FePt/GO纳米复合材料在放化疗中的应用

目的:探索FePt/GO纳米复合材料的抗肺癌效果。方法:通过化学还原的方法制备出径粒约为3 nm的Fe Pt纳米颗粒,并通过超声将Fe Pt纳米颗粒装载于氧化石墨烯(GO)表面得到FePt/GO纳米复合材料,运用TEM、AFM、XPS等技术对其进行表征。将得到FePt/GO纳米复合材料分别与非小细胞肺癌细胞(H1975)和人胚肺成纤维细胞(HELF)共同培养,用CCK-8法对其进行毒性评估;通过单细胞克隆形成实验与CCK-8法评估FePt/GO复合纳米材料的放射增敏作用。结果:成功制备出FePt/GO纳米复合材料,在一定浓度范围内,FePt/GO对H1975细胞表现出很明显的毒性而对正常HELF细胞无明显毒性,并且可以有效地增强X射线对H1975细胞的杀伤作用。结论:FePt/GO纳米复合材料是一种有可能用于临床的抗癌药物。     

高Z纳米介质放射增敏的宏观剂量效应评价及其局限

目的：建立高Z纳米介质对X—γ射线和质子／重离子的宏观剂量增强效应模型,讨论其评价高Z纳米介质放射增敏效应的局限性。方法：基于宏观剂量学的质能吸收系数、质量阻止本领、电子阻止本领以及传能线密度（LET）概念,推导组织内均匀分布的高Z纳米介质对X-γ光子、质子或重离子的宏观剂量增强比;分析剂量增强比随射线能量、纳米介质原子序数和组织内含量的变化规律;对比放射增敏比实验研究结果,讨论宏观剂量学模型评价高Z纳米介质放射增敏效应的局限性。结果：宏观剂量学分析表明高Z纳米介质可以对X-γ射线和质子／重离子产生宏观剂量增强效应,但基于多重均匀化假设的宏观剂量增强比计算结果对实际放射增敏效应有明显低估。结论：高Z纳米介质放射增敏的准确量效关系需建立严格的微观剂量学模型评价,微观剂量学模型需要考虑四方面因素：（1）次级电子局域剂量分布;（2）纳米颗粒非均匀团聚分布;（31纳米颗粒亚细胞分布：（4）局域剂量的自由基效应。     

纳米壳聚糖对重离子的放射增敏和防护作用******◆

背景：相关研究表明壳聚糖能够提高机体免疫力,具有辐射保护作用。 目的：研究在重离子放疗中纳米壳聚糖对肿瘤细胞的放射增敏作用和对骨细胞的防护作用。 方法：MTT法检测纳米壳聚糖对人鼻咽癌KB细胞重离子辐射的增敏作用、对鼠成骨细胞MC3T3-E1细胞重离子辐射的防护作用。 结果与结论：纳米壳聚糖对人鼻咽癌KB细胞具有放射增敏作用,随着纳米壳聚糖剂量的增加,重离子对肿瘤细胞的杀伤作用显著增强,同时也发现壳聚糖可增强鼠成骨细胞对重离子辐射损伤的耐受性。说明纳米壳聚糖具有对肿瘤细胞放射增敏和对正常组织细胞辐射防护的双重作用。 关键词：纳米壳聚糖;重离子;人鼻咽癌KB细胞;鼠成骨细胞MC3T3-E1细胞;放射增敏 doi:10.3969/j.issn.1673-8225.2012.03.006     

甲氟喹对胶质瘤细胞的放射增敏作用

目的:研究甲氟喹对胶质瘤细胞的放射增敏作用,并对其机制进行初步探索。方法:取指数生长期的胶质瘤U251细胞,采用CCK-8检测法研究甲氟喹作用后U251细胞的存活率;细胞克隆形成实验评估甲氟喹对U251细胞的放射增敏效果;流式细胞技术检测甲氟喹联合X射线作用后U251细胞的活性氧水平和细胞凋亡率,探索联合作用下U251细胞的死亡机制。结果:甲氟喹对胶质瘤细胞具有良好的放射增敏效果,其对U251细胞的最大放射增敏比为1.64。X射线联合甲氟喹作用于U251细胞后,细胞的凋亡水平增加,活性氧水平增加,活性氧抑制剂谷胱甘肽能抑制X射线联合甲氟喹作用诱导的U251细胞凋亡。结论:甲氟喹对U251细胞有放射增敏作用,其作用机制可能为通过增加细胞活性氧水平、诱导细胞凋亡导致放射敏感性增加。     

