高效率光热转换试剂的开发及其治疗肿瘤应用

发布时间：2018-03-27 12:26

本文选题：光热治疗　切入点：光热转换试剂　出处：《东华大学》2016年博士论文

【摘要】：光热治疗技术是近年来新兴发展的一种肿瘤治疗方法,其工作原理是:利用对生物组织有较好通透性的近红外光(NIR)照射光热转换试剂,在局部位置生成“高热”并诱导癌细胞死亡、肿瘤坏死。该技术因具有简便、可控、副作用小等特点而备受青睐。光热转换试剂是光热治疗技术革新的关键。随着纳米科技的不断发展,纳米材料在光热治疗研究中取得了越来越广泛的应用。一些具有NIR响应的纳米材料和功能复合物被陆续报道并用于光热治疗和联合治疗肿瘤当中。本论文首先简要介绍光热治疗技术,并对光热转换试剂可能存在的光吸收机制进行了小结,然后对近几年来光热转换试剂取得的重要进展进行评论,以期为开发更加低毒、高效、功能多样的光热转换试剂提供有益参考。在此基础上,就光热转换试剂存在的某些问题,如光热转换效率低、合成复杂且毒性大、功能单一,开展了以下几方面的具体工作:(1)亲水性、高光热转换效率的Bi_2S_3纳米花的调控合成及热消融癌细胞应用目前报道的铋基材料光热转换效率较低。本论文利用一步溶剂热法分别制备了亲水性的Bi_2S_3纳米花和Bi_2S_3纳米带。研究发现,反应中加入合适量的聚乙烯吡咯烷酮(PVP)后,不但导致Bi_2S_3纳米材料的形貌从纳米带状转变成尺寸均匀的纳米花,而且还对其胶体分散性、结晶度以及NIR吸收都有很大改变。在相同实验条件下的808 nm激光器照射下,Bi_2S_3纳米花的光热转换效率高达64.3%,几乎是Bi_2S_3纳米带(ηT=36.5%)的两倍,比金纳米棒也要高(ηT=54.3%)。将Bi_2S_3纳米花用于808 nm激光驱动的光热治疗中,在体内外都能够快速诱导癌细胞死亡。Bi_2S_3纳米花高效的光热转换效率可以归功于以下三个方面:首先,Bi_2S_3纳米花在激发波长(808 nm)处具有很强的吸收,其质量吸收系数达20.5L?g~(-1)?cm~(-1);其次,Bi_2S_3纳米花的三维超结构和大比表面,增强了光电子在材料表面的反射、折射、吸收等作用,延长了其与材料相互作用的时间,进一步提高了材料对光电子的利用率;最后,Bi_2S_3纳米花具有更窄的能量带隙(Eg=0.79 e V),可以提高材料对低能量光的利用率。这些有效提高光热转换效率的策略,将为开发具有高光热转换效率的新型光热转换试剂提供有益的借鉴。(2)水合氧化钌光热转换试剂的开发及其光热治疗肿瘤应用基于绿色环保合成纳米材料的考虑,利用一步水热法,通过RuCl_3?xH_2O在水相中水解制备了具有较好NIR吸收的水合氧化钌(RuO_2?xH_2O)纳米粒子。RuO_2?xH_2O纳米粒子的近红外光吸收可能与RuO_2晶体对水或质子的吸附/脱附作用有关。因为H2O或H+的吸/脱附作用可以使Ru元素的化学环境发生改变,导致Ru在多种价态电子对中发生电子跃迁,从而使RuO_2?xH_2O纳米材料在水溶液中拥有较强的近红外光吸收。PVP改性后的RuO_2?xH_2O纳米材料(PVP-RuO_2)在生理介质中有良好的分散性及生物相容性,其在808 nm激光诱导下的光热转换效率为54.8%,在体内外都可以快速升温并杀死癌细胞,并完全抑制肿瘤生长。因此,水合氧化钌可以作为一类新型的潜在光热转换试剂用于癌症的热疗。(3)核壳结构的FeWO_4@PPy纳米复合材料的制备及在肿瘤诊疗中的应用成像诊断可以指导癌症的治疗。根据报道,聚吡咯(PPy)是一种生物相容性好的可降解有机光热转换试剂,但性能简单;FeWO_4是一种潜在的MRI/CT双模造影成像剂,但光热转换性能差。将这两种廉价易得的材料复合构成具有成像诊断和光热治疗的多功能纳米复合物,在诊疗癌症方面具有潜在应用价值。本论文首先用水热法合成了FeWO_4纳米材料,再用原位聚合的方法在其表面包覆了一层聚吡咯,制备了一种无机/有机杂化的核壳结构的FeWO_4@PPy纳米复合材料。FeWO_4@PPy纳米复合材料在溶液中获得了较好的MRI/CT双模成像造影效果,其横向弛豫率r2为1.46 m M~(-1)?s~(-1),对X射线衰减系数为12.99HU?m M~(-1),而后者比碘海醇的衰减系数还高(5.74 HU?m M~(-1))。因此,将FeWO_4@PPy纳米复合材料注射到荷瘤鼠后,实现了对He La肿瘤的MRI/CT成像信号的增敏作用,提高了肿瘤的辨识度。血液循环代谢和组织分布研究表明,静脉注射的FeWO_4@PPy纳米复合材料,4小时内可以完全从血液中清除,在网状内皮系统有很高的富集,如肝脏(67.2±1.8%ID/g)和脾脏(33.1±5.0%ID/g)。由于肿瘤特有的高通透及滞留(EPR)效应,纳米复合材料在He La肿瘤中也有一定的富集率(1.2±0.4%ID/g)。在808 nm激光诱导下,该纳米复合材料可以产生足够高温(光热转换效率为56.1%)并杀死癌细胞,完全抑制肿瘤生长。因此,FeWO_4@PPy纳米复合材料在癌症的多模成像诊断和光热治疗中展现了巨大的应用潜力。
[Abstract]:The light and heat treatment technology is a new method for the treatment of tumor development in recent years, its working principle is: the use of a good permeability near infrared (NIR) radiation on biological tissue photothermal conversion reagent, locally generated "high fever" and induce cancer cell death and tumor necrosis. The technology has a simple, controllable, side the role of small favored. Photothermal conversion reagent is the key innovation of photothermal therapy technology. With the development of nano technology, nano materials has been more and more widely used in photothermal therapy research. Some have NIR ring nano materials and functional composites should be reported and used in photothermal therapy and combined treatment of tumors. This paper first briefly