金属富勒烯与顺铂联合使用的抑瘤作用及其机理的研究
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摘要
新型纳米材料水溶性金属富勒烯[Gd@C_(82)(OH)_(22)]_n以其独特的生物学特性在抗癌研究中发挥着重要作用,它以低毒和高效抑瘤的特点引起各国学者的关注。对其抗癌机制和毒副作用的深入研究将为临床癌症治疗提供信息。本研究以接种肝癌H22肿瘤细胞的小鼠为动物模型,应用纳米颗粒的表征技术、电镜技术、激光动态光散射仪、流式细胞仪、质谱、组织化学技术、分子技术等手段在动物水平、细胞水平、分子水平研究了[Gd@C_(82)(OH)_(22)]_n和传统化疗药物顺铂对正常小鼠、腹水瘤小鼠和实体瘤小鼠进行了抑瘤机制和毒副作用、逆转肿瘤抗药性方面做了探讨,取得了以下研究结果:
1、[Gd@C_(82)(OH)_(22)]_n在生物体系中良好的稳定性,提供了研究其抑瘤作用的可行性。
[Gd@C_(82)(OH)_(22)]_n在水溶液中呈聚集状态,大小为50 nm左右,分散性和水溶性较好。在水溶液中质地较软,具备完好的笼型结构。表面电荷为-8.52±1.65 mV,呈弱负电形式,具备稳定的微晶结构。此颗粒在生理盐水或1640培养基中同样具备很好的稳定性和分散性,这为研究它在抑瘤方面的作用提供了前提条件。
2、[Gd@C_(82)(OH)_(22)]_n与顺铂的联合作用有效提高对小鼠肝癌实体瘤的抑制效率。
[Gd@C_(82)(OH)_(22)]_n不能抑制小鼠肝癌腹水瘤,但可有效抑制实体瘤生长(抑制率50%),肿瘤细胞在不同的生长环境中营养方式供给的差异造成细胞增殖速度不同可能是造成这种现象的原因。细胞实验证实[Gd@C_(82)(OH)_(22)]_n对小鼠肝癌细胞不具备直接杀伤作用。另外,[Gd@C_(82)(OH)_(22)]_n对正常鼠肝癌实体瘤的抑制效果好于裸鼠肝癌实体瘤的抑制效果,说明[Gd@C_(82)(OH)_(22)]_n的抑瘤作用有可能是通过激活细胞免疫激活机制达到抑瘤作用的。有趣的是,在细胞和动物水平上证实了[Gd@C_(82)(OH)_(22)]_n与顺铂的联合作用可有效提高实体瘤的抑制效率,与单独使用顺铂相比其抑制率提高了17%。
3、首次将铁代谢与顺铂造成的脾损伤联系起来研究其相互关系。顺铂对小鼠脾脏的特异性损伤可能与铁在脾脏的巨噬细胞中的沉积相关。
利用组织化学技术分析[Gd@C_(82)(OH)_(22)]_n处理小鼠后的脏器结构表明,[Gd@C_(82)(OH)_(22)]_n对机体无毒副作用。低剂量顺铂可造成小鼠脾脏的特异性损伤,而对其它器官没有伤害,通过低剂量顺铂连续注射小鼠会使其脾脏中的含铁血黄素沉积显著升高。进一步研究其机制发现,顺铂处理使动物体红细胞受损,受损红细胞被脾脏中的巨噬细胞吞噬,铁从红细胞内释放铁后增加了巨噬细胞内铁的含量。高铁诱导了FPN1、Ferritin和Hepcidin的表达,Ferritin与FPN1在结合铁上存在竞争,限制了铁的外排,另外,Hepcidin会与FPN1结合使其内化,减弱了FPN1外排铁的能力,两种因素最终导致铁在脾脏的巨噬细胞中沉积,使脾脏组织受损。本研究可为动物体铁代谢研究提供快速建立小鼠脾脏铁沉积的模型。另外低剂量顺铂对除脾脏之外的器官无损伤的结果可为顺铂临床治疗提供参考。
4、对[Gd@C_(82)(OH)_(22)]_n与化疗药物顺铂的联合使用可作为免疫增强剂,尝试在临床中的应用提供了有力的实验证据。
流式细胞仪和Elisa测定的数据表明,[Gd@C_(82)(OH)_(22)]_n能显著提高CD4+型T细胞的比例,在正常鼠和荷瘤鼠两组处理中,与对照组相比CD4+型T细胞的比例显著升高(P<0.01),分别提高了21.9%和62.6%。细胞因子分析表明,[Gd@C_(82)(OH)_(22)]_n是通过增加CD4+型T细胞的Th1亚型细胞来实现对实体瘤的免疫抑制作用的,它可刺激IL-2和IFN-α细胞因子的分泌增多。细胞因子IL-2可促进CD8+ T细胞的增殖,进而增加CD8+型T细胞的比例,使具有细胞毒功能的细胞数量增加,增强对肿瘤的细胞免疫功能。同时[Gd@C_(82)(OH)_(22)]_n通过刺激机体的巨噬细胞增殖,使TNF-α因子的分泌增加,进而杀死肿瘤细胞。顺铂单独使用不能产生以上的免疫增强反应,反而有较大的抑制作用,但与[Gd@C_(82)(OH)_(22)]_n联合使用会大大增强对机体的免疫刺激能力,提示[Gd@C_(82)(OH)_(22)]_n可做为与化疗药物配合使用的免疫增强剂在临床中使用。
