Abstract

Carbon nanomaterials (CNMs) and single- and multiwalled carbon nanotubes and fullerene derivatives are considered as promising agents for the delivery of pharmacological agents to target organs in anticancer therapy and theranostics. Cytostatic cyclophosphamide (CP) is one of the chemotherapeutic drugs the targeted delivery of which is possible by CNMs. However, due to the presence of its own toxic effect in various CNMs, the question about their possible effect on the general toxic and immunotoxic effect of CP when administered together arises. The combined effect of CP and CNMs, i.e., multiwalled carbon nanotubes (MWCNTs), single-walled carbon nanotubes (SWCNTs), and polyhydroxylated fullerenol (PHF60), administered orally daily at a dose of 0.1 mg/kg of body weight, was studied in Wistar rats. In two experiments lasting 16 and 35 days with different scenarios of CP-induced immunosuppression, the lethality and integral parameters were assessed; the contents of erythrocytes and leukocytes; the biochemical parameters; the levels of cytokines, chemokines, and growth factors; and the activity of glutathione peroxidase-I of erythrocytes were studied in the blood. The concentration of selenium and the excretion of creatinine and 8-oxo-2-deoxyguanosine were studied in the urine. The level of reduced glutathione was studied in the liver homogenate. In the first experiment, the consumption of both MWCNTs and SWCNTs led to an almost twofold decrease in lethality caused by the introduction of CP. In the second experiment, a twofold decrease in the lethality was noted only for SWCNTs; nevertheless, MWCNTs and PHF60 also had a positive effect on the survival of animals. Consumption of CNMs did not have a significant effect on the biochemical parameters, the state of the erythropoiesis system, the weight of the thymus and spleen, or the levels of key regulatory molecules impaired due to CP treatment. At the same time, MWCNTs, SWCNTs, and PHF60 are able to reduce a number of manifestations of the CP immunotoxic effect, including the lethality, lymphopenia, and impaired balance of cytokines and chemokines/growth factors: IL-4, IL-13, IL-17A, IFN-γ, IL-18, GM-CSF, GRO-KC, IL-12p70, IL-1β, IL-7, TNF-α, and VEGF. Thus, MWCNTs and SWCNTs, when administered together with CP, have a paradoxical effect consisting in the partial cancellation of the disturbances caused by it, which can be explained by the known ability of CNTs to enhance the mobilization, migration, and adhesion of blood cells and to trigger immune responses.

中文翻译：

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碳纳米材料联合给药对环磷酰胺毒性指标的影响

摘要

碳纳米材料（CNM）以及单壁和多壁碳纳米管以及富勒烯衍生物被认为是在抗癌治疗和治疗学中将药理剂输送到靶器官的有前途的药物。细胞生长抑制性环磷酰胺（CP）是化学治疗药物之一，其靶向递送可以通过CNM来实现。但是，由于在各种CNM中都存在其自身的毒性作用，因此出现了当它们一起给药时可能对CP的一般毒性和免疫毒性作用产生影响的问题。研究了CP和CNM（即多壁碳纳米管（MWCNT），单壁碳纳米管（SWCNT）和多羟基化富勒烯醇（PHF60））的联合作用，其口服剂量为每天0.1 mg / kg体重。在Wistar大鼠中。在两个持续16天和35天的实验中，在不同的CP诱导免疫抑制情况下，评估了杀伤力和整体参数。红细胞和白细胞的含量；生化参数；细胞因子，趋化因子和生长因子的水平；并研究了血液中谷胱甘肽过氧化物酶-I的活性。研究了尿液中硒的浓度以及肌酐和8-氧代-2-脱氧鸟苷的排泄量。在肝脏匀浆中研究了还原型谷胱甘肽的水平。在第一个实验中，MWCNTs和SWCNTs的消耗导致了CP的引入导致致死率几乎降低了两倍。在第二个实验中，仅SWCNT的致死率降低了两倍。但是，MWCNT和PHF60对动物的存活也有积极作用。消费CNM对生化参数，红细胞生成系统的状态，胸腺和脾脏的重量或由于CP治疗而受损的关键调节分子的水平没有显着影响。同时，MWCNT，SWCNT和PHF60能够减少CP免疫毒性作用的多种表现，包括致死性，淋巴细胞减少以及细胞因子和趋化因子/生长因子的平衡受损：IL-4，IL-13， IL-17A，IFN-γ，IL-18，GM-CSF，GRO-KC，IL-12p70，IL-1β，IL-7，TNF-α和VEGF。因此，将MWCNT和SWCNT与CP一起使用时，会产生矛盾的作用，即部分抵消了由其引起的干扰，