發(fā)布時(shí)間：2018-10-23 16:39

【摘要】：傳統(tǒng)的腫瘤治療方法存在局限性,比如化療毒副作用較強(qiáng),而腫瘤中的乏氧環(huán)境又抑制了放療效果。納米材料應(yīng)用于生物醫(yī)學(xué)為腫瘤的診斷與治療提供了新的方法,它可以把多種成像方式選擇性地與治療模式結(jié)合起來。"診療一體化"——將成像與治療能力結(jié)合于同一納米材料,已廣泛應(yīng)用于藥物遞送示蹤、治療效果監(jiān)測(cè)以及成像引導(dǎo)下的治療。介孔有機(jī)氧化硅納米顆粒分散性好、尺寸均一、比表面積大、可生物降解且生物相容性高,是腫瘤診療體系的理想載體。本論文圍繞構(gòu)建基于介孔有機(jī)氧化硅的腫瘤診療一體化探針及其應(yīng)用展開了系統(tǒng)性研究,主要包括以下三方面工作:一、介孔有機(jī)氧化硅診療一體化系統(tǒng)用于腫瘤靶向成像與增效化療構(gòu)建基于含硫醚鍵的周期性蛋黃-蛋殼結(jié)構(gòu)介孔有機(jī)氧化硅(PMOs),表面穩(wěn)定連接近紅外熒光分子Cy5.5與靶向人表皮生長因子受體-2(Her2)的親合體(affibody),使之具備近紅外熒光成像及靶向Her2陽性腫瘤細(xì)胞的能力。利用納米粒子骨架內(nèi)硫醚鍵的結(jié)構(gòu),空腔內(nèi)裝載的化療藥物阿霉素(DOX)可在腫瘤細(xì)胞內(nèi)谷胱甘肽(GSH)的作用下響應(yīng)性釋放。在10mM的GSH溶液中24h內(nèi)藥物釋放量可達(dá)84.8%,是無GSH刺激條件下釋放量的兩倍多。此外,藥物還可在pH的刺激下響應(yīng)性釋放,中性環(huán)境(pH 7.4)中24 h內(nèi)藥物釋放量為31.7%,而酸性環(huán)境下(pH 5.0)24 h釋放量可達(dá)53.6%。激光共聚焦掃描顯微鏡以及細(xì)胞流式分析證明該診療系統(tǒng)可高效靶向Her2陽性腫瘤細(xì)胞并被其攝取,從而有效殺傷腫瘤細(xì)胞。同時(shí),Cy5.5具有良好的近紅外熒光成像能力,可用來監(jiān)測(cè)細(xì)胞內(nèi)藥物的分布、遞送以及釋放。同時(shí),細(xì)胞實(shí)驗(yàn)以及動(dòng)物器官組織病理切片表明該診療一體化系統(tǒng)具有良好的生物相容性,為后續(xù)生物應(yīng)用打下良好基礎(chǔ)�？傊�,該研究開發(fā)了具有靶向腫瘤細(xì)胞、近紅外熒光成像以及GSH/pH雙響應(yīng)藥物釋放能力的新型腫瘤細(xì)胞靶向成像與增效化療系統(tǒng)。二、三響應(yīng)可降解介孔有機(jī)氧化硅硫化銅診療一體化系統(tǒng)用于溫?zé)嵩鰪?qiáng)腫瘤化療熱療與化療有協(xié)同治療作用,二者的聯(lián)合治療可大幅度提高腫瘤治療效果。該研究提出溫?zé)嵝?yīng)可增強(qiáng)化療療效的新觀念,并在體外細(xì)胞與在體腫瘤模型中探討驗(yàn)證了協(xié)同治療機(jī)制。通過原位生長硫化銅的方法構(gòu)建了一種新型的基于硫化銅、周期性蛋黃-蛋殼結(jié)構(gòu)介孔有機(jī)氧化硅(CuS@PMOs)可生物降解診療一體化系統(tǒng),用于光熱轉(zhuǎn)化以及藥物遞送。制備的CuS@PMOs具有很強(qiáng)的化療藥物DOX裝載能力,高達(dá)470 mg/g。DOX的釋放可由三重刺激精確控制,包括腫瘤細(xì)胞內(nèi)高濃度的GSH、腫瘤內(nèi)酸性環(huán)境以及外部激光照射。實(shí)驗(yàn)結(jié)果表明,激光照射CuS產(chǎn)生的溫?zé)針O大提高了體外腫瘤細(xì)胞和在體腫瘤對(duì)納米顆粒的攝取,從而顯著增強(qiáng)化療療效,完全抑制了腫瘤的生長。同時(shí),DOX本身的熒光成像能力可用于監(jiān)測(cè)藥物的遞送與釋放。三、溫?zé)犴憫?yīng)性的全氟戊烷氣化用于針對(duì)乏氧腫瘤的增效放療腫瘤的乏氧環(huán)境造成對(duì)放療的耐受,因此,尋找可高效輸送氧氣至腫瘤區(qū)域的方法是解決問題的關(guān)鍵。全氟戊烷(PFP)對(duì)氧氣有強(qiáng)親和力,在體內(nèi)的沸點(diǎn)為40-50℃,構(gòu)建基于硫化銅、中空介孔有機(jī)氧化硅納米顆粒(HMON@CuS)的遞送系統(tǒng),將攜帶氧氣的PFP(O2-PFP@HMON@CuS-PEG)輸送至腫瘤區(qū)域,用于乏氧腫瘤的增效放療。激光照射后CuS產(chǎn)生的溫?zé)峥墒筆FP發(fā)生液氣相變,產(chǎn)生的氣泡不僅可以增強(qiáng)超聲成像信號(hào),還可以促進(jìn)氧氣快速釋放,推動(dòng)氧氣在乏氧腫瘤內(nèi)擴(kuò)散,細(xì)胞實(shí)驗(yàn)證明該方法可大幅度增強(qiáng)乏氧腫瘤細(xì)胞的放療療效。硅球表面螯合核素64Cu后,可利用正電子發(fā)射斷層掃描(PET)成像觀察納米顆粒在小鼠體內(nèi)的分布,實(shí)驗(yàn)結(jié)果表明納米顆粒有較長的血液半衰期,尾靜脈注射24 h后在腫瘤區(qū)域聚集達(dá)到高峰,并可持續(xù)至48 h。另外CuS還具有光聲(PA)成像能力。因此,在近紅外激光的刺激下,該診療一體化系統(tǒng)可實(shí)現(xiàn)PET/超聲/光聲三模態(tài)精確影像引導(dǎo)下的針對(duì)乏氧腫瘤的增效放療,具有很好的臨床應(yīng)用前景。
[Abstract]:Traditional methods of tumor therapy have limitations, such as the strong toxic and side effects of chemotherapy, and the spent oxygen environment in tumors also inhibits the effect of radiotherapy. The application of nano-materials in biomedicine provides a new method for diagnosis and treatment of tumor, which can combine multiple imaging methods with the treatment mode. "Integration of diagnosis and treatment" The combination of imaging and therapeutic capabilities