5、[Gd@C_(82)(OH)_(22)]_n与顺铂的联合作用可逆转肿瘤细胞的抗药性是与其增强对细胞内吞作用的激活有关。
[Gd@C_(82)(OH)_(22)]_n与顺铂联合作用可有效杀伤具顺铂抗性的肿瘤细胞,通过内吞抑制剂阻断细胞内吞的实验证明,[Gd@C_(82)(OH)_(22)]_n是通过增强抗药性细胞的内吞作用,使进入细胞内的顺铂增多,从而增强了对抗性细胞的毒性,达到逆转肿瘤细胞抗药性的目的。
小结:[Gd@C_(82)(OH)_(22)]_n能显著抑制小鼠肝癌实体瘤,但对肝癌腹水瘤没有治疗效果,细胞实验证实该纳米颗粒对H22细胞没有直接毒性。进一步研究其机制发现[Gd@C_(82)(OH)_(22)]_n能激活体内的免疫系统,通过增加Th1型CD4+型T细胞及其释放的细胞因子IFN-γ、IL-2和TNF-α完成杀伤肿瘤的效果,与顺铂联合应用能显著提高治疗效果,尤其是在免疫激活方面表现出良好的保护效果。针对顺铂抗性肿瘤细胞的体外实验发现,[Gd@C_(82)(OH)_(22)]_n联合顺铂能有效逆转PC-3抗性细胞的顺铂耐药性,其机制有可能是通过促进抗性细胞内吞作用来增加细胞对顺铂的摄入量,从而增强顺铂对癌细胞的毒性。低剂量顺铂的应用虽然对大多器官不造成显著损伤,但它会引起脾脏的严重损伤,主要表现为严重的脾脏缩小、含铁血黄素在脾脏中聚集增加、脾铁含量增加、FPN1和Ferritin表达显著升高,初步认为顺铂干扰脾脏铁代谢的机制是造成脾损伤的一个重要因素。
Water-soluble metallofullerene [Gd@C_(82)(OH)_(22)]_n is a novel nanomaterial, It has attracted considerable attention globally for its low toxicity and high performance for inhibiting tumor. Now it plays an important role in anti-cancer research due to its unique biological properties. Studies focused on anti-cancer mechanisms and toxicity would provide crucial information both theoretically and practically, thus it will be benefit for the further clinical cancer treatment. In our study we characterized the physical properties of the metallofullerene [Gd@C_(82)(OH)_(22)]_n , discussed its anti-cancer activity, toxicity, and ability to circumvent multidrug resistance when combined with cisplatin on the normal mice , H22 ascites tumor bearing mice and H22 solid tumor bearing mice models. Electron microscopy, Dynamic light scattering, Flow cytometry, Mass spectrometry, Histochemistry and Molecular technology were used in this study. Our results demonstrated that:
1. [Gd@C_(82)(OH)_(22)]_n have an stable structure in biological systems,providing the feasibility to study the effect of inhibiting tumor.
