缺氧介导的 ROS 扩增通过 PD-L1/ROS 响应、双靶向、载药硫缩酮纳米颗粒触发线粒体介导的细胞凋亡,ACS Applied Materials & Interfaces

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缺氧介导的 ROS 扩增通过 PD-L1/ROS 响应、双靶向、载药硫缩酮纳米颗粒触发线粒体介导的细胞凋亡
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2021-05-10 , DOI: 10.1021/acsami.1c03594
Asmita Banstola ₁ , Kishwor Poudel ₂ , Shiva Pathak ₃ , Prakash Shrestha ₂ , Jong Oh Kim ₂ , Jee-Heon Jeong ₂ , Simmyung Yook ₁

Affiliation

由于纳米粒子的高肿瘤特异性，活性氧 (ROS) 响应刺激与纳米粒子的合并引起了相当大的兴趣。缺氧在加速细胞内 ROS 产生中起关键作用。在此，我们报告了癌细胞 (PD-L1) 和 ROS 响应、双靶向、替莫唑胺 (TMZ) 负载纳米系统的构建，该纳米系统在缺氧肿瘤微环境中提供更好的抗癌效果。双靶向系统促进了癌细胞的渗透。提高高 ROS 水平的缺氧条件加速了原位TMZ 从抗 PD-L1-TKNPs 中释放。TMZ 产生的超积累 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）中制造的TMZ在体内条件下提供了极好的肿瘤积累和延缓肿瘤生长。在用抗 PD-L1-TMZ-TKNPs 治疗后，随着凋亡标记物、DNA 双链断裂标记物的激活和肿瘤组织中血管生成标记物的下调，细胞凋亡效应的增强发挥了强大的抗癌作用。总的来说，纳米结构提供了深入的肿瘤渗透和高药物释放，并拓宽了 ROS 响应纳米系统的应用，以取得成功的抗癌效果。

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Hypoxia-Mediated ROS Amplification Triggers Mitochondria-Mediated Apoptotic Cell Death via PD-L1/ROS-Responsive, Dual-Targeted, Drug-Laden Thioketal Nanoparticles

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 in situ 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 in vivo 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.

更新日期：2021-05-19

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