Chemoresistance originating from cancer stem cells (CSCs) is a major cause of cancer treatment failure and highlights the need to develop CSC-targeting therapies. Although enormous progress in both photodynamic therapy (PDT) and chemodynamic therapy (CDT) has been made in recent decades, the efficacy of these modalities against CSC remains limited. Here, we report a new generation photosensitizer, CA9-BPS-Cu(ii), a system that combines three subunits within a single molecule, namely a copper catalyst for CDT, a boron dipyrromethene photosensitizer for PDT, and acetazolamide for CSC targeting via carbonic anhydrase-9 (CA9) binding. A therapeutic effect in MDA-MB-231 cells was observed that is ascribed to elevated oxidative stress mediated by a combined CDT/PDT effect, as well as through copper-catalysed glutathione oxidation. The CSC targeting ability of CA9-BPS-Cu(ii) was evident from the enhanced affinity of CA9-BPS-Cu(ii) towards CD133-positive MDA-MB-231 cells where CA9 is overexpressed vs. CD133-negative cells. Moreover, the efficacy of CA9-BPS-Cu(ii) was successfully demonstrated in a xenograft mouse tumour model.
Bibliographical noteFunding Information:
This work was supported by CRI project (2018R1A3B1052702, JSK) and the Basic Science Research Programs (2020R1F1A1073235, HSJ and 2022R1A2C2007696, JH and 2022R1C1C2007637, SK) from the National Research Foundation of Korea (NRF) funded by the Ministry of Education. The work in Austin was supported through May of 2020 by the National Institutes of Health (CA68682, JLS). Further support was provided by the Robert A. Welch Foundation (F-0018, JLS). We also gratefully acknowledge support from Korea University, Hyupsung University and the University of Texas at Austin.
© 2023 The Royal Society of Chemistry.
ASJC Scopus subject areas
- General Chemistry