The fine cage-structure of Gd@C82(OH)22 is soluble in aqueous solution, and it can form soft aggregates of up to 50nm. The value of Zeta potential was recorded as -8.52±1.65 mV, and the microcrystalline structure was stable. It also was stable and well dispersed in saline solution and 1640 media, These are preconditions for its inhibiting tumor properties.
2. In combination with cisplatin, [Gd@C_(82)(OH)_(22)]_n can improve the inhibitive rate of hepatoma solid tumor of mice comparing with cisplatin alone.
These particles can effectively inhibit H22 solid tumor (50% inhibition), but fail to inhibit hepatoma ascites tumor due to highly malignancy of tumor and indirect cytotoxicity to tumor cells via intraperitoneally injection. In addition, the inhibiting effect on H22 solid tumor by [Gd@C_(82)(OH)_(22)]_n in normal mice was better than in the nude mice. It indicates that [Gd@C_(82)(OH)_(22)]_n could inhibit the solid tumor through activating the cellular immunity. In vivo tests show a significant increase in H22 solid tumor inhibition (up to 17%) when cisplatin is combined with [Gd@C_(82)(OH)_(22)]_n, comparing with cisplatin alone.
3. For the first time to study the relationship between the iron metabolism and spleen injury initiated by cisplatin. The specificity injury initiated by cisplatin in mice spleen can be related with iron deposited in the spleen macrophages.
[Gd@C_(82)(OH)_(22)]_n were not toxic to organism by histochemistry analysis. Low dose cisplatin has no distinguish injury to organs of mice except spleen and could lead to increased deposition of hemosiderin in spleen. The mechanism was found to be that: Cisplatin treatment can provoke erythrocytes damage, then the damaged erythrocytes damaged are endocyted by macrophages in spleen, which increases the iron concentration in macrophages. High iron concentration induced the expression of FPN1, Ferritin and Hepcidin. Ferritin will compete with FPN1 to bind iron thus limiting the excretion of iron, whereas hepcidin joined to FPN1 initiates FPN1 internalization, also resulting in iron reduced excretion. Finally, these two pathways lead to iron deposition in spleen macrophages, which cause damage to spleen. In this study, we established a model for rapid iron depositon in spleen and this fact supports the study of iron metabolism in animal. In addition, the result in which low doses of cisplatin show no distinguish toxicity in organs of mice except to spleen, can be taked in account as a reference in clinic cancer therapy.
4. Study the immunostimulation effects of [Gd@C_(82)(OH)_(22)]_n combined with ciaplatin can provide important data for clinical research.
[Gd@C_(82)(OH)_(22)]_n significantly increased the ratio of CD4+ T cell through the detection of flow cytometry and ELISA. In a parallel treatment with normal mice and tumor-bearing mice, comparing with control, the ratio of CD4+ T cells increased 21.9% and 62.6%, respectively. [Gd@C_(82)(OH)_(22)]_n stimulated an increasing secretion of IL-2 and IFN-α, and they promoted solid tumor immunoinhibition through proliferation increasing of Th1 subtype CD4+ T cells. IL-2 can promote CD8+ T cells proliferation thus enhance the cytoimmunotoxicity to tumor cell. Meanwhile [Gd@C_(82)(OH)_(22)]_n stimulate the proliferation of macrophages, increase TNF-αsecretion, then kill the tumor cells. Cisplatin alone can not enhance immunoresponse and strongly inhibit those effects. But when the cisplatin was combined with [Gd@C_(82)(OH)_(22)]_n , immune system was notably activated, which indicated that [Gd@C_(82)(OH)_(22)]_n could utilize as immunostimulator combined with chemotherapy agents in clinical treatments.