纳米复合材料GO@AgPt对非小细胞肺癌的放射增敏作用

目的:制备新型纳米复合材料GO@AgPt，探究其对非小细胞肺癌的放射增敏效果。方法:通过改进型的水热法合成纳米复合材料GO@AgPt，通过透射电子显微镜、原子力显微镜、X射线光电子能谱分析、傅里叶红外光谱仪等方法对材料进行形貌及组分分析。应用细胞活性检测试剂盒CCK-8检测材料对肺癌细胞A549和人肺微血管细胞HPMEC的细胞活性的影响；然后通过流式检测及细胞克隆形成实验探究材料对于A549细胞的放射增敏效果。结果:成功制备出粒径大小均匀、化学成分稳定的纳米复合材料GO@AgPt。在一定浓度范围内该材料对肺癌细胞A549有毒性而对正常细胞HPMEC没有明显毒性。该材料能促进癌细胞产生活性氧，与X射线联合作用能促进细胞的凋亡。细胞克隆形成的结果也显示该材料对肺癌细胞具有放射增敏效果。结论:成功制备了纳米复合材料GO@AgPt，证明了该材料对于非小细胞肺癌有明显的放疗增敏效果。     

新型MRI/CT双模态造影剂Au/Fe_3O_4复合纳米团簇制备及表征

目的制备一种新型的MRI/CT双模态Au/Fe3O4复合纳米团簇造影剂,并对其相关性能进行研究。方法利用高温有机热分解法制备粒径可控且分散性良好的Au、Fe3O4纳米颗粒并合成两亲性聚乙二醇-聚乳酸（mPEG-PLA）嵌段共聚物。通过组装的方法以mPEG-PLA为纽带,将Au和Fe3O4纳米颗粒组装为复合纳米团簇。并利用透射电子显微镜（TEM）、X射线能谱仪（EDS）和动态光散射（DLS）分别对所制备纳米团簇的形貌、组成、尺寸及稳定性进行表征。研究不同的组装条件对纳米颗粒的包覆效率（EE）、装载能力（LC）及相应的MRI和CT成像效果的影响。结果制备的Au、Fe3O4纳米颗粒呈球形,分散性、均一性良好,平均粒径分别为7.25nm、9.00nm。两亲性聚合物mPEG-PLA相对分子质量约为11000。为了优化复合纳米团簇的EE和LC及磁学特性,制备Au、Fe3O4纳米颗粒不同配比的纳米团簇。随着Au纳米颗粒比重的增加,mPEG-PLA对纳米颗粒的EE和LC呈现先增加后降低又增加的趋势。通过对其横向弛豫率测量证明,该造影剂缩短T2时间效果明显,并随着Fe3O4纳米颗粒比重的提高,横向弛豫率呈现升高趋势。MRI研究证明,MRI信号强度的改变随Fe3O4纳米颗粒比重的提高而增强。而micro-CT成像研究则表明,随Au纳米颗粒比重的提高,成像效果越明显。结论利用该方法制备出的造影剂粒径可控,稳定性良好,具备良好的MRI/CT造影性质,具有潜在的临床使用价值。     

P162对食管癌细胞株Eca109的放射增敏作用及其对p75NTR表达的影响

 目的：研究靶向Ras-GTP酶激活蛋白SH3功能区结合蛋白(G3BP)的新药P162对人食管癌细胞株Eca109的放射增敏作用及其对p75神经营养因子受体(p75NTR)表达的影响。方法：CCK-8法检测P162对食管癌细胞株Eca109增殖抑制的影响;集落形成实验检测P162对Eca109细胞的放射增敏效应,单击多靶模型拟合细胞存活曲线并计算放射增敏比;倒置显微镜观察细胞形态学改变;流式细胞术检测p75NTR的表达。结果：P162对食管癌细胞株Eca109有增殖抑制作用,且呈时间和剂量依赖性,2.5、5.0、10 μmol/L P162对Eca109细胞的放射增敏比分别为1.54、2.35和2.33。随着照射剂量的增加,食管癌细胞中p75NTR的表达增加,经5 μmol/L P162处理的实验组中p75NTR的表达明显低于未经处理的对照组。结论：P162对Eca109细胞有放射增敏作用,并且能抑制食管癌干细胞p75NTR的表达。P162的增敏作用可能与抑制食管癌干细胞有关。     

