An NIR-II Absorbing Injectable Hydrogel for Boosted Photo-Immunotherapy Toward Human Papillomavirus Associated Cancer

Abstract

Human papillomavirus (HPV) is a highly prevalent venereal pathogen accounting for genital warts and various cancers like cervical, anal, and oropharyngeal cancers. Although imiquimod, a topical medication, is commonly used to treat genital warts induced by HPV, its potential as an in situ immune response regulator for HPV-related cancers has rarely been explored. In this study, we developed an innovative synergistic therapeutic platform by integrating near-infrared-II (NIR-II) absorbing aggregation-induced emission (AIE) agent (TPE-BT-BBTD) and imiquimod into an injectable hydrogel named TIH. TPE-BT-BBTD molecule that serves as a photothermal agent, with exposure to a 1064 nm laser, effectively destroys tumor cells and releases tumor-related antigens. During the thermogenesis process, the hydrogel melts and releases imiquimod. The released imiquimod, in conjunction with the dead tumor antigens, stimulates dendritic cell maturation, activating the immune system to ultimately eliminate residual cancer cells. This novel approach combines the immunomodulatory effects of imiquimod with a 1064 nm-excitable photothermal agent in a hydrogel delivery system, offering a promising tactic for combating HPV-associated cancers.

Keywords

aggregation-induced emission / human papillomavirus / injectable hydrogel / NIR-II phototheranostics / photo-immunotherapy

References

[1] K. A. Szymonowicz and J. Chen, “Biological and Clinical Aspects of HPV-Related Cancers,” Cancer Biology & Medicine 17 (2020): 864-878.

[2] T. Lasanen, F. Frejborg, L. M. Lund, et al., “Single Therapeutic Dose of an Antiviral UL29 siRNA Swarm Diminishes Symptoms and Viral Load of Mice Infected Intranasally With HSV-1,” Smart Medicine 2 (2023): e20230009.

[3] R. S. Riley, C. H. June, R. Langer, and M. J. Mitchell, “Delivery Technologies for Cancer Immunotherapy,” Nature Reviews Drug Discovery 18 (2019): 175-196.

[4] F. Ma, J. Zhang, J. Zhang, and C. Zhang, “The TLR7 Agonists Imiquimod and Gardiquimod Improve DC-Based Immunotherapy for Melanoma in Mice,” Cellular & Molecular Immunology 7 (2010): 381-388.

[5] V. Kesic, X. Carcopino, M. Preti, et al., “The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) consensus statement on the Management of Vaginal Intraepithelial Neoplasia,” International Journal of Gynecological Cancer 33 (2023): 446-461.

[6] G. L. Szeto and S. D. Finley, “Integrative Approaches to Cancer Immunotherapy,” Trends in Cancer 5 (2019): 400-410.

[7] Y. Wang, X. Ma, W. Zhou, C. Liu, and H. Zhang, “Reregulated Mitochondrial Dysfunction Reverses Cisplatin Resistance Microenvironment in Colorectal Cancer,” Smart Medicine 1 (2022): e20220013.

[8] X. Yin, Y. Cheng, Y. Feng, et al., “Phototheranostics for Multifunctional Treatment of Cancer With Fluorescence Imaging,” Advanced Drug Delivery Reviews 189 (2022): 114483.

[9] W. Liu, X. Wang, X. Gao, et al., “Biotemplated Multichannel Mesoporous Bioactive Glass Microtubes as a Drug Carrier,” Ceramics International 39 (2013): 8521-8526.

[10] D. Xu, J. Ge, Y. An, et al., “Molecular Engineering of NIR-II/IIb Emitting AIEgen for Multimodal Imaging-Guided Photo-Immunotherapy,” Small 19 (2023): 2300859.

[11] Y. Chen, S. Zhi, J. Ou, et al., “Cancer Cell Membrane-Coated Nanoparticle Co-Loaded With Photosensitizer and Toll-Like Receptor 7 Agonist for the Enhancement of Combined Tumor Immunotherapy,” ACS Nano 17 (2023): 16620.