5. [Gd@C_(82)(OH)_(22)]_n can effectively circumvent multidrug resistance in cancer combined with cisplatin, relating with intracellular cisplatin concentration increase through endocytosis reinforced in resistant tumor cells.
Cisplatin combined with [Gd@C_(82)(OH)_(22)]_n can effectively kill cisplatin resistant tumor cells. The endocytosis inhibition tests proved that, [Gd@C_(82)(OH)_(22)]_n circumvented multidrug resistant tumor cells through enhancing endocytosis of the tumor cell, increasing intracellular cisplatin concentration, thus promoting cisplatin cytotoxicity in resistant cells. Conclusion: [Gd@C_(82)(OH)_(22)]_n can significantly inhibit hepatoma solid tumor in mice, but fail to treat hepatoma ascites tumor. Cytotoxicity tests confirmed that the nanoparticles have no direct toxicity to H22 tumor cell. The following mechanism study revealed that [Gd@C_(82)(OH)_(22)]_n can stimulate immune system through promoting the Th1 CD4+ T cell proliferation and they can increase the secretion of IFN-γ, IL-2 and TNF-α, leading to tumor inhibition. These nanoparticles in combination with cisplatin can notably enhance the effectiveness of the treament, activating immune system and reducing systematic toxicity. In vitro tests with cisplatin resistant cell lines indicated that combination therapy of cisplatin and [Gd@C_(82)(OH)_(22)]_n can effectively circumvent drug resistance in PC-3 cisplatin resistance cell lines probably through enhancing endocytosis to increase intracellular cisplatin cancentration, which leads to enhanced cytotoxicity. Low dose of cisplatin generate severe spleen damage, although it may not be that toxic to the other organs. The main phenomenons of severe spleen damage were dramatically shrinking, increasing hemociderin deposition and splenic iron accumulation, significant up-regulation of FPN1 and Ferritin. These results indicat that cisplatin interference in spleen iron metabolism may be of great importance to spleen damage.
1、[Gd@C_(82)(OH)_(22)]_n在生物体系中良好的稳定性,提供了研究其抑瘤作用的可行性。
[Gd@C_(82)(OH)_(22)]_n在水溶液中呈聚集状态,大小为50 nm左右,分散性和水溶性较好。在水溶液中质地较软,具备完好的笼型结构。表面电荷为-8.52±1.65 mV,呈弱负电形式,具备稳定的微晶结构。此颗粒在生理盐水或1640培养基中同样具备很好的稳定性和分散性,这为研究它在抑瘤方面的作用提供了前提条件。
2、[Gd@C_(82)(OH)_(22)]_n与顺铂的联合作用有效提高对小鼠肝癌实体瘤的抑制效率。
