Fluorescent Nanoparticles Achieve Efficient Photothermal Conversion and Enhanced Antitumor Efficacy Through Intermolecular Aggregation-Caused Quenching

Abstract

The efficacy of photothermal therapy (PTT) in antitumor applications is often limited by inadequate tumor targeting and low photothermal conversion efficiency (PCE) of photosensitizers. In this study, we designed a photothermal nanoparticle, MPF@IR780, to enhance photosensitizers' targeting and PCE. First, MPF@IR780 improves the delivery of photosensitizers to tumor tissue through the enhanced permeability and retention (EPR) effect. Furthermore, hydrophobic ferrocene was incorporated into the nanoparticle core to increase structural compactness, leading to a strong aggregation-caused quenching (ACQ) effect and an improved PCE of the photosensitizer under near-infrared (NIR) irradiation. Mechanistically, MPF@IR780 induces PANoptosis and ferroptosis in cancer cells through thermal damage and oxidative stress, providing an efficient approach for oncotherapy. This strategy of amplifying the effects of PTT by enhancing the ACQ of photosensitizers offers a promising method for advancing the next generation of PTT.

Keywords

aggregation-caused quenching / ferroptosis / PANoptosis / photothermal therapy

References

[1] H. Sung, J. Ferlay, R. L. Siegel, et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 71 (2021): 209-249.

[2] Z. Chen, P. Zhang, Y. Xu, et al., “Surgical Stress and Cancer Progression: The Twisted Tango,” Molecular Cancer 18 (2019): 132.

[3] A. Aref and A. Abdalla, “Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Induction or Consolidation Chemotherapy?,” Journal of Clinical Oncology 40 (2022): 2515-2519.

[4] M. C. Vozenin, J. Bourhis, and M. Durante, “Towards Clinical Translation of FLASH Radiotherapy,” Nature Reviews Clinical Oncology 19 (2022): 791-803.

[5] M. Yi, X. Zheng, M. Niu, S. Zhu, H. Ge, and K. Wu, “Combination Strategies With PD-1/PD-L1 Blockade: Current Advances and Future Directions,” Molecular Cancer 21 (2022): 28.

[6] A. U. Kishan, Y. Sun, H. Hartman, et al., “Androgen Deprivation Therapy Use and Duration With Definitive Radiotherapy for Localised Prostate Cancer: An Individual Patient Data Meta-analysis,” Lancet Oncology 23 (2022): 304-316.

[7] X. Li, J. F. Lovell, J. Yoon, and X. Chen, “Clinical Development and Potential of Photothermal and Photodynamic Therapies for Cancer,” Nature Reviews Clinical Oncology 17 (2020): 657-674.

[8] A. R. Rastinehad, H. Anastos, E. Wajswol, et al., “Gold Nanoshell-Localized Photothermal Ablation of Prostate Tumors in a Clinical Pilot Device Study,” Proceedings of the National Academic of Sciences 116 (2019): 18590-18596.

[9] C. Zhou, L. Zhang, T. Sun, et al., “Activatable NIR-II Plasmonic Nanotheranostics for Efficient Photoacoustic Imaging and Photothermal Cancer Therapy,” Advanced Materials 33 (2021): e2006532.

[10] P. Wang, J. Li, M. Wei, et al., “Tumor-Microenvironment Triggered Signal-to-noise Boosting Nanoprobes for NIR-IIb Fluorescence Imaging Guided Tumor Surgery and NIR-II Photothermal Therapy,” Biomaterials 287 (2022): 121636.

[11] H. Luo and S. Gao, “Recent Advances in Fluorescence Imaging-Guided Photothermal Therapy and Photodynamic Therapy for Cancer: From Near-Infrared-I to Near-Infrared-II,” Journal of Controlled Release 362 (2023): 425-445.

[12] Y. Yang, X. Fan, L. Li, et al., “Semiconducting Polymer Nanoparticles as Theranostic System for Near-Infrared-II Fluorescence Imaging and Photothermal Therapy Under Safe Laser Fluence,” ACS Nano 14 (2020): 2509-2521.

[13] Y. Xu, X. Zhai, P. Su, et al., “Highly Stable Semiconducting Polymer Nanoparticles for Multi-Responsive Chemo/Photothermal Combined Cancer Therapy,” Theranostics 10(2020): 5966-5978.

[14] C. Li, G. Jiang, J. Yu, et al., “Fluorination Enhances NIR-II Emission and Photothermal Conversion Efficiency of Phototheranostic Agents for Imaging-Guided Cancer Therapy,” Advanced Materials 35 (2023): e2208229.

[15] X. Y. Ran, P. Chen, Y. Z. Liu, et al., “Rational Design of Polymethine Dyes With NIR-II Emission and High Photothermal Conversion Efficiency for Multimodal-Imaging-Guided Photo-Immunotherapy,” Advanced Materials 35 (2023): e2210179.

