金纳米颗粒在肿瘤放射增敏中的研究进展

金纳米颗粒(AuNPs)以其独特的理化性质及良好的生物相容性在生物医药方面广泛应用,其中金纳米颗粒肿瘤放射增敏作用是目前研究热点。大量体、内外研究证实AuNPs具有放射增敏效果,但AuNPs放射增敏相关机制仍有待进一步研究,目前普遍认为增敏主要由AuNPs促进肿瘤细胞由放疗不敏感期(G₀+G₁期)转为放疗敏感期(G₂+M期)所致。影响AuNPs放射增敏效果的因素有很多,其中包括AuNPs粒径大小及其表面修饰和微观分布、放射线能量及剂量大小和肿瘤细胞类别等。此外值得注意的是,AuNPs用于肿瘤放射增敏的同时也要关注它的安全性。目前已开展了AuNPs有关临床试验,尚需继续进行AuNPs放射增敏的研究才能实现真正的临床转化。     

金纳米颗粒在恶性肿瘤放疗中的基础与临床应用研究进展

对45篇有关金纳米颗粒在恶性肿瘤放疗中应用文献(近5年20篇,近10年20篇)进行阅读,并通过对金纳米颗粒特点简介、理论研究、细胞实验、动物实验,以及靶向放疗临床前景进行综述。目前金纳米颗粒放射增敏研究尚未解决3个关键问题:金纳米颗粒在肿瘤细胞内微观分布及其影响因素;金纳米颗粒微观剂量提升作用;金纳米颗粒放射增敏的分子生物学机制。因此,该技术投入临床应用还有很多工作要做。     

纳米金对SPC-A1肺癌细胞体外放射增敏作用的研究

目的 研究纳米金联合兆伏级射线对肺腺癌SPC-A1细胞的体外放射增敏作用,并从细胞周期、细胞凋亡角度探讨纳米金的放射增敏机制。方法 选用肺腺癌SPC-A1细胞进行体外培养,采用CCK-8法检测不同浓度纳米金（0、1、0.5、0.25、0.125、0.0625 mmol／L）处理SPC-A1细胞24、48、72 h后的细胞毒性,确定纳米金溶液的实验浓度;经纳米金溶液培养的SPC-A1细胞株分别给予6 MV X线和4 MeV电子线照射0、1、2、4、6、8 Gy后,体外细胞培养克隆法研究纳米金的放射增敏作用,计算存活分数。使用单击多靶模型公式拟合,计算出Dq、D0等放射生物学参数和放射增敏比（SER）;流式细胞仪检测纳米金处理SPC-A1细胞24 h后各组的细胞凋亡和细胞周期的变化。结果 不同浓度纳米金处理不同时间后,对SPC-A1细胞的增殖无明显抑制,确定以纳米金溶液初始浓度（0.25 mmol／L）作为实验浓度。直径25 nm、0.25 mmol／L的纳米金粒子联合6 MV X线和4 MeV 电子线照射SPC-A1细胞的SER分别是1.111和1.214。流式细胞仪检测显示,纳米金不增加细胞的凋亡,但能明显增加射线对细胞的凋亡作用。细胞周期显示纳米金能加速细胞的G0／G1期,使细胞周期阻滞在G2／M期。结论 纳米金联合6 MV X线或4 MeV 电子线对SPC-A1细胞有放射增敏作用,其机制可能与增加射线对细胞的凋亡和细胞周期同步化有关。     

金纳米颗粒在肿瘤放射增敏中的相关研究进展

纳米技术被广泛用于肿瘤的诊断和治疗中,逐渐成为研究的热点。在纳米材料中金纳米颗粒由于低毒性、较好的生物相容性及增强的穿透滞留效应等独特优势在肿瘤诊断、成像、治疗等领域受到广泛关注。目前多项研究表明金纳米颗粒可作为理想的放射增敏剂,研究其在体内、外放射增敏作用将对纳米医学的临床转化具有重要意义。     

C225-GNPs对人肝癌SMMC-7721细胞放射增敏作用的实验研究

纳米材料和纳米技术在肿瘤的诊断和治疗中已经进入到临床应用阶段［1］。本实验选用C225?GNPs观察其对EGFR高表达SMMC?7721人肝癌细胞的放射增敏效应,探讨其作用机制,希望在靶向纳米金应用方面具有一定参考意义。     

