![]() Transcriptomic profiling reveals perturbed p53, NF-κB, and GnRH signaling pathways interconnected with NOX inhibition. Moreover, the NDC selectively diminishes non-mitochondrial reactive oxygen species (ROS) but significantly elevates cytotoxic ROS through mitochondrial membrane depolarization. NOX inhibition reprograms the metabolic phenotype by simultaneously impairing mitochondrial respiration and glycolysis. The self-assembled nanoparticle-drug conjugate (NDC) enables hyaluronidase-activatable controlled release and facilitates cellular trafficking. Here, we rationally design diversified cyclodiaryliodonium NADPH oxidase (NOX) inhibitors with tens of nanomolar optimal growth inhibition and implement CD44-targeted delivery using synthesized sulfated glycosaminoglycan derivatives. Pancreatic cancer renders a principal cause of cancer mortalities with a dismal prognosis, lacking sufficiently safe and effective therapeutics.
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