[16] M. Farokhi, F. Mottaghitalab, M. R. Saeb, and S. Thomas, “Functionalized Theranostic Nanocarriers With Bio-inspired Polydopamine for Tumor Imaging and Chemo-photothermal Therapy,” Journal of Controlled Release 309 (2019): 203-219.

[17] X. Li, T. Yong, Z. Wei, et al., “Reversing Insufficient Photothermal Therapy-Induced Tumor Relapse and Metastasis by Regulating Cancer-Associated Fibroblasts,” Nature Communications 13 (2022): 2794.

[18] K. B. Pointer, S. P. Pitroda, and R. R. Weichselbaum, “Radiotherapy and Immunotherapy: Open Questions and Future Strategies,” Trends in Cancer 8 (2022): 9-20.

[19] Y. H. Cheng, C. He, J. E. Riviere, N. A. Monteiro-Riviere, and Z. Lin, “Meta-Analysis of Nanoparticle Delivery to Tumors Using a Physiologically Based Pharmacokinetic Modeling and Simulation Approach,” ACS Nano 14 (2020): 3075-3095.

[20] Z. Deng, C. Fang, X. Ma, X. Li, Y. J. Zeng, and X. Peng, “One Stone Two Birds: Zr-Fc Metal-Organic Framework Nanosheet for Synergistic Photothermal and Chemodynamic Cancer Therapy,” ACS Applied Materials & Interfaces 12 (2020): 20321-20330.

[21] K. Laxman, B. P. K. Reddy, S. K. Mishra, et al., “BF2-Oxasmaragdyrin Nanoparticles: A Non-Toxic, Photostable, Enhanced Non-Radiative Decay-Assisted Efficient Photothermal Cancer Theragnostic Agent,” ACS Applied Materials & Interfaces 12 (2020): 52329-52342.

[22] S. Liu, X. Zhou, H. Zhang, et al., “Molecular Motion in Aggregates: Manipulating TICT for Boosting Photothermal Theranostics,” Journal of the American Chemical Society 141 (2019): 5359-5368.

[23] Q. Zou, M. Abbas, L. Zhao, S. Li, G. Shen, and X. Yan, “Biological Photothermal Nanodots Based on Self-Assembly of Peptide-Porphyrin Conjugates for Antitumor Therapy,” Journal of the American Chemical Society 139 (2017): 1921-1927.

[24] L. Martin-Banderas, J. Alvarez-Fuentes, M. Duran-Lobato, et al., “Cannabinoid Derivate-Loaded PLGA Nanocarriers for Oral Administration: Formulation, Characterization, and Cytotoxicity Studies,” International Journal of Nanomedicine 7 (2012): 5793-5806.

[25] J. Lin, H. Yang, Y. Zhang, et al., “Ferrocene-Based Polymeric Nanoparticles Carrying Doxorubicin for Oncotherapeutic Combination of Chemotherapy and Ferroptosis,” Small 19 (2023): e2205024.

[26] R. K. S. Malireddi, S. Kesavardhana, and T. D. Kanneganti, “ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-Optosis),” Frontiers in Cellular and Infection Microbiology 9 (2019): 406.

[27] M. Zheng, R. Karki, P. Vogel, and T. D. Kanneganti, “Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense,” Cell 181 (2020): 674-687.e13.

[28] R. Karki, B. Sundaram, B. R. Sharma, et al., “ADAR1 Restricts ZBP1-Mediated Immune Response and PANoptosis to Promote Tumorigenesis,” Cell Reports 37 (2021): 109858.

[29] D. K. W. Ocansey, F. Qian, P. Cai, et al., “Current Evidence and Therapeutic Implication of PANoptosis in Cancer,” Theranostics 14 (2024): 640-661.

[30] S. Kesavardhana, R. K. S. Malireddi, A. R. Burton, et al., “The Zα2 Domain of ZBP1 Is a Molecular Switch Regulating Influenza-Induced PANoptosis and Perinatal Lethality During Development,” Journal of Biological Chemistry 295 (2020): 8325-8330.

[31] H. Cai, M. Lv, and T. Wang, “PANoptosis in Cancer, the Triangle of Cell Death,” Cancer Medicine 12 (2023): 22206-22223.

[32] Z. Shi, H. Bai, J. Wu, et al., “Acceptor Engineering Produces Ultrafast Nonradiative Decay in NIR-II Aza-BODIPY Nanoparticles for Efficient Osteosarcoma Photothermal Therapy via Concurrent Apoptosis and Pyroptosis,” Research 6 (2023): 0169.

[33] J. Yan, X. Ma, D. Liang, et al., “An Autocatalytic Multicomponent DNAzyme Nanomachine for Tumor-Specific Photothermal Therapy Sensitization in Pancreatic Cancer,” Nature Communications 14 (2023): 6905.

[34] T. X. Zhang, X. Hou, Y. Kong, et al., “A Hypoxia-Responsive Supramolecular Formulation for Imaging-Guided Photothermal Therapy,” Theranostics 12 (2022): 396-409.

