一。然而，有效的光热治疗一般需要光热治疗剂的辅助。目前的无机光热治疗剂具有较高的光热转换效率，但是由于表面修饰困难，，导致其靶向性差、携载药物困难，同时无机光热治疗剂的不可降解性也令人担忧；有机光热治疗剂一般具有良好的生物相容性，但是其较低的光热转换效率及光热稳定性、复杂的合成方法限制了其进一步应用。此外，成功的光热治疗还需要借助于合适的成像技术。所以开发具有成像功能、高靶向性和载药能力、高的光热转换效率和光热稳定性、制备方法简单的新型光热治疗剂具有重要的研究意义。针对目前硫化铜纳米粒子光热治疗剂靶向性差、携载药物困难等问题，本研究通过将硫化铜纳米粒子与微泡超声造影剂结合，实现了在超声诊断辅助下的靶向递送硫化铜纳米粒子至肿瘤部位进行有效的肿瘤光热治疗，大大提高了光热治疗的精准度与疗效。进一步根据肿瘤部位含有大量的明胶水解酶的特性，通过高碘酸盐氧化法合成了键连有化疗药物阿霉素的明胶-阿霉素共聚物，并将其作为稳定剂制备了集酶响应药物释放、光声成像与光热治疗于一体的酶响应硫化铜纳米粒子，实现了光热治疗与化疗对肿瘤组织的协同治疗，大大提高了治疗效果。为了避免无机光热治疗剂在体内长期存留所引起的潜在毒性，本研究开发了生物相容的有机聚吡咯纳米粒子作为新型具有光声成像功能的光热治疗剂。通过一步液相分散聚合法制备了形貌均一，平均粒径为~46nm的聚吡咯纳米粒子。聚吡咯纳米粒子在水溶液及生物介质中具有优良的分散性能及稳定性，与传统的光热治疗剂金纳米棒相比，具有更高的光热转换效率及光热稳定性。由于其显著的近红外光吸收特性，聚吡咯纳米粒子能够很好地对深部组织进行光声成像，体外光声成像深度达到了4.3cm，并且体内外肿瘤的光热消融实验证实了聚吡咯纳米粒子用于肿瘤光热治疗的巨大潜力。由于有机聚吡咯材料的溶解性极差，严重限制了聚吡咯材料的进一步加工应用。为了克服这一缺陷，本研究合成了可溶性的聚吡咯复合物，并通过简单的水包油乳液法制备了包裹有液态氟碳的聚吡咯微/纳米胶囊。其内部包裹的液态氟碳能够显著增强体内外超声回声信号，而聚吡咯壳层则保证了其优良的光热转换性能。制备得到的聚吡咯微/纳米胶囊在水溶液及生物介质中具有良好的分散性及升温性能，体内外的肿瘤光热消融实验证实了包裹有液态氟碳的聚吡咯微/纳米胶囊是一种新型的具有超声成像功能的多功能光热治疗剂，在肿瘤的光热治疗方面具有很大的潜力。针对简单功能模块组合得到的多功能光热治疗剂可能会增加患者在治疗时使用的药物剂量，从而加重了患者的代谢负担及潜在的全身毒副作用。本研究利用可溶性有机聚吡咯复合物与聚乙烯吡咯烷酮高分子之间的π-π共轭作用，通过一步水包油微乳液法制备了组成单一，具有超声成像功能的多功能聚吡咯空心微球光热治疗剂。聚吡咯空心微球在水溶液及生物介质中具有良好的分散性，内部的空腔使得其具有良好的超声造影增强的能力。体内外的肿瘤光热消融实验证实了在近红外激光的照射下，聚吡咯空心微球能够有效的杀死肿瘤细胞，在超声成像监测下的肿瘤光热治疗方面具有非常广阔的应用前景。综上所述，本研究通过将无机光热治疗剂硫化铜纳米粒子与微泡超声造影剂结合，实现了超声成像及靶向递送硫化铜纳米粒子至肿瘤部位进行有效的光热治疗；进一步根据肿瘤部位高含量的明胶水解酶特性，成功制备了集酶响应释放药物、光声成像与光热治疗功能于一体的酶响应硫化铜纳米粒子，并实现了光热治疗与化疗的协同作用，提高了肿瘤治疗的疗效；为了避免无机光热治疗剂在体内长期存留引起的潜在毒性，论文开发了生物相容的有机聚吡咯纳米粒子作为具有高光热转换效率及光热稳定性的多功能光热治疗剂用于光声成像与肿瘤的光热治疗；通过合成可溶性的聚吡咯复合物克服了传统聚吡咯材料溶解性差的缺陷，成功制备了集超声诊断与光热治疗功能于一体的聚吡咯微/纳米胶囊及聚吡咯空心微球，在肿瘤的可视化治疗中具有非常好的应用前景。
[Abstract]:The photothermal treatment is a minimally invasive tumor treatment technology developed in recent years, the local temperature of the tumor is increased to kill the tumor cells by laser, the fixed point killing can be realized, the toxicity of the whole body system is greatly reduced, Photothermal therapy is therefore seen as one of the most promising techniques for the treatment of tumors. However, effective photothermal treatment generally requires the assistance of photothermal therapeutic agents. The present inorganic photothermal therapeutic agent has high photothermal conversion efficiency, but due to the difficulty of surface modification, the target of the inorganic photothermal therapeutic agent is poor, the drug is difficult to carry, and the non-degradable property of the inorganic photothermal therapeutic agent is also worrying; and the organic photothermal therapeutic agent generally has good biocompatibility, But its lower photothermal conversion efficiency and light thermal stability limit its further application. In addition, successful photothermal treatment also requires the use of suitable imaging techniques. Therefore, the novel photothermal therapeutic agent with the imaging function, the high targeting property and the drug loading capability, the high photothermal conversion efficiency and the photothermal stability is of great significance to the development of the novel photothermal therapeutic agent. Aiming at the problems that the current copper sulfide nano-particle photothermal therapeutic agent has poor targeting property and drug-carrying difficulty and the like, the invention is characterized in that the copper sulfide nano-particles and the micro-bubble ultrasonic contrast agent are bonded, In addition, the targeted delivery of the copper sulfide nanoparticles to the tumor site under the aid of ultrasonic diagnosis is realized, the effective tumor photothermal treatment is carried out, the precision and the treatment of the photothermal treatment are greatly improved, And the gelatin-adriamycin copolymer with the chemotherapy drug adriamycin is synthesized by the periodate oxidation method according to the characteristic of a large amount of the gelatin hydrolase in the tumor part, and the gelatin-adriamycin copolymer with the chemotherapeutic drug adriamycin is prepared by the periodate oxidation method, and the enzyme-collecting response drug release agent is prepared as a stabilizing agent. The enzyme-responsive copper sulfide nanoparticles integrated with photo-thermal treatment and photo-thermal treatment have the advantages that the synergistic treatment of the photothermal treatment and the chemotherapy on the tumor tissue is realized, the treatment effect is greatly improved, In order to avoid the potential toxicity of the inorganic photothermal therapeutic agent in the long-term retention of the in vivo, the present study has developed a