[Gd@C_(82)(OH)_(22)]_n不能抑制小鼠肝癌腹水瘤,但可有效抑制实体瘤生长(抑制率50%),肿瘤细胞在不同的生长环境中营养方式供给的差异造成细胞增殖速度不同可能是造成这种现象的原因。细胞实验证实[Gd@C_(82)(OH)_(22)]_n对小鼠肝癌细胞不具备直接杀伤作用。另外,[Gd@C_(82)(OH)_(22)]_n对正常鼠肝癌实体瘤的抑制效果好于裸鼠肝癌实体瘤的抑制效果,说明[Gd@C_(82)(OH)_(22)]_n的抑瘤作用有可能是通过激活细胞免疫激活机制达到抑瘤作用的。有趣的是,在细胞和动物水平上证实了[Gd@C_(82)(OH)_(22)]_n与顺铂的联合作用可有效提高实体瘤的抑制效率,与单独使用顺铂相比其抑制率提高了17%。
3、首次将铁代谢与顺铂造成的脾损伤联系起来研究其相互关系。顺铂对小鼠脾脏的特异性损伤可能与铁在脾脏的巨噬细胞中的沉积相关。
利用组织化学技术分析[Gd@C_(82)(OH)_(22)]_n处理小鼠后的脏器结构表明,[Gd@C_(82)(OH)_(22)]_n对机体无毒副作用。低剂量顺铂可造成小鼠脾脏的特异性损伤,而对其它器官没有伤害,通过低剂量顺铂连续注射小鼠会使其脾脏中的含铁血黄素沉积显著升高。进一步研究其机制发现,顺铂处理使动物体红细胞受损,受损红细胞被脾脏中的巨噬细胞吞噬,铁从红细胞内释放铁后增加了巨噬细胞内铁的含量。高铁诱导了FPN1、Ferritin和Hepcidin的表达,Ferritin与FPN1在结合铁上存在竞争,限制了铁的外排,另外,Hepcidin会与FPN1结合使其内化,减弱了FPN1外排铁的能力,两种因素最终导致铁在脾脏的巨噬细胞中沉积,使脾脏组织受损。本研究可为动物体铁代谢研究提供快速建立小鼠脾脏铁沉积的模型。另外低剂量顺铂对除脾脏之外的器官无损伤的结果可为顺铂临床治疗提供参考。
4、对[Gd@C_(82)(OH)_(22)]_n与化疗药物顺铂的联合使用可作为免疫增强剂,尝试在临床中的应用提供了有力的实验证据。
流式细胞仪和Elisa测定的数据表明,[Gd@C_(82)(OH)_(22)]_n能显著提高CD4+型T细胞的比例,在正常鼠和荷瘤鼠两组处理中,与对照组相比CD4+型T细胞的比例显著升高(P<0.01),分别提高了21.9%和62.6%。细胞因子分析表明,[Gd@C_(82)(OH)_(22)]_n是通过增加CD4+型T细胞的Th1亚型细胞来实现对实体瘤的免疫抑制作用的,它可刺激IL-2和IFN-α细胞因子的分泌增多。细胞因子IL-2可促进CD8+ T细胞的增殖,进而增加CD8+型T细胞的比例,使具有细胞毒功能的细胞数量增加,增强对肿瘤的细胞免疫功能。同时[Gd@C_(82)(OH)_(22)]_n通过刺激机体的巨噬细胞增殖,使TNF-α因子的分泌增加,进而杀死肿瘤细胞。顺铂单独使用不能产生以上的免疫增强反应,反而有较大的抑制作用,但与[Gd@C_(82)(OH)_(22)]_n联合使用会大大增强对机体的免疫刺激能力,提示[Gd@C_(82)(OH)_(22)]_n可做为与化疗药物配合使用的免疫增强剂在临床中使用。
5、[Gd@C_(82)(OH)_(22)]_n与顺铂的联合作用可逆转肿瘤细胞的抗药性是与其增强对细胞内吞作用的激活有关。
[Gd@C_(82)(OH)_(22)]_n与顺铂联合作用可有效杀伤具顺铂抗性的肿瘤细胞,通过内吞抑制剂阻断细胞内吞的实验证明,[Gd@C_(82)(OH)_(22)]_n是通过增强抗药性细胞的内吞作用,使进入细胞内的顺铂增多,从而增强了对抗性细胞的毒性,达到逆转肿瘤细胞抗药性的目的。
小结:[Gd@C_(82)(OH)_(22)]_n能显著抑制小鼠肝癌实体瘤,但对肝癌腹水瘤没有治疗效果,细胞实验证实该纳米颗粒对H22细胞没有直接毒性。进一步研究其机制发现[Gd@C_(82)(OH)_(22)]_n能激活体内的免疫系统,通过增加Th1型CD4+型T细胞及其释放的细胞因子IFN-γ、IL-2和TNF-α完成杀伤肿瘤的效果,与顺铂联合应用能显著提高治疗效果,尤其是在免疫激活方面表现出良好的保护效果。针对顺铂抗性肿瘤细胞的体外实验发现,[Gd@C_(82)(OH)_(22)]_n联合顺铂能有效逆转PC-3抗性细胞的顺铂耐药性,其机制有可能是通过促进抗性细胞内吞作用来增加细胞对顺铂的摄入量,从而增强顺铂对癌细胞的毒性。低剂量顺铂的应用虽然对大多器官不造成显著损伤,但它会引起脾脏的严重损伤,主要表现为严重的脾脏缩小、含铁血黄素在脾脏中聚集增加、脾铁含量增加、FPN1和Ferritin表达显著升高,初步认为顺铂干扰脾脏铁代谢的机制是造成脾损伤的一个重要因素。