[35] J. Peng, Y. Xiao, W. Li, et al., “Photosensitizer Micelles Together With IDO Inhibitor Enhance Cancer Photothermal Therapy and Immunotherapy,” Advanced Science 5 (2018): 1700891.

[36] Y. Huang, Y. Lin, B. Li, et al., “Combination Therapy to Overcome Ferroptosis Resistance by Biomimetic Self-Assembly Nano-Prodrug,” Asian Journal of Pharmaceutical Sciences 18 (2023): 100844.

[37] G. Gong, J. Pan, Y. He, et al., “Self-assembly of Nanomicelles With Rationally Designed Multifunctional Building Blocks for Synergistic Chemo-Photodynamic Therapy,” Theranostics 12 (2022): 2028-2040.

[38] M. Yu, Z. Ye, S. Liu, et al., “Redox-Active Ferrocene Quencher-Based Supramolecular Nanomedicine for NIR-II Fluorescence-Monitored Chemodynamic Therapy,” Angewandte Chemie International Edition 63 (2024): e202318155.

[39] J. Li, J. Wang, J. Zhang, et al., “A Facile Strategy of Boosting Photothermal Conversion Efficiency Through State Transformation for Cancer Therapy,” Advanced Materials 33 (2021): e2105999.

[40] Y. Yin, L. Gao, P. Sun, et al., “pH/ROS Dual Stimuli-Responsive Anionic Flexible Supramolecular Organic Frameworks for Synergistic Therapy,” Acta Biomaterialia 172 (2023): 395-406.

[41] Y. Tian, M. R. Younis, Y. Tang, et al., “Dye-Loaded Mesoporous Polydopamine Nanoparticles for Multimodal Tumor Theranostics With Enhanced Immunogenic Cell Death,” Journal of Nanobiotechnology 19 (2021): 365.

[42] S. Y. Luo, Y. Wang, S. H. Shen, et al., “IR780-Loaded Hyaluronic Acid@Gossypol-Fe(III)-EGCG Infinite Coordination Polymer Nanoparticles for Highly Efficient Tumor Photothermal/Coordinated Dual Drugs Synergistic Therapy,” Advanced Functional Materials 31 (2021): 2100954.

[43] R. Zhang, Z. Wang, Y. Wu, H. Fu, and J. Yao, “A Novel Redox-Fluorescence Switch Based on a Triad Containing Ferrocene and Perylene Diimide Units,” Organic Letters 10 (2008): 3065-3068.

[44] Y. Liu, H. Wang, C. Xiong, Y. Yuan, Y. Chai, and R. Yuan, “A Sensitive Electrochemiluminescence Immunosensor Based on Luminophore Capped Pd@Au Core-Shell Nanoparticles as Signal Tracers and Ferrocenyl Compounds as Signal Enhancers,” Biosensors & Bioelectronics 81 (2016): 334-340.

[45] D. Yin, C. Yao, Y. Chen, et al., “HClO-Activated Near-Infrared Fluorogenic Aza-BODIPY-Bisferrocene Triad With High Turn-On Ratio for In Vivo Biosensing,” Advanced Healthcare Materials 11 (2022): e2201139.

[46] R. Wei, J. Li, W. Lin, et al., “Nanoparticle-Mediated Blockade of CXCL12/CXCR4 Signaling Enhances Glioblastoma Immunotherapy: Monitoring Early Responses With MRI Radiomics,” Acta Biomaterialia 177 (2024): 414-430.

[47] S. Li, K. H. Lui, W. S. Lau, et al., “MSOT-Guided Nanotheranostics for Synergistic Mild Photothermal Therapy and Chemotherapy to Boost Necroptosis/Apoptosis,” ACS Applied Materials & Interfaces 14 (2022), 33712-33725.

[48] X. Jiang, M. Yang, Y. Fang, et al., “A Photo-Activated Thermoelectric Catalyst for Ferroptosis-/Pyroptosis-Boosted Tumor Nanotherapy,” Advanced Healthcare Materials 12 (2023): e2300699.

[49] J. F. Lin, P. S. Hu, Y. Y. Wang, et al., “Phosphorylated NFS1 Weakens Oxaliplatin-Based Chemosensitivity of Colorectal Cancer by Preventing PANoptosis,” Signal Transduction and Targeted Therapy 7 (2022): 54.

[50] B. R. Stockwell, “Ferroptosis Turns 10: Emerging Mechanisms, Physiological Functions, and Therapeutic Applications,” Cell 185 (2022): 2401-2421.

[51] Y. Liu, K. Ai, J. Liu, M. Deng, Y. He, and L. Lu, “Dopamine-Melanin Colloidal Nanospheres: An Efficient Near-Infrared Photothermal Therapeutic Agent for in Vivo Cancer Therapy,” Advanced Materials 25 (2013): 1353-1359.

[52] W. Ren, Y. Yan, L. Zeng, et al., “A Near Infrared Light Triggered Hydrogenated Black TiO₂ for Cancer Photothermal Therapy,” Advanced Healthcare Materials 4 (2015): 1526-1536.

RIGHTS & PERMISSIONS

2024 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.