biocompatible, organic, polyorganosiloxane nanoparticles as a new photothermal imaging function the therapeutic agent is prepared by one-step liquid-phase dispersion polymerization method, The nanoparticles have excellent dispersion and stability in the aqueous solution and the biological medium, and have higher photothermal conversion efficiency and photothermal conversion compared with the traditional photothermal therapeutic agent gold nanorod. Because of its remarkable near-infrared-light absorption characteristics, the photo-acoustic imaging of the deep tissues can be well done by the nanoparticles, the depth of the photoacoustic imaging in the body reaches 4.3 cm, and the photothermal ablation of the external tumors in the body has confirmed that the poly-encapsulated nanoparticles are used in the treatment of tumor photothermal therapy. The large potential. Due to the poor solubility of the organic polyfluorocarbon material, it severely limits the advance of the polyfluorocarbon material. In order to overcome this defect, the soluble polyfluorocarbon polymer is synthesized by the present study, and the liquid fluorocarbon-coated poly-phenylene oxide is prepared by a simple oil-in-water emulsion process. / nanocapsules. The internal wrap of the liquid fluorocarbon can significantly enhance the in-vivo ultrasound echo signal, while the poly-encapsulated shell layer ensures its superior light The preparation method has good dispersibility in the aqueous solution and the biological medium, and a novel multifunctional photothermal therapeutic agent with an ultrasonic imaging function is proved by the photothermal ablation experiment of the tumor outside the body and has the advantages of being provided with a novel multifunctional photothermal therapeutic agent with an ultrasonic imaging function, The multi-functional photothermal therapeutic agent obtained for the combination of simple functional modules may increase the amount of drug used by the patient at the time of treatment, thus increasing the patient's metabolic burden and potential The present study makes use of the co-agglutination of the soluble organic polyoxometalate complex with the high molecular weight of the polyethylene and the alkanone polymer, and a single-step oil-in-water microemulsion method is adopted to prepare the multi-functional multi-functional poly-phenylene ether hollow body with the function of ultrasonic imaging. The microballoon photothermal therapeutic agent has good dispersibility in the aqueous solution and the biological medium, and the internal cavity is made to have good ultrasound. The experimental results of photothermal ablation of the tumor outside the body confirm that the hollow microspheres can effectively kill the tumor cells under the irradiation of near-infrared laser, and have a very important role in the photothermal treatment of the tumor under the ultrasound imaging monitoring. In conclusion, by combining the inorganic photothermal therapeutic agent copper sulfide nanoparticles with the microbubble ultrasound contrast agent, the ultrasonic imaging and the targeted delivery of the copper sulfide nanoparticles to the tumor site are realized. effective photothermal treatment is carried out; further, according to the characteristics of the high content of the gelatin hydrolase in the tumor site, the enzyme-responsive copper sulfide nanoparticles with the enzyme-collecting response release medicament, the photoacoustic imaging and the photothermal treatment function are successfully prepared, and the synergistic effect of the photothermal treatment and the chemotherapy is realized, in order to avoid the potential toxicity of the inorganic photothermal therapeutic agent in the long-term storage of the in vivo, the biological compatible organic polycarbodiimide nano-particles are used as a multifunctional photothermal therapeutic agent with high photothermal conversion efficiency and light thermal stability, Photo-thermal treatment of the image and the tumor is achieved; the defect of poor solubility of the traditional polycondensing agent is overcome through the synthesis of the soluble polyagglutination complex, and the polyacrylate micro/ nano glue integrating the ultrasonic diagnosis and the photothermal treatment function is successfully prepared. Vesicle and poly-encapsulated hollow microsphere, and its use in the visual treatment of tumo
【学位授予单位】：哈尔滨工业大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R318.08

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