Water-soluble metallofullerene [Gd@C_(82)(OH)_(22)]_n is a novel nanomaterial, It has attracted considerable attention globally for its low toxicity and high performance for inhibiting tumor. Now it plays an important role in anti-cancer research due to its unique biological properties. Studies focused on anti-cancer mechanisms and toxicity would provide crucial information both theoretically and practically, thus it will be benefit for the further clinical cancer treatment. In our study we characterized the physical properties of the metallofullerene [Gd@C_(82)(OH)_(22)]_n , discussed its anti-cancer activity, toxicity, and ability to circumvent multidrug resistance when combined with cisplatin on the normal mice , H22 ascites tumor bearing mice and H22 solid tumor bearing mice models. Electron microscopy, Dynamic light scattering, Flow cytometry, Mass spectrometry, Histochemistry and Molecular technology were used in this study. Our results demonstrated that:
1. [Gd@C_(82)(OH)_(22)]_n have an stable structure in biological systems,providing the feasibility to study the effect of inhibiting tumor.
The fine cage-structure of Gd@C82(OH)22 is soluble in aqueous solution, and it can form soft aggregates of up to 50nm. The value of Zeta potential was recorded as -8.52±1.65 mV, and the microcrystalline structure was stable. It also was stable and well dispersed in saline solution and 1640 media, These are preconditions for its inhibiting tumor properties.
2. In combination with cisplatin, [Gd@C_(82)(OH)_(22)]_n can improve the inhibitive rate of hepatoma solid tumor of mice comparing with cisplatin alone.
These particles can effectively inhibit H22 solid tumor (50% inhibition), but fail to inhibit hepatoma ascites tumor due to highly malignancy of tumor and indirect cytotoxicity to tumor cells via intraperitoneally injection. In addition, the inhibiting effect on H22 solid tumor by [Gd@C_(82)(OH)_(22)]_n in normal mice was better than in the nude mice. It indicates that [Gd@C_(82)(OH)_(22)]_n could inhibit the solid tumor through activating the cellular immunity. In vivo tests show a significant increase in H22 solid tumor inhibition (up to 17%) when cisplatin is combined with [Gd@C_(82)(OH)_(22)]_n, comparing with cisplatin alone.
3. For the first time to study the relationship between the iron metabolism and spleen injury initiated by cisplatin. The specificity injury initiated by cisplatin in mice spleen can be related with iron deposited in the spleen macrophages.
