Dual tumor- and subcellular-targeted photodynamic therapy using glucose-functionalized MoS2 nanoflakes for multidrug-resistant tumor ablation. (November 2022)

• Record Type: Journal Article
• Authors: Xu, Shaohui; Zhang, Pan; Heing-Becker, Isabelle; Zhang, Junmei; Tang, Peng; Bej, Raju; Bhatia, Sumati; Zhong, Yinan; Haag, Rainer
• Is Part Of: Biomaterials. Volume 290(2022)
• Publication Date: 2022-11
• Subjects: precise subcellular organelle targeting -- Endoplasmic reticulum stress -- Mitochondrial dysfunction -- Molybdenum disulfide -- Reversal of tumor multidrug-resistance -- Photodynamic therapy; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2022.121844
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Photodynamic therapy (PDT) is emerging as an efficient strategy to combat multidrug-resistant (MDR) cancer. However, the short half-life and limited diffusion of reactive oxygen species (ROS) undermine the therapeutic outcomes of this therapy. To address this issue, a tumor-targeting nanoplatform was developed to precisely deliver mitochondria- and endoplasmic reticulum (ER)-targeting PDT agents to desired sites for dual organelle-targeted PDT. The nanoplatform is constructed by functionalizing molybdenum disulfide (MoS2 ) nanoflakes with glucose-modified hyperbranched polyglycerol (hPG), and then loading the organelle-targeting PDT agents. The resultant nanoplatform Cy7.5-TG@GPM is demonstrated to mediate both greatly enhanced internalization within MDR cells and precise subcellular localization of PDT agents, facilitating in situ near-infrared (NIR)-triggered ROS generation for augmented PDT and reversal of MDR, causing impressive tumor shrinkage in a HeLa multidrug-resistant tumor mouse model. As revealed by mechanistic studies of the synergistic mitochondria- and ER-targeted PDT, ROS-induced ER stress not only activates the cytosine-cytosine-adenosine-adenosine thymidine/enhancer-binding protein homologous protein (CHOP) pro-apoptotic signaling pathway, but also cooperates with ROS-induced mitochondrial dysfunction to trigger cytochrome C release from the mitochondria and induce subsequent cell death. Furthermore, the mitochondrial dysfunction reduces ATP production and thereby contributes to the reversal of MDR. This nanoplatform, with its NIR-responsive properties and ability to target tumors and subcellular organelles, offers a promising strategy for effective MDR cancer therapy. Graphical abstract: Glucosylated MoS2 nanoflakes co-loaded with mitochondria and endoplasmic reticulum targeting photodynamic agents precisely damage subcellular organelles by reactive oxygen species, resulting in an impressive tumor shrinkage in multidrug-resistant tumor models. Mechanistic studies reveal that the nanoplatform triggers tumor cell apoptosis via synergistically inducing endoplasmic reticulum stress and promoting the release of cytochrome C into the cytoplasm. Image 1