Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Science, Chernogolovka, Moscow Region, Russia.
P. G. Demidov Yaroslavl State University, Yaroslavl, Russia.
Bull Exp Biol Med. 2024 Aug;177(4):569-577. doi: 10.1007/s10517-024-06224-7. Epub 2024 Sep 17.
A new system for delivery of anthracycline antibiotics based on chitosan-polyaminoxyls (CPA) was studied in a model of non-tumor (human embryonic mesenchymal stem cells) and tumor cells (human hepatocellular carcinoma) in vitro. The presence of CPA micelles considerably suppresses daunorubicin-induced ROS generation in normal cells without affecting this process in tumor cells. CPA micelles do not reduce the cytotoxic effect of daunorubicin and do not prevent its accumulation in cells. The use of CPA significantly increases accumulation of Nrf2 transcription factor in the nuclei of both normal and tumor cells in comparison with free daunorubicin. Increased nuclear translocation of Nrf2 leads to a significant increase in the expression of its target gene TXN1, but not the NQO1, GPX1, and HMOX1 genes, the increased expression of which can lead to the development of resistance to anthracycline antibiotics. Redox-active CPA micelles have great potential for the development of nanoparticles for the transport of anthracycline antibiotics in experimental tumor chemotherapy, and also as promising activators of Nrf2 transcription factor.
一种基于壳聚糖-聚胺氧基（CPA）的新型蒽环类抗生素给药系统在非肿瘤（人胚胎间充质干细胞）和肿瘤细胞（人肝癌）体外模型中进行了研究。CPA 胶束的存在可显著抑制正常细胞中柔红霉素诱导的 ROS 生成，而不影响肿瘤细胞中的这一过程。CPA 胶束不会降低柔红霉素的细胞毒性作用，也不会阻止其在细胞内积累。与游离柔红霉素相比，CPA 的使用可显著增加 Nrf2 转录因子在正常和肿瘤细胞核中的积累。Nrf2 的核易位增加导致其靶基因 TXN1 的表达显著增加，但 NQO1、GPX1 和 HMOX1 基因的表达没有增加，这些基因的增加表达可能导致对蒽环类抗生素的耐药性。具有氧化还原活性的 CPA 胶束在实验性肿瘤化疗中用于输送蒽环类抗生素的纳米颗粒的开发方面具有巨大潜力，并且作为 Nrf2 转录因子的有前途的激活剂。