with the same nanomaterials has been widely used in drug delivery tracing, treatment effectiveness monitoring, and imaging guided therapy. The mesoporous organic silicon oxide nano-particles have good dispersibility, uniform size, large specific surface area, biodegradability and high biocompatibility, and is an ideal carrier of the tumor diagnosis and treatment system. In this paper, a systematic study on the diagnosis and treatment of tumor diagnosis and treatment based on mesoporous organic silicon oxide is carried out, which mainly includes the following three aspects: 1. the mesoporous organic silicon oxide diagnosis and treatment integration system is used for constructing a periodic egg yolk-eggshell structure mesoporous organic silicon oxide (PMOP) based on a thioether bond for tumor target imaging and synergistic chemotherapy, The surface stably connects the near-infrared fluorescent molecule Cy5. 5 with the affinity body of the target human epidermal growth factor receptor-2 (Her2) so as to have the capability of near-infrared fluorescence imaging and targeting Her2 positive tumor cells. With the structure of the sulfide bond in the nano particle framework, the chemotherapy drug adriamycin (DOX) loaded in the cavity can be released in response to the action of glutathione (GSH) in the tumor cells. The amount of drug released within 24h of 10mM GSH solution can reach 84.8%, which is more than double the release amount under the condition of GSH-free stimulation. In addition, the release of drug in 24 h in neutral environment (pH 7.4) was 31.7% in neutral environment (pH 7.4), while the release amount of pH 5.0 was 53.6% in acidic environment (pH 5.0). Laser confocal scanning microscope and cell-flow analysis show that the diagnosis and treatment system can target Her2-positive tumor cells efficiently and can be taken up, thereby effectively killing tumor cells. At the same time, Cy5.5 has good near infrared fluorescence imaging capabilities to monitor the distribution, delivery, and release of intracellular drugs. At the same time, the cell experiment and pathological section of animal organ tissue show that the diagnosis and treatment integration system has good biocompatibility and lays a good foundation for the subsequent biological application. In summary, this study has developed a novel tumor cell targeting imaging and synergistic chemotherapy system with targeted tumor cells, near infrared fluorescence imaging, and GSH/ pH dual response drug release capabilities. secondly, the three-response degradable mesoporous organic silicon oxide thermal treatment integrated system is used for the combination therapy of hyperthermia and chemotherapy and chemotherapy, and the combination therapy can greatly improve the treatment effect of the tumor. This study suggested that the warming effect could enhance the efficacy of chemotherapy, and