Rational Design of Biocompatible Ir(III) Photosensitizer to Overcome Drug‐Resistant Cancer via Oxidative Autophagy Inhibition
Abstract Autophagy is a crucial quality control mechanism that degrades damaged cellular components through lysosomal fusion with autophagosomes. However, elevated autophagy levels can promote drug resistance in cancer cells, enhancing their survival. Downregulation of autophagy through oxidative st...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407236 |
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| author | Mingyu Park Jung Seung Nam Taehyun Kim Gwangsu Yoon Seoyoon Kim Chaiheon Lee Chae Gyu Lee Sungjin Park Kochan S. Bejoymohandas Jihyeon Yang Yoon Hee Kwon Yoo Jin Lee Jeong Kon Seo Duyoung Min Taiho Park Tae‐Hyuk Kwon |
| author_facet | Mingyu Park Jung Seung Nam Taehyun Kim Gwangsu Yoon Seoyoon Kim Chaiheon Lee Chae Gyu Lee Sungjin Park Kochan S. Bejoymohandas Jihyeon Yang Yoon Hee Kwon Yoo Jin Lee Jeong Kon Seo Duyoung Min Taiho Park Tae‐Hyuk Kwon |
| author_sort | Mingyu Park |
| collection | DOAJ |
| description | Abstract Autophagy is a crucial quality control mechanism that degrades damaged cellular components through lysosomal fusion with autophagosomes. However, elevated autophagy levels can promote drug resistance in cancer cells, enhancing their survival. Downregulation of autophagy through oxidative stress is a clinically promising strategy to counteract drug resistance, yet precise control of oxidative stress in autophagic proteins remains challenging. Here, a molecular design strategy of biocompatible neutral Ir(III) photosensitizers is demonstrated, B2 and B4, for precise reactive oxygen species (ROS) control at lysosomes to inhibit autophagy. The underlying molecular mechanisms for the biocompatibility and lysosome selectivity of Ir(III) complexes are explored by comparing B2 with the cationic or the non‐lysosome‐targeting analogs. Also, the biological mechanisms for autophagy inhibition via lysosomal oxidation are explored. Proteome analyses reveal significant oxidation of proteins essential for autophagy, including lysosomal and fusion‐mediator proteins. These findings are verified in vitro, using mass spectrometry, live cell imaging, and a model SNARE complex. The anti‐tumor efficacy of the precise lysosomal oxidation strategy is further validated in vivo with B4, engineered for red light absorbance. This study is expected to inspire the therapeutic use of spatiotemporal ROS control for sophisticated modulation of autophagy. |
| format | Article |
| id | doaj-art-43759625b99747feae16da7e627f4310 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-43759625b99747feae16da7e627f43102025-01-13T15:29:43ZengWileyAdvanced Science2198-38442025-01-01122n/an/a10.1002/advs.202407236Rational Design of Biocompatible Ir(III) Photosensitizer to Overcome Drug‐Resistant Cancer via Oxidative Autophagy InhibitionMingyu Park0Jung Seung Nam1Taehyun Kim2Gwangsu Yoon3Seoyoon Kim4Chaiheon Lee5Chae Gyu Lee6Sungjin Park7Kochan S. Bejoymohandas8Jihyeon Yang9Yoon Hee Kwon10Yoo Jin Lee11Jeong Kon Seo12Duyoung Min13Taiho Park14Tae‐Hyuk Kwon15Department of Chemistry Ulsan National Institute of Science and Technology (UNIST) Ulsan 44919 Republic of KoreaDepartment of Chemistry Ulsan National Institute of Science and Technology (UNIST) Ulsan 44919 Republic of KoreaDepartment of Chemical Engineering Pohang University of Science and Technology (POSTECH) 77 Cheongam‐Ro, Nam‐Gu Pohang Gyeongbuk 37673 Republic of KoreaDepartment of Chemistry Ulsan National Institute of Science and Technology (UNIST) Ulsan 44919 Republic of KoreaDepartment of Chemistry Ulsan National Institute of Science and Technology (UNIST) Ulsan 44919 Republic of KoreaDepartment of Chemistry Ulsan National Institute of Science and Technology (UNIST) Ulsan 44919 Republic of KoreaDepartment of Chemistry Ulsan National Institute of Science and Technology (UNIST) Ulsan 44919 Republic of KoreaDepartment of Chemical Engineering Pohang University of Science and Technology (POSTECH) 77 Cheongam‐Ro, Nam‐Gu Pohang Gyeongbuk 37673 Republic of KoreaDepartment of Chemical Engineering Pohang University of Science and Technology (POSTECH) 77 Cheongam‐Ro, Nam‐Gu Pohang Gyeongbuk 37673 Republic of KoreaResearch Center O2MEDi inc. Ulsan 44919 Republic of KoreaResearch Center O2MEDi inc. Ulsan 44919 Republic of KoreaDepartment of Chemistry Ulsan National Institute of Science and Technology (UNIST) Ulsan 44919 Republic of KoreaResearch Center O2MEDi inc. Ulsan 44919 Republic of KoreaDepartment of Chemistry Ulsan National Institute of Science and Technology (UNIST) Ulsan 44919 Republic of KoreaDepartment of Chemical Engineering Pohang University of Science and Technology (POSTECH) 77 Cheongam‐Ro, Nam‐Gu Pohang Gyeongbuk 37673 Republic of KoreaDepartment of Chemistry Ulsan National Institute of Science and Technology (UNIST) Ulsan 44919 Republic of KoreaAbstract Autophagy is a crucial quality control mechanism that degrades damaged cellular components through lysosomal fusion with autophagosomes. However, elevated autophagy levels can promote drug resistance in cancer cells, enhancing their survival. Downregulation of autophagy through oxidative stress is a clinically promising strategy to counteract drug resistance, yet precise control of oxidative stress in autophagic proteins remains challenging. Here, a molecular design strategy of biocompatible neutral Ir(III) photosensitizers is demonstrated, B2 and B4, for precise reactive oxygen species (ROS) control at lysosomes to inhibit autophagy. The underlying molecular mechanisms for the biocompatibility and lysosome selectivity of Ir(III) complexes are explored by comparing B2 with the cationic or the non‐lysosome‐targeting analogs. Also, the biological mechanisms for autophagy inhibition via lysosomal oxidation are explored. Proteome analyses reveal significant oxidation of proteins essential for autophagy, including lysosomal and fusion‐mediator proteins. These findings are verified in vitro, using mass spectrometry, live cell imaging, and a model SNARE complex. The anti‐tumor efficacy of the precise lysosomal oxidation strategy is further validated in vivo with B4, engineered for red light absorbance. This study is expected to inspire the therapeutic use of spatiotemporal ROS control for sophisticated modulation of autophagy.https://doi.org/10.1002/advs.202407236autophagydrug‐resistanceIr(III) complexesoxidationphotodynamic therapyprotein modifications |
| spellingShingle | Mingyu Park Jung Seung Nam Taehyun Kim Gwangsu Yoon Seoyoon Kim Chaiheon Lee Chae Gyu Lee Sungjin Park Kochan S. Bejoymohandas Jihyeon Yang Yoon Hee Kwon Yoo Jin Lee Jeong Kon Seo Duyoung Min Taiho Park Tae‐Hyuk Kwon Rational Design of Biocompatible Ir(III) Photosensitizer to Overcome Drug‐Resistant Cancer via Oxidative Autophagy Inhibition Advanced Science autophagy drug‐resistance Ir(III) complexes oxidation photodynamic therapy protein modifications |
| title | Rational Design of Biocompatible Ir(III) Photosensitizer to Overcome Drug‐Resistant Cancer via Oxidative Autophagy Inhibition |
| title_full | Rational Design of Biocompatible Ir(III) Photosensitizer to Overcome Drug‐Resistant Cancer via Oxidative Autophagy Inhibition |
| title_fullStr | Rational Design of Biocompatible Ir(III) Photosensitizer to Overcome Drug‐Resistant Cancer via Oxidative Autophagy Inhibition |
| title_full_unstemmed | Rational Design of Biocompatible Ir(III) Photosensitizer to Overcome Drug‐Resistant Cancer via Oxidative Autophagy Inhibition |
| title_short | Rational Design of Biocompatible Ir(III) Photosensitizer to Overcome Drug‐Resistant Cancer via Oxidative Autophagy Inhibition |
| title_sort | rational design of biocompatible ir iii photosensitizer to overcome drug resistant cancer via oxidative autophagy inhibition |
| topic | autophagy drug‐resistance Ir(III) complexes oxidation photodynamic therapy protein modifications |
| url | https://doi.org/10.1002/advs.202407236 |
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