【摘要】：電離輻射廣泛存在于太空、核設(shè)施及放射醫(yī)療過(guò)程中,對(duì)人類(lèi)生命安全造成極大的威脅,因此,研制有效的輻射防護(hù)藥物具有重要意義。GANRA藥物是本研究室前期合成的一類(lèi)新型輻射防護(hù)藥物,可以有效清除電離輻射產(chǎn)生的自由基,具有良好的輻射防護(hù)作用。但是GANRA藥物難溶于水,為之后的應(yīng)用推廣造成極大的困難。本研究利用親水性納米分子材料包裹GANRA藥物制成GANRA納米藥,顯著提高了其水溶性。為進(jìn)一步評(píng)估GANRA納米藥物的輻射防護(hù)作用,我們以淋巴母細(xì)胞(PENG-EBV)作為細(xì)胞模型,以細(xì)胞增殖率、微核率以及胞內(nèi)自由基(ROS)含量等為檢測(cè)指標(biāo),測(cè)定了GANRA納米藥對(duì)淋巴母細(xì)胞的毒性作用和輻射防護(hù)效果。結(jié)果顯示:GANRA納米藥物對(duì)細(xì)胞增殖沒(méi)有抑制作用。GANRA納米藥預(yù)處理可以顯著緩解X-射線照射引發(fā)的淋巴母細(xì)胞增殖速度降低,提高受輻照細(xì)胞的活性,降低受輻照細(xì)胞的微核形成率,并且對(duì)X-射線輻照產(chǎn)生的ROS具有良好的清除作用。前期的實(shí)驗(yàn)研究還發(fā)現(xiàn):電離輻射影響循環(huán)血中免疫相關(guān)的microRNAs(miR-150,miR-574,miR-223和miR-34a)表達(dá)。為了進(jìn)一步確定電離輻射對(duì)人淋巴母細(xì)胞中microRNAs的影響,我們檢測(cè)了不同劑量的X-射線輻照及GANRA納米藥物處理對(duì)細(xì)胞中miR-150,miR-574,miR-223和miR-34a的影響。結(jié)果顯示:X-射線輻照可以明顯改變淋巴母細(xì)胞中miR-150,miR-574,miR-223和miR-34a的表達(dá)。GANRA納米藥單獨(dú)處理可以提高淋巴母細(xì)胞中miR-150,miR-574,miR-223和miR-34a表達(dá)水平,GANRA納米藥預(yù)處理可以降低淋巴母細(xì)胞中因X-射線或~12C~(6+)輻照誘導(dǎo)的miR-150,mi R-574,mi R-223和miR-34a表達(dá)變化。最后,通過(guò)轉(zhuǎn)染miR-574類(lèi)似物,研究了miR-574對(duì)電離輻射引起的淋巴母細(xì)損傷的影響。發(fā)現(xiàn)轉(zhuǎn)染mi R-574類(lèi)似物,可以緩解淋巴母細(xì)胞因X-射線輻射導(dǎo)致細(xì)胞活性降低、微核率和細(xì)胞內(nèi)ROS水平的升高。推測(cè)GANRA納米藥可能是通過(guò)miR-574減少細(xì)胞的輻損傷并起到輻射防護(hù)作用。以上結(jié)果表明GANRA納米藥物可以作為一種有潛力的輻射防護(hù)藥物。此外,GANRA納米藥物預(yù)處理導(dǎo)致的輻射敏感miRNA的差異性表達(dá),可能是GANRA納米藥物發(fā)揮輻射防護(hù)作用的一種機(jī)制。
[Abstract]:The widespread presence of ionizing radiation in space, nuclear facilities and radiotherapeutic processes poses a great threat to the safety of human life. It is of great significance to develop effective radiation protection drugs. GannRA is a kind of new radiation protection drugs synthesized in our laboratory. It can effectively scavenge the free radicals produced by ionizing radiation and has good radiation protection effect. However, GANRA drugs are insoluble in water, causing great difficulties for later application. In this study, GANRA nanopharmaceuticals were prepared by encapsulating GANRA drugs with hydrophilic nanomolecular materials, and their water solubility was improved significantly. In order to further evaluate the radiation protection of GANRA nanopharmaceuticals, we used lymphoblastic cells (PENG-EBV) as cell model, cell proliferation rate, micronucleus rate and intracellular free radical (ROS) content as the detection index. The toxic effect and radiation protective effect of GANRA nanoparticles on lymphoblastic cells were determined. The results showed that the proliferation of lymphoblastocytes induced by X- ray irradiation was significantly reduced and the activity of irradiated cells was increased. The micronucleus formation rate of irradiated cells was decreased, and the ROS produced by X- ray irradiation was removed well. Previous studies have also shown that ionizing radiation affects the expression of immune-related microRNAs (miR-150 miR-574, miR-223 and miR-34a) in circulating blood. In order to determine the effect of ionizing radiation on microRNAs in human lymphoblastic cells, we examined the effects of different doses of X- ray irradiation and GANRA nanopharmaceutical treatment on the miR-150 miR-574 miR-223 and miR-34a in human lymphoblastoid cells. The results showed that the expression of miR-150 miR-574miR-223 and miR-34a in lymphoblastic cells could be obviously changed by the irradiation of w ~ (-) -ray. The pretreatment of miR-150 miR-574 miR-223 and miR-34a in lymphoblastocytes alone could increase the expression level of miR-150 miR-574mmiR-223 and miR-34a. Pretreatment with GANRA nanopharmaceuticals could reduce the expression of miR-150, miR-574miR-223 and miR-34a in lymphoblastocytes. The changes of expression of miR-150Mi R-574mi R-223 and miR-34a induced by X-rays or 12C6 irradiation were observed. Finally, by transfection of miR-574 analogue, the effect of miR-574 on lymphatic mother damage induced by ionizing radiation was studied. It was found that the transfection of mi R-574 analogue could alleviate the decrease of cell activity, the increase of micronucleus rate and the increase of intracellular ROS level in lymphoblastocytes induced by X- ray radiation. It is speculated that GANRA nanopharmaceuticals may reduce radiation damage and protect cells from radiation through miR-574. These results suggest that GANRA nanopharmaceuticals can be used as a potential radiation protection drug. In addition, the differential expression of radiosensitive miRNA induced by GANRA nanopharmaceuticals pretreatment may be a mechanism of radiation protection of GANRA nanopharmaceuticals.
【學(xué)位授予單位】：中國(guó)科學(xué)院大學(xué)(中國(guó)科學(xué)院近代物理研究所)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R818

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