discussed the mechanism of synergistic treatment in vitro and in vivo tumor model. The invention discloses a novel biodegradable diagnosis and treatment integrated system based on a human body, a periodic egg yolk-eggshell structure and a mesoporous organic silicon oxide (CuS @ PMOs), which is used for photothermal conversion and drug delivery. The prepared CuS @ PMOP has strong chemotherapeutics DOX loading capacity, and the release of DOX is up to 470 mg/ g. The release of DOX can be controlled accurately by triple stimulation, including high concentration of GSH in tumor cells, acidic environment in tumor and external laser irradiation. The experimental results show that the hyperthermia produced by laser irradiation greatly improves the tumor cells in vitro and the uptake of nano-particles in body tumors, thus remarkably enhancing the curative effect of chemotherapy, and completely inhibiting the growth of the tumor. Meanwhile, the fluorescence imaging capability of DOX itself can be used to monitor drug delivery and release. Three, thermoresponsive perfluoropentane gasification is a key to solving the problem by finding a way to efficiently deliver oxygen to a tumor region due to a spent oxygen environment of a synergistic radiotherapy tumor for a spent oxygen tumor. Perfluoropentane (PFP) has a strong affinity for oxygen, the boiling point in the body is 40-50 DEG C, and a delivery system based on hydrogen cyanide, hollow mesoporous organic silicon oxide nanoparticles (HMON @ CuS) is constructed, and PFP (O2-PFP @ HMON @ CuS-PEG) carrying oxygen is delivered to the tumor area for synergistic radiotherapy of the spent oxygen tumor. The heat generated by the CuS after laser irradiation can cause the PFP to generate liquid-gas phase change, the generated bubbles can not only enhance the ultrasonic imaging signal, but also promote the rapid release of oxygen, promote the diffusion of oxygen in the spent oxygen tumor, The cell experiment proves that the method can greatly enhance the radiotherapy curative effect of the spent oxygen tumor cells. The distribution of nano-particles in mice can be observed by positron emission tomography (PET) imaging. The experimental results show that the nanoparticles have a long half-life of blood, and after 24 hours after intravenous injection, the peak is reached in the tumor area. and may continue to 48 h. Alternatively, the CuS also has an optical acoustic (PA) imaging capability. Therefore, under the stimulation of the near infrared laser, the integrated system of the diagnosis and treatment can realize the synergistic radiotherapy aiming at the spent oxygen tumor under the precise image guidance of the PET/ ultrasonic/ optical sound three modes, and has good clinical application prospect.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R730.5

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