2-甲氧雌二醇对人肺癌细胞的放射增敏作用

目的:探讨2-甲氧雌二醇(2-ME)对肺癌细胞A549和GLC-82的放射增敏作用及其对细胞周期的影响,并从分子角度初步探讨2-ME可能的增敏机制。方法:将体外培养的人肺癌细胞A549和GLC-82分为实验组和对照组,其中实验组加入不同浓度的2-ME,对照组不含2-ME。通过MTT法定量检测2-ME对2株细胞增殖的抑制作用,集落形成实验测定2-ME对这2株细胞的放射增敏作用,流式细胞术检测细胞周期分布的变化,通过免疫沉淀法检测细胞周期素依赖性蛋白激酶2(CDK2)活性的改变。结果:分别以2-ME对人肺癌细胞GLC-82和A549的最小有效浓度(0.15625×10-6mol/L和1.25×10-6mol/L)作为放射增敏浓度,均可增加细胞对X线的敏感性,2株细胞存活曲线均见2-ME增敏组比单纯照射组整体下移,D0、Dq值均降低,增敏比:GLC-82细胞为1.98;A549细胞为2.06。细胞周期的检测表明2-ME使细胞周期阻滞于G2/M期,并呈剂量依赖性。2-ME作用后2株细胞CDK2活性均无明显改变。结论:2-ME可通过对细胞周期的调节增加非小细胞肺癌(NSCLC)细胞GLC-82和A549对射线的敏感性。     

黄岑苷对宫颈癌细胞株HeLa的放射增敏作用

 目的: 探讨黄岑苷对宫颈癌细胞株HeLa的放射增敏作用及机制。方法: MTT法检测不同浓度黄岑苷对HeLa细胞的活力抑制能力,并计算IC₅₀筛选实验药物浓度;克隆形成实验检测放射组与联合组在不同照射剂量下细胞的放射增敏作用;流式细胞术检测单药组、放射组与联合组的细胞周期变化;Western blot检测不同组细胞中Akt、p-Akt、Bad和p-Bad的蛋白水平。结果: 黄岑苷呈浓度依赖性抑制HeLa细胞的活力,IC₅₀为43.65 mg/L,采用20% IC₅₀浓度8 mg/L进行放射增敏实验。克隆形成实验结果显示8 mg/L黄岑苷联合放射治疗可使生存曲线左移,D0、Dq值显著小于放射组(P<0.05)。流式细胞仪检测结果显示黄岑苷阻滞HeLa细胞于G₂/M期。联合组细胞中p-Akt和p-Bad的蛋白水平均显著高于其它各组(P<0.05)。结论: 黄岑苷对HeLa细胞具有放射增敏作用,其机制可能与其阻滞细胞于G₂/M期和活化PI3K/Akt信号通路有关。     

高Z重金介质的肿瘤放疗增敏效应研究现状

目的：探讨高Z重金介质的放射剂量增强效应及其应用于肿瘤放疗增敏的研究历史、当前进展与未来发展方向。方法：全面检索高Z介质表面/界面的剂量效应及其用于肿瘤放疗增敏的早期研究和最新报道。针对近年来开展的重金介质放疗增敏相关研究,按照放疗射线类型和增敏效应研究手段分别进行总结述评,以把握该领域的发展历史和研究现状,并对现存的问题进行讨论和展望。结果：目前针对高Z重金介质的放疗增敏研究主要包括质粒DNA辐照、体外细胞辐照、动物肿瘤模型试验以及剂量学模拟等手段。针对传统X-γ射线放疗的增敏效应研究最为深入,针对同步辐射放疗、质子重离子放疗等先进放疗技术的重金增敏研究也有开展。研究结果已充分证明了重金介质的放射增敏效应及其用于肿瘤放疗增敏的可行性,为临床前试验的进一步开展提供了重要的理论和实验依据。结论：高Z重金介质的肿瘤放疗增敏效应研究近年来取得了较快的进展,部分研究已从增敏效应验证进入放疗试验的增敏参数优化和作用机理研究阶段,为实现其在临床肿瘤放疗中的应用,增敏效应的微观作用机理是必须深入研究的重要课题。     

