Design and synthesis of nanoscale titanium-porphyrin coordination nanomaterials for photodynamic-sonodynamic synergistic therapy of tumor cells

Abstract

Aim: Multifunctional nanomaterials with photodynamic-sonodynamic therapy (PSDT) potential offer significant advantages in cancer treatment. However, designing and preparing single-component “two-in-one” multifunctional nanomaterials remains challenging. Hematoporphyrin monomethyl ether (HMME), a second-generation porphyrin-related sonosensitizer, is a porphyrin derivative with two asymmetric carboxyl groups. Notably, the carboxyl groups in HMME can coordinate with metal ions to construct metal-organic coordination nanomaterials (MCPs). Titanium (Ti), a biocompatible metal element, is commonly used in medical devices such as implantable metal alloys. Therefore, this study reported the synthesis of “two-in-one” type Ti-HMME coordination nanomaterials (TiCPs) as efficient nanoscale photo/sonosensitizers. Methods: Under a nitrogen atmosphere, TiCPs were synthesized via self-assembly between HMME and Ti⁴⁺ ions. Results: The average particle size of TiCPs was approximately 70 nm. Additionally, TiCPs contained the photo/sonosensitizer HMME, which could convert O₂ into cytotoxic reactive oxygen species (ROS) under light and ultrasound (US) excitation. The generation of ROS could be detected using 1,3-diphenylisobenzofuran (DPBF). When the mixed solution (TiCPs + DPBF) was irradiated with light, the DPBF peak rapidly decreased with increasing irradiation time, indicating the production of ROS by TiCPs under light. Similarly, the absorbance of TiCPs + DPBF significantly decreased with increasing US time, demonstrating the sonodynamic effect of TiCPs + US. After 10 min of light or US excitation, 49.4% (Light) and 38.1% (US) of DPBF were oxidized by ROS generated by TiCPs, showcasing excellent photodynamic/sonodynamic effects. In vitro cell experiments further demonstrated that TiCPs had excellent biocompatibility, could be effectively internalized by cells, and significantly reduced cell viability under light and US excitation, effectively killing tumor cells. Conclusions: This study not only demonstrated TiCPs as “two-in-one” type multifunctional nanomaterials for PSDT but also provided insights into designing other photo/sonosensitizer molecules with similar HMME structures for tumor theranostics.

Keywords

Metal-organic coordination nanomaterials / two-in-one / hematoporphyrin monomethyl ether / photodynamic therapy / sonodynamic therapy

References

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71: 209-49.

[2] Siddique A, Garakani MM, Cooke ME, Weber MH, Rosenzweig DH. Nanoparticle-functionalized acrylic bone cement for local therapeutic delivery to spine metastases. Explor BioMat-X. 2024; 1: 135-57.

[3] Li Y, Wang W, Zhang YT, Xiao SZ, Lan HC, Geng P. Design and Synthesis of Nanoscale Zr-Porphyrin IX Framework for Synergistic Photodynamic and Sonodynamic Therapy of Tumors. Acta Chim Sinica. 2024; 82: 443-8.

[4] Yang L, Liu Y, Ren X, Jia R, Si L, Bao J, et al. Microemulsion-Assisted Self-Assembly of Indium Porphyrin Photosensitizers with Enhanced Photodynamic Therapy. ACS Nano. 2024; 18: 3161-72.

[5] Zhang J, Ye W, Wan L, Shi N, Peng C, Shi Y, et al. Beating xenograft liposarcoma using metal selenides with NIR-III photothermal ablation and bioactive selenium derivates. Chem Eng J. 2024; 481: 148521.

[6] Geng P, Yu N, Macharia DK, Meng RR, Qiu P, Tao C, et al. MOF-derived CuS@Cu-MOF nanocomposites for synergistic photothermal-chemodynamic-chemo therapy. Chem Eng J. 2022; 441: 135964.

[7] Li Y, Huang L, Li X, Geng P, Xiang J, Wang W, et al. From biomaterials to biotherapy: cuttlefish ink with protoporphyrin IX nanoconjugates for synergistic sonodynamic-photothermal therapy. J Mater Chem B. 2024; 12: 1837-45.