[Gd@C_(82)(OH)_(22)]_n were not toxic to organism by histochemistry analysis. Low dose cisplatin has no distinguish injury to organs of mice except spleen and could lead to increased deposition of hemosiderin in spleen. The mechanism was found to be that: Cisplatin treatment can provoke erythrocytes damage, then the damaged erythrocytes damaged are endocyted by macrophages in spleen, which increases the iron concentration in macrophages. High iron concentration induced the expression of FPN1, Ferritin and Hepcidin. Ferritin will compete with FPN1 to bind iron thus limiting the excretion of iron, whereas hepcidin joined to FPN1 initiates FPN1 internalization, also resulting in iron reduced excretion. Finally, these two pathways lead to iron deposition in spleen macrophages, which cause damage to spleen. In this study, we established a model for rapid iron depositon in spleen and this fact supports the study of iron metabolism in animal. In addition, the result in which low doses of cisplatin show no distinguish toxicity in organs of mice except to spleen, can be taked in account as a reference in clinic cancer therapy.
4. Study the immunostimulation effects of [Gd@C_(82)(OH)_(22)]_n combined with ciaplatin can provide important data for clinical research.
[Gd@C_(82)(OH)_(22)]_n significantly increased the ratio of CD4+ T cell through the detection of flow cytometry and ELISA. In a parallel treatment with normal mice and tumor-bearing mice, comparing with control, the ratio of CD4+ T cells increased 21.9% and 62.6%, respectively. [Gd@C_(82)(OH)_(22)]_n stimulated an increasing secretion of IL-2 and IFN-α, and they promoted solid tumor immunoinhibition through proliferation increasing of Th1 subtype CD4+ T cells. IL-2 can promote CD8+ T cells proliferation thus enhance the cytoimmunotoxicity to tumor cell. Meanwhile [Gd@C_(82)(OH)_(22)]_n stimulate the proliferation of macrophages, increase TNF-αsecretion, then kill the tumor cells. Cisplatin alone can not enhance immunoresponse and strongly inhibit those effects. But when the cisplatin was combined with [Gd@C_(82)(OH)_(22)]_n , immune system was notably activated, which indicated that [Gd@C_(82)(OH)_(22)]_n could utilize as immunostimulator combined with chemotherapy agents in clinical treatments.
5. [Gd@C_(82)(OH)_(22)]_n can effectively circumvent multidrug resistance in cancer combined with cisplatin, relating with intracellular cisplatin concentration increase through endocytosis reinforced in resistant tumor cells.
Cisplatin combined with [Gd@C_(82)(OH)_(22)]_n can effectively kill cisplatin resistant tumor cells. The endocytosis inhibition tests proved that, [Gd@C_(82)(OH)_(22)]_n circumvented multidrug resistant tumor cells through enhancing endocytosis of the tumor cell, increasing intracellular cisplatin concentration, thus promoting cisplatin cytotoxicity in resistant cells. Conclusion: [Gd@C_(82)(OH)_(22)]_n can significantly inhibit hepatoma solid tumor in mice, but fail to treat hepatoma ascites tumor. Cytotoxicity tests confirmed that the nanoparticles have no direct toxicity to H22 tumor cell. The following mechanism study revealed that [Gd@C_(82)(OH)_(22)]_n can stimulate immune system through promoting the Th1 CD4+ T cell proliferation and they can increase the secretion of IFN-γ, IL-2 and TNF-α, leading to tumor inhibition. These nanoparticles in combination with cisplatin can notably enhance the effectiveness of the treament, activating immune system and reducing systematic toxicity. In vitro tests with cisplatin resistant cell lines indicated that combination therapy of cisplatin and [Gd@C_(82)(OH)_(22)]_n can effectively circumvent drug resistance in PC-3 cisplatin resistance cell lines probably through enhancing endocytosis to increase intracellular cisplatin cancentration, which leads to enhanced cytotoxicity. Low dose of cisplatin generate severe spleen damage, although it may not be that toxic to the other organs. The main phenomenons of severe spleen damage were dramatically shrinking, increasing hemociderin deposition and splenic iron accumulation, significant up-regulation of FPN1 and Ferritin. These results indicat that cisplatin interference in spleen iron metabolism may be of great importance to spleen damage.
引文
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