Multifunctional FePt Nanoparticles for Radiation-Guided Targeting and Imaging of Cancer

A multifunctional FePt nanoparticle was developed that targets tumor microvasculature via “radiation-guided” peptides, and is detected by both near-infrared (NIR) fluorescence imaging and analytical mass spectrometry methods. Tumor specific binding was first measured by biotinylated peptide linked to fluorophore-conjugated streptavidin. This showed tumor selective binding to tumors using the HVGGSSV peptide. FePt nanoparticles were synthesized sequentially by surface modification with poly(l)lysine, poly(ethylene) glycol conjugation, and functionalized with HVGGSSV peptide and fluorescent probe Alexa fluor 750. NIR fluorescence imaging and ICP-MS analysis showed significant HVGGSSV-FePt nanoparticle binding to irradiated tumors as compared to unirradiated tumors and controls. Results indicate that multifunctional FePt nanoparticles have potential application for radiation-guided targeting and imaging of cancer.     

Neoadjuvant treatment with docetaxel and the effects of irradiation for human ovarian adenocarcinoma and cervical squamous cell carcinoma in vitro

The in vitro radiosensitizing effects of docetaxel have been reported, but the DNA damage caused by the irradiation after docetaxel exposure has not been investigated. In this study, the authors attempted to evaluate the radiosensitizing effects in terms of cell survival and DNA single-strand breaks in a human ovarian adenocarcinoma cell line (known as line BG-1) and a human cervical squamous cell carcinoma cell line (known as line SiHa). The cell lines were exposed to various concentrations of docetaxel (from 2.27 x 10(-3) to 2.27 microg/ml) to investigate the cytocidal effects by colony-formation assay. DNA single-strand breaks after exposure to 2.27 microg/ml of docetaxel for 30 min or 100 min were measured by the alkaline-elution assay. The remarkable cytotoxicity of docetaxel followed by irradiation was observed when concentrations were greater than 2.27 x 10(-2) microg/ml in both cell lines. The combination of docetaxel and irradiation appears to be supraadditive. The DNA single-strand breaks induced by the irradiation were enhanced in both cell lines (BG-1; P < 0.01, SiHa; P < 0.05). The synergistic cytocidal effect cannot be explained quantitatively only by the single-strand breaks.     

空气介质阻挡辉光放电增强硅橡胶/铁质纳米复合材料的表面亲水性

背景：医用硅橡胶的固有缺点是X射线显影性能欠佳和表面疏水性。添加显影标记物铁质纳米微粒可赋予硅橡胶X射线影像可视性的功能,铁质纳米微粒本体改性硅橡胶表面湿润性的变化尚不清楚,设想表面处理以提高硅橡胶/铁质纳米微粒复合材料的亲水性。 目的：观察硅橡胶/铁质纳米微粒复合材料表面湿润性、亲水改性及表征。 方法：使用空气介质阻挡辉光放电分别对前期制备出的配方比为95∶5,90∶10,85∶15的硅橡胶/纳米铁(INESR)和硅橡胶/碳包铁(Fe/CESR)复合材料表面进行改性,对照组为甲基乙烯基硅橡胶(MVSR)。 结果与结论：INESR和Fe/CESR与MVSR相比,表面水接触角减小幅度不大,疏水性未获得明显改善。经空气介质阻挡辉光放电对硅橡胶/铁质纳米微粒复合材料处理后,表面的亲水性得到较大提高,不同配方比INESR和Fe/CESR的水接触角均降低(P < 0.05);扫描电镜显示改性使试件表面受到刻蚀,粗糙度增加,但无空洞或裂隙;X射线光电子能谱分析表明材料表面的化学成分均发生变化,含氧基团大幅增加,含碳基团则明显减少,含硅基团小幅增加,出现含氮基团,说明改性使氮元素被结合到试件的表面,空气介质阻挡辉光放电处理硅橡胶/铁质纳米微粒复合材料的表面可实现亲水改性。     

Utilization of iron-catecholamine complexes involving ferric reductase activity in Listeria monocytogenes.