[8] Liang S, Xiao X, Bai L, Liu B, Yuan M, Ma P, et al. Conferring Ti-Based MOFs with Defects for Enhanced Sonodynamic Cancer Therapy. Adv Mater. 2021; 33: e2100333.

[9] Wang W, Zhang YT, Li Y, Huang YZ, Xiao SZ, Huang WQ, et al. Preparation of cuttlefish ink-porphyrin nanoconjugates and its application in photodynamic-photothermal synergistic treatment of tumor cells. Nano Med Mater. 2024; 4: 1895.

[10] Geng P, Xiang GC, Zhang W, Lan HC, Xiao SZ. Hollow copper sulfide loaded protoporphyrin for photothermal-sonodynamic therapy of cancer cells. Chinese J Inorg Chem. 2024; 40: 1903-10.

[11] Gao C, Kwong CHT, Wang Q, Kam H, Xie B, Lee SM, et al. Conjugation of Macrophage-Mimetic Microalgae and Liposome for Antitumor Sonodynamic Immunotherapy via Hypoxia Alleviation and Autophagy Inhibition. ACS Nano. 2023; 17: 4034-49.

[12] Jia T, Du J, Yang J, Li Y, Ohulchanskyy TY, Fang X, et al. Metalloporphyrin MOFs-Based Nanoagent Enabling Tumor Microenvironment Responsive Sonodynamic Therapy of Intracranial Glioma Signaled by NIR-IIb Luminescence Imaging. Adv Funct Mater. 2023; 34: 2307816.

[13] Gong F, Cheng L, Yang N, Betzer O, Feng L, Zhou Q, et al. Ultrasmall Oxygen-Deficient Bimetallic Oxide MnWO_X Nanoparticles for Depletion of Endogenous GSH and Enhanced Sonodynamic Cancer Therapy . Adv Mater. 2019; 31: e1900730.

[14] Meng X, Sun S, Gong C, Yang J, Yang Z, Zhang X, et al. Ag-Doped Metal-Organic Frameworks’ Heterostructure for Sonodynamic Therapy of Deep-Seated Cancer and Bacterial Infection. ACS Nano. 2023; 17: 1174-86.

[15] Geng P, Yu N, Liu X, Zhu Q, Wen M, Ren Q, et al. Sub 5 nm Gd³⁺-Hemoporfin Framework Nanodots for Augmented Sonodynamic Theranostics and Fast Renal Clearance . Adv Healthcare Mater. 2021; 10: e2100703.

[16] Geng P, Li Y, Macharia DK, Ren X, Meng R, Wang W, et al. One Stone, Three Birds: Design and Synthesis of “All-in-One” Nanoscale Mn-Porphyrin Coordination Polymers for Magnetic Resonance Imaging-Guided Synergistic Photodynamic-Sonodynamic Therapy. J Colloid Interface Sci. 2024; 660: 1021-9.

[17] Liu S, Wen M, Huang M, Wang H, Chen Z, Yu N. Nanoscale hematoporphrin-based frameworks for photo-sono synergistic cancer therapy via utilizing Al(III) as metal nodes rather than heavy metals. J Colloid Interface Sci. 2022; 616: 23-33.

[18] Zhu J, Wang Y, Yang P, Liu Q, Hu J, Yang W, et al. GPC3-targeted and curcumin-loaded phospholipid microbubbles for sono-photodynamic therapy in liver cancer cells. Colloids Surf B Biointerfaces. 2021; 197: 111358.

[19] Xu F, Hu M, Liu C, Choi SK. Yolk-structured multifunctional up-conversion nanoparticles for synergistic photodynamic-sonodynamic antibacterial resistance therapy. Biomater Sci. 2017; 5: 678-85.

[20] Liu Z, Liu S, Liu B, Bian Y, Yuan M, Yang C, et al. Fe(III)-Naphthazarin Metal-Phenolic Networks for Glutathione-Depleting Enhanced Ferroptosis-Apoptosis Combined Cancer Therapy. Small. 2023; 19: e2207825.

[21] Xu H, Yu N, Zhang J, Wang Z, Geng P, Wen M, et al. Biocompatible Fe-Hematoporphyrin coordination nanoplatforms with efficient sonodynamic-chemo effects on deep-seated tumors. Biomaterials. 2020; 257: 120239.