[12] Q. Wang, Y. Dai, J. Xu, et al., “All-in-One Phototheranostics: Single Laser Triggers NIR-II Fluorescence/Photoacoustic Imaging Guided Photothermal/Photodynamic/Chemo Combination Therapy,” Advanced Functional Materials 29 (2019): 1901480.

[13] W. Zhou, X. Ma, J. Wang, et al., “Co-Delivery CPT and PTX Prodrug With a Photo/Thermo-Responsive Nanoplatform for Triple-Negative Breast Cancer Therapy,” Smart Medicine 1 (2022): e20220036.

[14] A. L. Antaris, H. Chen, K. Cheng, et al., “A Small-Molecule Dye for NIR-II Imaging,” Nature Materials 15 (2015): 235-242.

[15] G. Hong, A. L. Antaris, and H. Dai, “Near-Infrared Fluorophores for Biomedical Imaging,” Nature Biomedical Engineering 1 (2017): e0010.

[16] D. Xu, L. Li, C. Chu, X. Zhang, and G. Liu, “Advances and Perspectives in Near-Infrared Fluorescent Organic Probes for Surgical Oncology,” Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 12 (2020): e1635.

[17] H. Kobayashi, A. Furusawa, A. Rosenberg, and C. PL, “Near-Infrared Photoimmunotherapy of Cancer: A New Approach That Kills Cancer Cells and Enhances Anti-Cancer Host Immunity,” International Immunology 33 (2021): 7-15.

[18] X. Yu, X. Cai, H. Cui, S.-W. Lee, X.-F. Yu, and B. Liu, “Fluorine-Free Preparation of Titanium Carbide MXene Quantum Dots With High Near-Infrared Photothermal Performances for Cancer Therapy,” Nanoscale 9 (2017): 17859.

[19] Z. Lu, S. Yang, X. Liu, et al., “Facile Synthesis and Separation of E / Z Isomers of Aromatic-Substituted Tetraphenylethylene for Investigating Their Fluorescent Properties via Single Crystal Analysis,” Journal of Materials Chemistry C 7 (2019): 4155-4163.

[20] Y. Q. Zhao, L. Yu, L. Zhang, H. Liu, Y. Zhou, and J. S. Kim, “Activated Aggregation-Induced Emission Therapeutics Agents for Triggering Regulated Cell Death,” Aggregate 5 (2024): e503.

[21] J. J. Hu, W. Jiang, L. Yuan, et al., “Recent Advances in Stimuli-Responsive Theranostic Systems With Aggregation-Induced Emission Characteristics,” Aggregate 2 (2021): 48-65.

[22] D. Ding, K. Li, B. Liu, and B. Z. Tang, “Bioprobes Based on AIE Fluorogens,” Accounts of Chemical Research 46 (2013): 2441-2453.

[23] X. Yu, J. Shuai, G. Meng, et al., “Ferritin-Nanocaged Aggregation-Induced Emission Nanoaggregates for NIR-II Fluorescence-Guided Noninvasive, Controllable Male Contraception,” Materials Today Bio 25 (2024): 100995.

[24] W. Tao, G. Xu, X. Yu, et al., “Robust Aptamer-Polydopamine-Functionalized M-PLGA-TPGS Nanoparticles for Targeted Delivery of Docetaxel and Enhanced Cervical Cancer Therapy,” International Journal of Nanomedicine 11 (2016): 2953-2965.

[25] Q. Zhang, P. Yu, Y. Fan, et al., “Bright and Stable NIR-II J-Aggregated AIE Dibodipy-Based Fluorescent Probe for Dynamic In Vivo Bioimaging,” Angewandte Chemie International Edition 60 (2020): 3967-3973.

[26] W. Xu, D. Wang, and B. Z. Tang, “NIR-II AIEgens: A Win-Win Integration Towards Bioapplications,” Angewandte Chemie International Edition 60 (2020): 7476-7487.

