The biological features of dendrimers are affected by the character of highly reactive terminal moieties. In some polyamine dendrimer types the surface charge makes them bioincompatible and prevent their direct medical application. Moreover, foreign particles can induce the immune response which is undesirable due to the adverse side effects in vivo. The reduction of cytotoxicity of positively charged macromolecules is possible through chemical modifications of terminal groups. In our study, we have developed new derivatives of PAMAM dendrimers modified with 4-carbomethoxypyrrolidone and evaluated their immunomodulatory properties. The experiments were conducted on two human cancer myeloid cell lines: THP-1 and U937. To evaluate the cytotoxicity of dendrimers, the reasazurin assay was applied. The expression level of NF-κB targets (NFKBIA, BTG2) and cytokine genes (IL1B, TNF) was determined by quantitative real-time RT-PCR. The measurement of binding of NF-κB to a consensus DNA probe was determined by electrophoretic mobility shift assay. The ELISA cytokine assay was performed to measure protein concentration of IL-1β and TNFα. We have found that PAMAM-pyrrolidone dendrimers did not impact THP-1 and U937 viability even at high concentrations (up to 200 μM). The surface modification prevented PAMAM dendrimers from stimulating NF-κB-related signal transduction, which have been determined on the level of nuclear translocation, gene expression and protein secretion. Pyrrolidone modification efficiently prevents PAMAM dendrimers from stimulating pro-inflammatory response in human cancer myeloid cell lines, thus it can be used to improve the biocompatibility of positively charged dendrimers and to broaden the scope of their biological applications.

中文翻译：

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吡咯烷酮修饰可防止PAMAM树状聚合物活化人单核细胞中促炎性信号通路

树状聚合物的生物学特征受高反应性末端部分的特性影响。在某些多胺树枝状聚合物类型中，表面电荷使它们具有生物不相容性，并阻止了其直接医学应用。此外，外来颗粒可诱导免疫反应，由于体内的不良副作用，这是不希望的。通过末端基团的化学修饰可以降低带正电荷的大分子的细胞毒性。在我们的研究中，我们开发了用4-羰基甲氧基吡咯烷酮修饰的PAMAM树状聚合物的新衍生物，并评估了它们的免疫调节特性。实验是在两种人类癌症髓样细胞系THP-1和U937上进行的。为了评估树状聚合物的细胞毒性，应用了芦荟灵分析。NF-κB靶标的表达水平（NFKBIA，BTG2）和细胞因子基因（IL1B，TNF通过定量实时RT-PCR确定。NF-κB与共有DNA探针的结合的测量通过电泳迁移率变动测定法确定。进行ELISA细胞因子测定以测量IL-1β和TNFα的蛋白质浓度。我们发现，即使在高浓度（高达200μM）下，PAMAM-吡咯烷酮树枝状大分子也不会影响THP-1和U937的活力。表面修饰阻止了PAMAM树枝状大分子刺激NF-κB相关信号转导，这已由核易位，基因表达和蛋白质分泌水平确定。吡咯烷酮修饰可有效防止PAMAM树状大分子刺激人类癌症髓样细胞系中的促炎反应，