Defeating relapsed and refractory malignancies through a nano-enabled mitochondria-mediated respiratory inhibition and damage pathway
Abstract
Hypoxia, which frequently reduces the sensitivity to many therapeutic interventions, including chemotherapy, radiotherapy and phototherapy, has been acknowledged as an important reason for poor prognosis. Burgeoning evidences have proved that the tumor hypoxia microenvironment can reduce the therapeutic effect on tumor through inhibiting the drug efficacy, limiting immune cell infiltration of tumors and accelerating tumor recurrence and metastasis. However, the relationship between oxygen supply and the proliferation of cancer cells is still ambiguous and argued. Different from the current commonly used oxygen supply strategies, this study concentrated on the reduction of endogenous oxygen consumption. Specifically, a novel photosensitizers (IR780) and metformin are packaged in PEG-PCL liposomes. Once such nanoparticles accumulated in tumor tissues, the tumor foci were irradiated through 808 nm laser, generated ROS to further release metformin and IR780. Metformin can directly inhibit the activity of complex Ⅰ in the mitochondrial electron transport chain, thus performed a potent inhibitor of cell respiration. After overcoming tumor hypoxia, the combination of mitochondria-targeted photodynamic therapy (PDT) and photothermic therapy (PTT) via IR780 may achieve superior synergistically therapeutic efficacy. Benefit from excellent characteristics of IR780, such synergistic PDT PTT with the inhibition of mitochondrial respiration can be monitored through near-infrared/photoacoustic dual-modal imaging. Such a conception of reducing endogenous oxygen consumption may offer a novel way to solve the important puzzles of hypoxia-induced tumor resistance to therapeutic interventions, not limited to phototherapy.
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Metformin alleviates tumor hypoxia by reducing oxygen consumption by inhibiting complex I in the mitochondrial electron transport chain.
“In addition, studies have shown that metformin (Met), a typical antidiabetic drug, also alleviates tumor hypoxia by reducing oxygen consumption by inhibiting complex I in the mitochondrial electron transport chain.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [277]
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- Authors
- Yang, Z., Wang, J., Liu, S., Li, X., Miao, L., Yang, B., Zhang, C., He, J., Ai, S., & Guan, W.
- Affiliations
- Nanjing Drum Tower Hospital (CN)
- Nanjing University (CN)
- Corresponding author
- He, Jian
- Ai, Shichao
- Guan, Wenxian
- ORCID
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 229
- Pages
- 119580
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W2982391580
- Cited by
- 165
- References
- 74
- Citations by year
- 2026: 7 · 2025: 21 · 2024: 24 · 2023: 17 · 2022: 35 · 2021: 37 · 2020: 23 · 2019: 1
- FWCI
- 8.46
- Type
- journal article
- Language
- en
- Update notices
- erratum (2022-05-01)
- Open access
- closed
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Key Research Plan and Social Development Project of Jiangsu Province China (BE2016603)
- State Commission of Science Technology of China (2016YFC0104105)
- National Natural Science Foundation of China (81372364)
- Technology and Education Jiangsu Provincial Medical Youth Talent (QNRC2016120)
- health promotion project of Jiangsu province (QNRC2016041)
- Medical Science and technology development Foundation Nanjing (YKK15067, QRX11178)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- tumor hypoxia, IR780, metformin, photodynamic therapy, photothermal therapy, mitochondrial complex I inhibition, mitochondrial respiration inhibition, photosensitizer delivery, dual-modality imaging, tumor microenvironment, drug resistance
- MeSH terms
- Humans, Mitochondria, Neoplasms, Photochemotherapy, Phototherapy, Photosensitizing Agents, Cell Line, Tumor, Nanoparticles, Tumor Microenvironment
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