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Endogenous ROS-Mediated Covalent Immobilization of Gold Nanoparticles in Mitochondria: A "Sharp Sword" in Tumor
Yan Zhao1, Yali Feng1, Jiachen Li1
1State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, P. R. China.
Abstract:
Mitochondria as one of the key subcellular organelles have been well recognized as a promising druggable target and are closely associated with energy supply and various cellular functions. Realizing high accumulation and prolonged retention of radiosensitizers in the cellular mitochondria of tumors is an effective way to improve radiotherapeutic efficacy. Herein, we develop mitochondria-targeting and protein sulfenic acid (PSA)-reactive gold nanoparticles (dAuNP-TPP) that are fabricated by incorporating triphenylphosphine and 1,3-cyclohexanedione onto the surface of AuNPs (∼20 nm) to improve CT imaging and radiotherapeutic efficacy of tumors. Taking advantage of the specific mitochondrial targeting and PSA-mediated on-site covalent immobilization, this nanosystem shows significantly enhanced accumulation and retention in mitochondria with approximately 5.22-fold higher enrichment than nonimmobilizable AuNP-TPP. More notably, the covalent immobilization of dAuNP-TPP in cellular mitochondria could induce a dramatic reduction of ATP, leading to serious mitochondrial disruption, combined with the radiosensitization effect, in consequence achieving efficient radiotherapy of breast tumors in vivo. This subcellular organelle-targeted and immobilizable strategy may offer a valuable and universal tool for efficient tumor treatment.
Insights
Researchers developed novel gold nanoparticles that target tumor mitochondria, enhancing radiotherapy. These nanoparticles improve imaging and treatment by accumulating in mitochondria, disrupting energy production, and sensitizing tumors to radiation.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Radiotherapy
Background:
- Mitochondria are crucial for cellular energy and function, making them a key target for cancer therapy.
- Improving radiosensitizer accumulation in tumor mitochondria enhances radiotherapy efficacy.
- Targeting subcellular organelles offers a novel strategy for cancer treatment.
Purpose of the Study:
- To develop mitochondria-targeting, protein sulfenic acid (PSA)-reactive gold nanoparticles (dAuNP-TPP) for improved CT imaging and tumor radiotherapy.
- To investigate the enhanced accumulation and retention of dAuNP-TPP in mitochondria.
- To evaluate the therapeutic efficacy of dAuNP-TPP in combination with radiotherapy for breast tumors.
Main Methods:
- Fabrication of gold nanoparticles (AuNPs) surface-modified with triphenylphosphine and 1,3-cyclohexanedione (dAuNP-TPP).
- Evaluation of mitochondrial targeting and PSA-mediated covalent immobilization of dAuNP-TPP in cancer cells.
- Assessment of ATP reduction, mitochondrial disruption, and radiosensitization effects in vitro.
- In vivo studies on breast tumor radiotherapy using the dAuNP-TPP nanosystem.
Main Results:
- dAuNP-TPP demonstrated specific targeting and covalent immobilization within mitochondria, achieving 5.22-fold higher enrichment than non-immobilizable nanoparticles.
- Covalent immobilization led to significant ATP reduction and mitochondrial disruption.
- The dAuNP-TPP nanosystem combined with radiotherapy achieved efficient in vivo treatment of breast tumors.
- Enhanced CT imaging capabilities were observed due to nanoparticle accumulation.
Conclusions:
- Mitochondria-targeted and immobilizable gold nanoparticles offer a promising strategy for enhancing tumor radiotherapy.
- This approach improves radiosensitizer retention and efficacy by leveraging specific organelle targeting and covalent binding.
- The developed nanosystem shows potential as a universal tool for efficient cancer treatment through subcellular organelle targeting.
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