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Dual tumor- and subcellular-targeted photodynamic therapy using glucose-functionalized MoS2 nanoflakes for multidrug-resistant tumor ablation

Shaohui Xu Orcid Logo, Pan Zhang, Isabelle Heing-Becker, Junmei Zhang, Peng Tang, Raju Bej Orcid Logo, Sumati Bhatia Orcid Logo, Yinan Zhong, Rainer Haag Orcid Logo

Biomaterials, Volume: 290, Start page: 121844

Swansea University Author: Sumati Bhatia Orcid Logo

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DOI (Published version): 10.1016/j.biomaterials.2022.121844

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 wa...

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Published in: Biomaterials
ISSN: 0142-9612
Published: Elsevier BV 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa64855
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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.
Keywords: Precise subcellular organelle targeting, Endoplasmic reticulum stress, Mitochondrial dysfunction, Molybdenum disulfide, Reversal of tumor multidrug-resistance, Photodynamic therapy
College: Faculty of Science and Engineering
Funders: The authors acknowledge financial support from the Collaborative Research Center 1449 of the DFG (Germany). S. Xu acknowledges the financial support of the China Scholarship Council (CSC). S. Bhatia acknowledges the financial support from DFG project number 458564133. P. Zhang and Y. Zhong acknowledge the National Natural Science Foundation of China NSFC 52273162 and 51803238.
Start Page: 121844

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