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

Abstract

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.

Two-photon excitable membrane targeting polyphenolic carbon dots for long-term imaging and pH-responsive chemotherapeutic drug delivery for synergistic tumor therapy

“…The strong green fluorescence in the cytoplasm is due to the higher accumulation and higher affinity of g-CQDs@Dox towards cell organelles in tumor cells. 20,62 Since Dox is known to target DNA and induce DNA damage, 59 we investigated the DNA damage mechanism via TUNEL assay, and the results are shown in Fig. 4e(iii).…”

Inflammation-sensing catalase-mimicking nanozymes alleviate acute kidney injury via reversing local oxidative stress

“…Recently, TK linkers have gained attention in developing ROS-responsive delivery systems to ROS-rich inflammation sites. TK bonds will be cleaved instantly by ROS oxidants, resulting in the loss of structural integrity of nanoparticulate systems, accelerating the release of loaded therapeutic agents [ 24 – 26 ]. Moreover, TK bonds are stable under physiological conditions.…”

Nanoparticles mediated tumor microenvironment modulation: current advances and applications

“…This elegant system can also enable drug delivery monitoring, thus providing valuable insights for tumor precision treatment and personalized medicine approaches. Banstola et al [ 83 ] constructed an interesting novel nano-based ROS system. They synthesized a PDL-1 cancer cell and ROS sensitive dual targeted TMZ nanosystem designed to enhance therapeutic efficacy in hypoxic TME.…”