College of Pharmacy, Keimyung University, Daegu 42601, South Korea.
College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, South Korea.
ACS Appl Mater Interfaces. 2021 May 19;13(19):22955-22969. doi: 10.1021/acsami.1c03594. Epub 2021 May 10.
Amalgamation of the reactive oxygen species (ROS)-responsive stimulus with nanoparticles has gained considerable interest owing to their high tumor specificity. Hypoxia plays a pivotal role in the acceleration of intracellular ROS production. Herein, we report the construction of a cancer cell (PD-L1)- and ROS-responsive, dual-targeted, temozolomide (TMZ)-laden nanosystem which offers a better anticancer effect in a hypoxic tumor microenvironment. A dual-targeted system boosted permeation in the cancer cells. Hypoxic conditions elevating the high ROS level accelerated the release of TMZ from anti-PD-L1-TKNPs. Hyperaccumulated ROS engendered from TMZ caused oxidative damage leading to mitochondria-mediated apoptosis. TMZ fabricated in the multifunctional nanosystem (anti-PD-L1-TMZ-TKNPs) provided excellent tumor accumulation and retarded tumor growth under conditions. The elevated apoptosis effect with the activation of an apoptotic marker, DNA double-strand breakage marker, and downregulation of the angiogenesis marker in the tumor tissue following treatment with anti-PD-L1-TMZ-TKNPs exerts robust anticancer effect. Collectively, the nanoconstruct offers deep tumor permeation and high drug release and broadens the application of the ROS-responsive nanosystem for a successful anticancer effect.
由于具有高肿瘤特异性，将活性氧（ROS）响应刺激物与纳米粒子结合已引起相当大的关注。缺氧在加速细胞内 ROS 产生方面起着关键作用。在此，我们报告了一种癌细胞（PD-L1）和 ROS 响应的、双靶向、载有替莫唑胺（TMZ）的纳米系统的构建，该系统在缺氧肿瘤微环境中提供了更好的抗癌效果。双靶向系统促进了癌细胞的渗透。缺氧条件下升高的高 ROS 水平加速了抗 PD-L1-TKNPs 中 TMZ 的释放。来自 TMZ 的过度积累的 ROS 引起氧化损伤，导致线粒体介导的细胞凋亡。在多功能纳米系统（抗 PD-L1-TMZ-TKNPs）中制备的 TMZ 在条件下提供了出色的肿瘤积累和肿瘤生长抑制。在使用抗 PD-L1-TMZ-TKNPs 治疗后，肿瘤组织中凋亡标志物的激活、DNA 双链断裂标志物的下调以及血管生成标志物的下调，产生了强大的抗癌作用。总之，该纳米结构提供了更深的肿瘤渗透和更高的药物释放，并拓宽了 ROS 响应纳米系统在成功抗癌效果方面的应用。