introduces photothermal therapy technology, and the possible photothermal conversion reagent absorption mechanism were summarized, and in recent years the photothermal conversion kit Important progress of comments, in order to develop more efficient, low toxicity, provide a useful reference reagent photothermal conversion of functional diversity. On this basis, some problems exist on the photothermal conversion reagent, such as photothermal conversion efficiency is low, the synthesis of complex and high toxicity, single function, carry out the following works: (1) hydrophilic, high light heat conversion efficiency Bi_2S_3 nanoflower control synthesis and thermal ablation of bismuth based photothermal cancer cell applications currently reported lower conversion efficiency. This paper made hydrophilic Bi_2S_3 nanoflower and Bi_2S_3 nanobelts were prepared by one-step solvothermal method. The study found that adding appropriate amount of in the reaction of polyvinylpyrrolidone (PVP), which not only led to the morphology of Bi_2S_3 nano materials from nano ribbon into nano uniform size of flowers, but also on the dispersion of the colloid, crystallinity and NIR absorption are greatly Change. In the same experimental conditions 808 nm laser irradiation, the photothermal conversion efficiency of Bi_2S_3 nano flowers up to 64.3%, almost Bi_2S_3 nanoribbons (n T=36.5%) two times, also higher than the gold nanorods (T=54.3%). Bi_2S_3 nano flower for light heat treatment of 808 nm laser driver. Can rapid photothermal induced cancer cell death.Bi_2S_3 nanoflower high conversion efficiency can be attributed to the following three aspects: firstly, both in vitro and in vivo Bi_2S_3 nanoflower at excitation wavelength (808 nm) with strong absorption, the absorption coefficient of 20.5L? G ~ (-1) cm~ (-1); second? Bi_2S_3, nano flowers three-dimensional super structure and high surface area, enhanced photoemission in material surface reflection, refraction, absorption, extend its interaction with material time, further improve the utilization rate of materials on the photoelectron; finally, Bi_2S_3 nanoflowers have narrower The energy band gap (Eg=0.79 e V), can improve the material utilization of the low energy light rate. These can effectively improve the thermal efficiency of the strategy, will develop new high light heat conversion efficiency of the solar thermal conversion kit provided useful reference. (2) the development of hydrated ruthenium oxide and photothermal photothermal conversion reagent used to treat tumor based on the green synthesis of nano materials, using a one-step hydrothermal method by RuCl_3? XH_2O in aqueous solution was prepared by hydrolysis with hydrated ruthenium oxide better absorption of NIR (RuO_2? XH_2O).RuO_2 nanoparticles? Near infrared absorption of xH_2O nanoparticles and RuO_2 crystal of water or proton adsorption / desorption effect because H2O or H+ adsorption / desorption effect can make the chemical