[22] Yu N, Li J, Wang Z, Yang S, Liu Z, Wang Y, et al. Blue Te Nanoneedles with Strong NIR Photothermal and Laser-Enhanced Anticancer Effects as “All-in-One” Nanoagents for Synergistic Thermo-Chemotherapy of Tumors. Adv Healthcare Mater. 2018; 7: e1800643.

[23] Zheng Q, Liu X, Zheng Y, Yeung KWK, Cui Z, Liang Y, et al. The recent progress on metal-organic frameworks for phototherapy. Chem Soc Rev. 2021; 50: 5086-125.

[24] Fan Y, Chen D, Chen L, Liu K, Zheng Y, Li L, et al. Fluorinated Iron Metal-Organic Frameworks for Activatable¹⁹F Magnetic Resonance Imaging and Synergistic Therapy of Tumors . Nano Lett. 2023; 23: 11989-98.

[25] Geng P, Yu N, Liu X, Wen M, Ren Q, Qiu P, et al. GSH-Sensitive Nanoscale Mn³⁺-Sealed Coordination Particles as Activatable Drug Delivery Systems for Synergistic Photodynamic-Chemo Therapy . ACS Appl Mater Interfaces. 2021; 13: 31440-51.

[26] Geng P, Yu N, Zhang J, Jin Z, Wen M, Jiang Q, et al. One Responsive Stone, Three Birds: Mn(III)-Hemoporfin Frameworks with Glutathione-Enhanced Degradation, MRI, and Sonodynamic Therapy. Adv Healthcare Mater. 2021; 10: e2001463.

[27] Zhang K, Meng X, Cao Y, Yang Z, Dong H, Zhang Y, et al. Metal-Organic Framework Nanoshuttle for Synergistic Photodynamic and Low-Temperature Photothermal Therapy. Adv Funct Mater. 2018; 28: 1804634.

[28] Wang H, Yu D, Fang J, Cao C, Liu Z, Ren J, et al. Renal-Clearable Porphyrinic Metal-Organic Framework Nanodots for Enhanced Photodynamic Therapy. ACS Nano. 2019; 13: 9206-17.

[29] Kong Q, Qi M, Li W, Shi Y, Su J, Xiao S, et al. A Novel Z-Scheme Heterostructured Bi₂S₃/Cu-TCPP Nanocomposite with Synergistically Enhanced Therapeutics against Bacterial Biofilm Infections in Periodontitis . Small. 2023; 19: e2302547.

[30] Li B, Wang X, Chen L, Zhou Y, Dang W, Chang J, et al. Ultrathin Cu-TCPP MOF nanosheets: a new theragnostic nanoplatform with magnetic resonance/near-infrared thermal imaging for synergistic phototherapy of cancers. Theranostics. 2018; 8: 4086-96.

[31] Wan S, Cheng Q, Zeng X, Zhang X. A Mn(III)-Sealed Metal-Organic Framework Nanosystem for Redox-Unlocked Tumor Theranostics. ACS Nano. 2019; 13: 6561-71.

[32] Zhao Y, Kuang Y, Liu M, Wang J, Pei R. Synthesis of Metal-Organic Framework Nanosheets with High Relaxation Rate and Singlet Oxygen Yield. Chem Mater. 2018; 30: 7511-20.

[33] Wang Z, Liu C, Zhao Y, Hu M, Ma D, Zhang P, et al. Photomagnetic nanoparticles in dual-modality imaging and photo-sonodynamic activity against bacteria. Chem Eng J. 2018; 356: 811-8.

[34] Zhang H, Chen J, Zhu X, Ren Y, Cao F, Zhu L, et al. Ultrasound induced phase-transition and invisible nanobomb for imaging-guided tumor sonodynamic therapy. J Mater Chem B. 2018; 6: 6108-21.

[35] Qin Q, Yang M, Shi Y, Cui H, Pan C, Ren W, et al. Mn-doped Ti-based MOFs for magnetic resonance imaging-guided synergistic microwave thermal and microwave dynamic therapy of liver cancer. Bioact Mater. 2023; 27: 72-81.

[36] Xing J, Yang Y, Zhang W, Yan J, Qian H, Hao J, et al. Injectable Hydrogel Containing TiO Nanosheets for Synergistic Photothermal/Thermodynamic Therapy. ACS Appl Mater Interfaces. 2023; 15: 34436-50.