紫龙金对鼻咽癌裸鼠移植瘤放射增敏作用的研究

[目的]探讨紫龙金对鼻咽癌细胞系裸小鼠移植瘤放射增敏作用及机制.[方法]建立CNE-Ⅰ裸小鼠移植瘤模型,观察空白对照组、紫龙金组、单纯照射组和紫龙金加照射组肿瘤体积变化,并计算抑瘤率和放射增敏比(SER);免疫组化检测肿瘤组织中p16和cyclinD1蛋白的表达;逆转录聚合酶链反应(RT-PCR)检测p16和cyclinD1 mRNA的表达.[结果]紫龙金加照射组抑瘤率明显高于其他组,SER(E/O)为2.45,提示紫龙金有放疗增敏效果.免疫组化分析法和RT-PCR显示,紫龙金组和紫龙金加照射组与空白对照组及单纯照射组相比,p16蛋白和p16 mRNA表达显著上调(P＜0.05);cyclinD1蛋白和cyclindl mRNA表达显著下调(P＜0.05).[结论]紫龙金对鼻咽癌细胞系CNE-Ⅰ裸小鼠移植瘤有放射增敏作用,其增敏作用机制可能与p16表达上调、cylinD1表达下调有关.     

放射增敏剂的研究进展

放射增敏剂可提高放射线对肿瘤细胞的杀伤作用。增加放疗效果。理想的放射增敏剂可以显著增加放疗疗效。对正常组织没有或很少有毒副反应。国内外学者进行了大量研究，在合成药物、分子靶向药物和天然药物等方面取得了新的进展，显示了放射增敏剂的发展趋势。文章主要对此进行综述。     

多功能纳米金在肺腺癌A549荷瘤小鼠模型中的放射增敏作用及Micro CT成像研究

目的 探究多功能纳米金在肺腺癌A549荷瘤小鼠模型中的放射增敏作用及Micro CT成像。方法 荷瘤小鼠瘤体内注射纳米金,分别行160 kV X线及6 MV X线不同能量级照射,并测量肿瘤体积变化。瘤体内注射纳米金,在不同时间点行Micro CT扫描,观察纳米金在瘤组织中的成像及沉积时间。结果 对照组与纳米金组肿瘤体积变化无明显差异(P=0.941)。6 MV X线联合纳米金组与6 MV X线组比较肿瘤体积略缩小,但两组没有统计学差异(P=0.730)。160 kV X线联合纳米金组肿瘤体积明显小于160 kV X线组(P=0.026)。Micro CT扫描显示纳米金在肿瘤中的沉积时间可持续30天,成像效果很好,且未见纳米金相关毒性。结论 多功能纳米金对160 kV X线照射肺腺癌A549移植瘤有明显的放射增敏作用;纳米金瘤体的稳定CT成像可作为图像引导放疗肿瘤靶区定位和勾画的一种潜在方法。     

金属纳米材料在放疗增敏领域中的研究进展

本文综述了放疗研究领域常用的金属纳米材料金纳米、银纳米、四氧化三铁纳米及其复合材料的制备方法和放疗增敏研究进展。金属纳米材料在放疗增敏领域已有一定的研究基础,具有广阔的临床应用前景。本综述为金属纳米材料在放疗增敏临床上的应用研究提供参考和理论基础。     

放疗增敏剂研究趋势

利用放射增敏剂提高肿瘤中乏氧细胞对放疗的敏感性,能提高放射线对肿瘤细胞的杀伤率,增强放疗效果。理想的放射增敏剂应可以显著增加放疗的疗效,对正常组织没有或很少有毒副反应。国内外学者进行了大量的研究,在基因和分子靶向药物等方面取得了新进展,显示了未来放疗增敏剂发展的趋势。     

Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen

Colony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization.     