environment of Ru elements changed, resulting in a variety of Ru valence electron pair in the electronic transition, so that the RuO_2? XH_2O nanoparticles in aqueous solution. A near infrared absorption.PVP modified RuO_2 strong? XH_2O nano materials (PVP-RuO_2) in physiological medium dispersion and good biological compatibility, the 808 nm laser induced photothermal conversion efficiency of 54.8%, both in vivo and in vitro can quickly heat up and kill cancer cells, and inhibit the tumor completely growth. Therefore, hydrous ruthenium oxide can be used as a new type of potential photothermal conversion reagent for the treatment of cancer. (3) FeWO_4@PPy nanocomposites with core-shell structure of the preparation and application of imaging in diagnosis and treatment of cancer diagnosis can guide the treatment of cancer. According to reports, polypyrrole (PPy) is a biocompatible good degradable organic photothermal conversion reagent, but the performance is simple; FeWO_4 is a potential MRI/CT dual-mode imaging agent, but the conversion of poor performance. The two kinds of cheap materials constitute the imaging diagnosis and light Multifunctional nano composite heat treatment, has the potential application value in the diagnosis and treatment of cancer. This paper first hydrothermal method FeWO_4 nanomaterials were synthesized by in situ polymerization method, coated with a layer of polypyrrole on the surface, the preparation of a novel inorganic / organic hybrid core-shell FeWO_4@PPy nanocomposite.FeWO_4@PPy nano composite the material has a better MRI/CT dual-mode imaging contrast effect in solution, the transverse relaxation rate of R2 was 1.46 m M~ (-1)? S~ (-1), X ray attenuation coefficient is 12.99HU? M M~ (-1), and the latter is higher than the attenuation coefficient of iohexol (5.74 HU? M M~ (-1)). Therefore, the injection of FeWO_4@PPy nano composite materials to tumor bearing mice after the sensitization of MRI/CT imaging signal on He La tumor, improve the tumor identification. The blood circulation metabolism and tissue distribution studies showed that intravenous injection of FeWO_4@PPy nano complex The material, within 4 hours can be completely removed from the blood, in the reticuloendothelial system has very high enrichment, such as liver (67.2 + 1.8%ID/g) and spleen (33.1 + 5.0%ID/g). The tumor specific high permeability and retention (EPR) effect, nano composite materials have a certain accumulation rate in He La tumors (1.2 + 0.4%ID/g). In the 808 nm laser induced by the nano composite material can produce enough high temperature (photothermal conversion efficiency of 56.1%) and kill cancer cells, completely inhibited tumor growth. Therefore, FeWO_4@PPy nanocomposites show great potential applications in the diagnosis and treatment of cancer in multimode photothermal imaging.

【学位授予单位】：东华大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.5

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