[27] J. S. Ni, P. Zhang, T. Jiang, et al., “Red/NIR-Emissive Benzo[d]Imidazole-Cored AIEgens: Facile Molecular Design for Wavelength Extending and In Vivo Tumor Metabolic Imaging,” Advanced Materials 30 (2018): 1805220.

[28] T. Zhang, X. Yang, X. Ou, et al., “Tailoring the Amphiphilic Structure of Zwitterionic AIE Photosensitizers to Boost Antitumor Immunity,” Advanced Materials 35 (2023): e2303186.

[29] X. Yu, M. Lyu, X. Ou, et al., “AIEgens/Mitochondria Nanohybrids as Bioactive Microwave Sensitizers for Non-Thermal Microwave Cancer Therapy,” Advanced Healthcare Materials 12 (2023): 2202907.

[30] X. Yu, Y.-C. Zhang, X. Yang, et al., “Bonsai-Inspired AIE Nanohybrid Photosensitizer Based on Vermiculite Nanosheets for Ferroptosis-Assisted Oxygen Self-Sufficient Photodynamic Cancer Therapy,” Nano Today 44 (2022): 101477.

[31] W. Tao, X. Zeng, J. Wu, et al., “Polydopamine-Based Surface Modification of Novel Nanoparticle-Aptamer Bioconjugates for In Vivo Breast Cancer Targeting and Enhanced Therapeutic Effects,” Theranostics 6 (2016): 470-484.

[32] S. Bai, Z. Lu, Y. Jiang, et al., “Nanotransferrin-Based Programmable Catalysis Mediates Three-Pronged Induction of Oxidative Stress to Enhance Cancer Immunotherapy,” ACS Nano 16 (2021): 997-1012.

[33] Z. Lu, S. Bai, Y. Jiang, et al., “Porphyrin-Based Covalent Organic Framework for Imaging-Guided Cancer Combinatorial Immuno-Sonodynamic Therapy,” Advanced Functional Materials 32 (2022): 2207749.

[34] W. Tao, X. Zhu, X. Yu, et al., “Black Phosphorus Nanosheets as a Robust Delivery Platform for Cancer Theranostics,” Advanced Materials 29 (2016): 1603276.

[35] Z. Lu, S. Bai, Y. Jiang, et al., “Amplifying Dendritic Cell Activation by Bioinspired Nanometal Organic Frameworks for Synergistic Sonoimmunotherapy,” Small 18 (2022): e2203952.

[36] X. Yang, T. Yang, Q. Liu, et al., “Biomimetic Aggregation-Induced Emission Nanodots With Hitchhiking Function for T Cell-Mediated Cancer Targeting and NIR-II Fluorescence-Guided Mild-Temperature Photothermal Therapy,” Advanced Functional Materials 32 (2022): 2206346.

[37] Y. Pan, M. Suo, Q. Huang, et al., “Near-Infrared Laser-Activated Aggregation-Induced Emission Nanoparticles Boost Tumor Carbonyl Stress and Immunotherapy of Breast Cancer,” Aggregate 5 (2024): e432.

[38] X. Xu, G. Deng, Z. Sun, et al., “A Biomimetic Aggregation-Induced Emission Photosensitizer With Antigen-Presenting and Hitchhiking Function for Lipid Droplet Targeted Photodynamic Immunotherapy,” Advanced Materials 33 (2021): 2102322.

[39] D. V. Krysko, A. D. Garg, A. Kaczmarek, O. Krysko, P. Agostinis, and P. Vandenabeele, “Immunogenic Cell Death and DAMPs in Cancer Therapy,” Nature Reviews Cancer 12 (2012): 860-875.

[40] M. Zhu, M. Yang, J. Zhang, et al., “Immunogenic Cell Death Induction by Ionizing Radiation,” Frontiers in Immunology 12 (2021): 705361.

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2025 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.