Listeria monocytogenes is a ubiquitous potentially pathogenic organism requiring iron for growth and virulence. Although it does not produce siderophores, L. monocytogenes is able to obtain iron by using either exogenous siderophores produced by various microorganisms or natural catechol compounds widespread in the environment. In the presence of tropolone, an iron-chelating agent, growth of L. monocytogenes is completely inhibited. However, the growth inhibition can be relieved by the addition of dopamine or norepinephrine under their different isomeric forms, while the catecholamine derivatives 4-hydroxy-3-methoxyphenylglycol and normetanephrine did not relieve the inhibitory effect of tropolone. Preincubation of L. monocytogenes with chlorpromazine and yohimbine did not antagonize the growth-promoting effect of catecholamines in iron-complexed medium. In addition, norepinephrine stimulated the growth-promoting effect induced by human transferrin in iron-limited medium. Furthermore, dopamine and norepinephrine allowed 55Fe uptake by iron-deprived bacterial cells. The uptake of iron was energy dependent, as indicated by inhibition of 55Fe uptake at 0 degrees C as well as by preincubating the bacteria with KCN. Inhibition of 55Fe uptake by L. monocytogenes was also observed in the presence of Pt(II). Moreover, when assessed by a whole-cell ferric reductase assay, reductase activity of L. monocytogenes was inhibited by Pt(II). These data demonstrate that dopamine and norepinephrine can function as siderophore-like compounds in L. monocytogenes owing to their ortho-diphenol function and that catecholamine-mediated iron acquisition does not involve specific catecholamine receptors but acts through a cell-bound ferrireductase activity.     

In vivo Characterization of the Radiosensitizing Effect of a Very Low Dose of BrdU in Murine Cells Exposed to Low-Dose Radiation

The aim of the present study was to characterize the in vivo radiosensitizing effect of a very low dose of bromodeoxyuridine (BrdU) in mice exposed to low-dose radiation by establishing the following: (1) the radiosensitizing effect during DNA synthesis using single-cell gel electrophoresis (SCGE) in murine bone marrow cells, and (2) the number and timing of the mechanisms of genotoxicity and cytotoxicity, as well as the correlation of both end points, using flow cytometry analysis of the kinetics of micronucleus induction in reticulocytes. Groups of mice received intraperitoneal injections of 0.125 mg/g of BrdU 24 h prior to irradiation with 0.5 Gy of ⁶⁰Co gamma rays. DNA breaks measured using SCGE were determined at 30 min after exposure to radiation. The kinetics of micronucleated reticulocyte (MN-RET) induction was determined every 8 h after irradiation up to 72 h. The results from both experimental models indicated that low-level BrdU incorporation into DNA increased the sensitivity to 0.5 Gy of radiation, particularly in the S phase. The formation of micronuclei by gamma rays was produced at three different times using two main mechanisms. In the BrdU-substituted cells, the second mechanism was associated with a high cytotoxic effect that was absent in the irradiated BrdU-unsubstituted cells. The third mechanism, in which micronucleus formation was increased in irradiated substituted cells compared with the irradiated nonsubstituted control cells, was also related to an increase in cytotoxicity. Environ. Mol. Mutagen. 60:534–545, 2019. © 2019 Wiley Periodicals, Inc.     

载顺铂超顺磁γ-Fe2O3纳米粒子的制备与表征*☆

背景：将化疗药物联接在磁性纳米载体上,在外加磁场的引导下使所载药物定向集中于靶向治疗部位,在增强疗效同时还可降低毒性不良反应。 目的：制备海藻酸钠改性的磁性纳米粒子及其负载顺铂药物,分析产物的磁学性质。 方法：通过Fe2+在乙醇胺水溶液中一步合成磁性纳米粒子,用海藻酸钠作偶联剂使磁性纳米粒子与顺铂相连,制备磁性纳米粒子药物。 结果与结论：X射线衍射花样证明产物为γ-Fe2O3纯相,透射电子显微镜表明磁性纳米粒子直径平均约10 nm,载顺铂后药物包覆于纳米粒子周围,磁化曲线显示纳米粒子为超顺磁性,核磁共振得到纳米粒子的弛豫率为0.116 02 mmol/ms。表明所制备磁性纳米粒子及其载顺铂超顺磁性纳米粒子药物性质稳定,具有作为磁性纳米粒子药物的特性。 关键词：磁性纳米粒子药物;顺铂;超顺磁性;Fe2O3;生物材料与药物控释 doi:10.3969/j.issn.1673-8225.2012.12.011     