Increased apoptotic potential and dose-enhancing effect of gold nanoparticles in combination with single-dose clinical electron beams on tumor-bearing mice

High atomic number material, such as gold, may be used in conjunction with radiation to provide dose enhancement in tumors. In the current study, we investigated the dose-enhancing effect and apoptotic potential of gold nanoparticles in combination with single-dose clinical electron beams on B16F10 melanoma tumor-bearing mice. We revealed that the accumulation of gold nanoparticles was detected inside B16F10 culture cells after 18 h of incubation, and moreover, the gold nanoparticles were shown to be colocalized with endoplasmic reticulum and Golgi apparatus in cells. Furthermore, gold nanoparticles radiosensitized melanoma cells in the colony formation assay ( P =  0.02). Using a B16F10 tumor-bearing mouse model, we further demonstrated that gold nanoparticles in conjunction with ionizing radiation significantly retarded tumor growth and prolonged survival compared to the radiation alone controls ( P <  0.05). Importantly, an increase of apoptotic signals was detected inside tumors in the combined treatment group ( P <  0.05). Knowing that radiation-induced apoptosis has been considered a determinant of tumor responses to radiation therapy, and the length of tumor regrowth delay correlated with the extent of apoptosis after single-dose radiotherapy, these results may suggest the clinical potential of gold nanoparticles in improving the outcome of melanoma radiotherapy. ( Cancer Sci 2008; 99: 1479–1484)     

Thermal radiosensitization of human tumour cell lines with different sensitivities to 41.1oC

While much work on radiosensitization by hyperthermia in the 43oC and higher temperature range has been done, relatively little work has been done at temperatures in the 41-42oC range. In this moderate hyperthermia range there are dramatic differences in the resistance of mammalian cells to hyperthermia. Therefore, thermal radiosensitization was measured in two human colon adenocarcinoma cell lines, one that expresses chronic thermotolerance and proliferates at 41.1oC, NSY 42129 (NSY) cells and one that is slowly killed at 41.1oC, HCT15 cells. Heat-resistant NSY cells were found to be more radioresistant than heatsensitive HCT15 cells. Hyperthermia at 41.1oC enhanced the radiation sensitivity in NSY cells, but no significant induction of heat-induced radiosensitization was observed in HCT15 cells. The radiation sensitivity induced by 41.1oC in NSY cells appeared to be related to both intrinsic heat-induced radiosensitization (HIR) and cell-cycle redistribution at 41.1oC. Incidentally, cells incubated at 41.1oC for between 8-16h displayed an identical radiosensitivity to those heated for 24h. This result implies that modest hyperthermia for 2h or more can have a radiosensitizing effect in heat-resistant cells.     

Paclitaxel-loaded poly(D,L-lactide-co-glycolide) nanoparticles for radiotherapy in hypoxic human tumor cells in vitro

Radioresistant hypoxic cells may contribute to the failure of radiation therapy in controlling certain tumors. Some studies have suggested the radiosensitizing effect of paclitaxel. The poly (D,L-lactide-co-glycolide)(PLGA) nanoparticles containing paclitaxel were prepared by o/w emulsification-solvent evaporation method. The physicochemical characteristics of the nanoparticles (i.e., encapsulation efficiency, particle size distribution, morphology, in vitro release) were studied. The morphology of the two human tumor cell lines: a carcinoma cervicis (HeLa) and a hepatoma (HepG(2)), treated with paclitaxel-loaded nanoparticles was photomicrographed. Flow cytometry was used to quantify the number of the tumor cells held in the G(2)/M phase of the cell cycle. The cellular uptake of nanoparticles was evaluated by transmission electronic microscopy. Cell viability was determined by the ability of single cell to form colonies in vitro. The prepared nanoparticles were spherical in shape with size between 200 nm and 800 nm. The encapsulation efficiency was 85.5%. The release behaviour of paclitaxel from the nanoparticles exhibited a biphasic pattern characterised by a fast initial release during the first 24 h, followed by a slower and continuous release. Co-culture of the two tumor cell lines with paclitaxel-loaded nanoparticles demonstrated that the cell morphology was changed and the released paclitaxel retained its bioactivity to block cells in the G(2)/M phase. The cellular uptake of nanoparticles was observed. The free paclitaxel and paclitaxel-loaded nanoparticles effectively sensitized hypoxic HeLa and HepG(2) cells to radiation. Under this experimental condition, the radiosensitization of paclitaxel-loaded nanoparticles was more significant than that of free paclitaxel.     

Thermal radiosensitization of human tumour cell lines with different sensitivities to 41.1 degrees C.

