State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China.
School & Hospital of Stomatology, Wenzhou Medical University, Xueyuan West Road, Lucheng District, Wenzhou 325027, China.
Carbohydr Polym. 2022 Nov 1;295:119878. doi: 10.1016/j.carbpol.2022.119878. Epub 2022 Jul 19.
At present, the tumor's poor oxygen perfusion and limited tumor drug permeation are the major bottlenecks that limit the therapeutic effectiveness of the oxygen-sensitive antitumor therapies, like doxorubicin (Dox)-mediated chemotherapy and photodynamic therapy (PDT). To our best knowledge, the abnormal tumor mitochondria oxidative phosphorylation (OXPHOS) was the vital cause of such phenomenon, which induced the hypoxia tumor microenvironment and enhanced drug efflux from tumor cells via enhanced multidrug resistance protein 1 (MDR-1) expression. In this study, it was newly revealed that biguanide-modified chitosan (Bi-Ch) possessed ideal mitochondria depression capacity, leading to the following decreased dosage needed to disrupt mitochondrial function to reverse tumor hypoxia and depress MDR-1 expression. By doing this, Bi-Ch effectively enhanced Dox accumulation in tumor cells and amplified its cytotoxicity owing to the amplified ROS generation by Dox. Therefore, Bi-Ch could be used to improve the efficacy of oxygen-sensitive tumor therapies in vitro.
目前，肿瘤乏氧灌注和有限的肿瘤药物渗透是限制氧敏感抗肿瘤治疗（如多柔比星（Dox）介导的化疗和光动力疗法（PDT））疗效的主要瓶颈。据我们所知，异常的肿瘤线粒体氧化磷酸化（OXPHOS）是导致这种现象的重要原因，它诱导了缺氧肿瘤微环境，并通过增强多药耐药蛋白 1（MDR-1）的表达增强了药物从肿瘤细胞中的流出。在这项研究中，新发现二甲双胍修饰壳聚糖（Bi-Ch）具有理想的线粒体抑制能力，从而降低了破坏线粒体功能以逆转肿瘤缺氧和抑制 MDR-1 表达所需的剂量。通过这种方式，Bi-Ch 有效地增加了肿瘤细胞中 Dox 的积累，并由于 Dox 产生的 ROS 增加放大了其细胞毒性。因此，Bi-Ch 可用于提高体外氧敏感肿瘤治疗的疗效。