Photonuclear dose calculations for high-energy photon beams from Siemens and Varian linacs

The dose from photon-induced nuclear particles (neutrons, protons, and alpha particles) generated by high-energy photon beams from medical linacs is investigated. Monte Carlo calculations using the MCNPX code are performed for three different photon beams from two different machines: Siemens 18 MV, Varian 15 MV, and Varian 18 MV. The linac head components are simulated in detail. The dose distributions from photons, neutrons, protons, and alpha particles are calculated in a tissue-equivalent phantom. Neutrons are generated in both the linac head and the phantom. This study includes (a) field size effects, (b) off-axis dose profiles, (c) neutron contribution from the linac head, (d) dose contribution from capture gamma rays, (e) phantom heterogeneity effects, and (f) effects of primary electron energy shift. Results are presented in terms of absolute dose distributions and also in terms of DER (dose equivalent ratio). The DER is the maximum dose from the particle (neutron, proton, or alpha) divided by the maximum photon dose, multiplied by the particle quality factor and the modulation scaling factor. The total DER including neutrons, protons, and alphas is about 0.66 cSv/Gy for the Siemens 18 MV beam (10 cm x 10 cm). The neutron DER decreases with decreasing field size while the proton (or alpha) DER does not vary significantly except for the 1 cm x 1 cm field. Both Varian beams (15 and 18 MV) produce more neutrons, protons, and alphas particles than the Siemens 18 MV beam. This is mainly due to their higher primary electron energies: 15 and 18.3 MeV, respectively, vs 14 MeV for the Siemens 18 MV beam. For all beams, neutrons contribute more than 75% of the total DER, except for the 1 cm x 1 cm field (approximately 50%). The total DER is 1.52 and 2.86 cSv/Gy for the 15 and 18 MV Varian beams (10 cm x 10 cm), respectively. Media with relatively high-Z elements like bone may increase the dose from heavy charged particles by a factor 4. The total DER is sensitive to primary electron energy shift. A Siemens 18 MV beam with 15 MeV (instead of 14 MeV) primary electrons would increase by 40% the neutron DER and by 210% the proton + alpha DER. Comparisons with measurements (neutron yields from different materials and neutron dose equivalent) are also presented. Using the NCRP risk assessment method, we found that the dose equivalent from leakage neutrons (at 50-cm off-axis distance) represent 1.1, 1.1, and 2.0% likelihood of fatal secondary cancer for a 70 Gy treatment delivered by the Siemens 18 MV, Varian 15 MV, and Varian 18 MV beams, respectively.     

不规则形貌纳米 Fe3O4 介导的磁场机械力杀伤肿瘤细胞

目的 考察Fe₃O₄纳米颗粒在低频振动磁场(low-frequency vibrating magnetic field, VMF)驱动下通过磁场机械力杀伤肿瘤细胞的效果。方法 通过共沉淀法合成一种磁性强、具有不规则形貌的立方相Fe₃O₄纳米颗粒。将其置于本课题组自制的VMF中,研究其介导的磁场机械力对肿瘤细胞的杀伤效果。结果 单纯施加VMF对细胞活力无影响;加入Fe₃O₄纳米颗粒后,细胞活力随VMF处理时间和Fe₃O₄纳米颗粒浓度的增加而降低,受损细胞释放的乳酸脱氢酶也随磁场处理时间延长而增加。结论 不规则形貌Fe₃O₄纳米颗粒在VMF下可将机械力转移到肿瘤细胞,破坏细胞结构,导致细胞死亡;所采用的VMF装置结构简单、使用安全、操作方便。所采用的磁性粒子及其杀伤肿瘤细胞的方法,有临床转化潜力。