While much work on radiosensitization by hyperthermia in the 43 degrees C and higher temperature range has been done, relatively little work has been done at temperatures in the 41-42 degrees C range. In this moderate hyperthermia range there are dramatic differences in the resistance of mammalian cells to hyperthermia. Therefore, thermal radiosensitization was measured in two human colon adenocarcinoma cell lines, one that expresses chronic thermotolerance and proliferates at 41.1 degrees C, NSY 42129 (NSY) cells and one that is slowly killed at 41.1 degrees C, HCT15 cells. Heat-resistant NSY cells were found to be more radioresistant than heat-sensitive HCT15 cells. Hyperthermia at 41.1 degrees C enhanced the radiation sensitivity in NSY cells, but no significant induction of heat-induced radiosensitization was observed in HCT15 cells. The radiation sensitivity induced by 41.1 degrees C in NSY cells appeared to be related to both intrinsic heat-induced radiosensitization (HIR) and cell-cycle redistribution at 41.1 degrees C. Incidentally, cells incubated at 41.1 degrees C for between 8-16 h displayed an identical radiosensitivity to those heated for 24 h. This result implies that modest hyperthermia for 2 h or more can have a radiosensitizing effect in heat-resistant cells.     

Some peculiarities of the sequential action of heat and ionizing radiation on yeast cells

The dependence of the thermal enhancement ratio after a sequential action of heat and ionizing radiation on the dose and dose rate of ionizing radiation as well as on the temperature and duration of its application was studied for yeast cells. The combined effect of heat and ionizing radiation on cell killing depended on both the sequence of application (i.e. whether heat is applied prior to or following irradiation) and the temperature. The effectiveness of treatment with heat and ionizing radiation was greatly dependent on the duration of heat exposure. For an equal amount of cell killing from heat alone, long action of heat (50°C) was more effective for radiosensitization than a short acute action of high heat (58°C). For heating at 50°C, heating after irradiation produced more radiosensitization than heating before irradiation. However, high heating at 58°C before irradiation gave the same radiosensitization as heating after irradiation. These data confirm similar observations for mammalian cells. The results were interpreted by means of a mathematical model in which the synergistic effect of the sequential application of heat and ionizing radiation results from the additional lethal damage arising from the interaction of sublesions induced by both agents. These sublesions are not lethal after the action of these modalities, each taken alone. The model appears to be appropriate and the conclusions are valid.     

Enhanced apoptosis and radiosensitization by combined 13-cis-retinoic acid and interferon-alpha2a; role of RAR-beta gene.

PURPOSE: Combined use of 13-cis-retinoic acid (cRA) and interferon-alpha2a (IFNalpha) induced significant radiosensitization in human cervical cancer ME-180 cell line, whereas it failed to achieve similar radiation enhancement in HeLa cells. The differential radiosensitization could be from the difference of retinoic acid receptor (RAR) expression because RAR-beta was highly expressed in ME-180 cells in contrast to the HeLa cells where RAR-beta was not detectable. We examined the role of this gene in mediating radiosensitization by cRA and IFNalpha, and explored the mechanism of radiation-induced cell killing. METHODS AND MATERIALS: Human cervical cancer cell lines, ME-180 and HeLa, were treated with cRA and IFNalpha followed by radiation. Apoptosis and radiosensitization were quantitated by TUNEL assay (in situ DNA nick end labeling) and colony-forming ability of surviving cells. The cells were transfected with bcl-2 gene and RAR-beta gene to test the role of these genes in mediating radiosensitization and apoptosis. RESULTS: Synergistic radiosensitization and apoptosis was observed by combined use of cRA and IFNalpha with radiation in ME-180 cells which express high level of RAR-beta mRNA, whereas these were not seen in HeLa cells where RAR-beta mRNA is not detectable. Both radiosensitization and apoptosis were abolished by bcl-2 gene in ME-180 cells. RAR-beta gene transfection induced similar radiation enhancement and apoptosis in HeLa cells. CONCLUSION: Apoptosis and radiation response were enhanced in the cells with high level of RAR-beta mRNA expression. The RAR-beta gene appears to mediate the radiation-induced apoptosis by cRA and IFNalpha. These findings indicate that presence of RAR-beta in the cancer cells could be exploited for patient selection in using these drugs for apoptosis and radiosensitization.