Natural supramolecular photosensitizer with in situ switchable photothermal/photodynamic effects as an imaging platform for precise and controlled cancer synergistic therapy

Abstract

Treatment of cancer can be challenging, because of the disease’s intricate and varied nature. Consequently, developing nanomedicines with multimodal therapeutic capabilities for precise tumor therapy holds substantial promise in advancing cancer treatment. Herein, a nanoplatform strategy involving supramolecular photosensitizers (ETSCe6 NPs) and chelated metal ions (Au and Bi) was found to induce a shift in tumor microenvironment responsiveness from photothermal therapy to photodynamic therapy, thus facilitating tumor visualization for precise diagnosis and treatment. Self-assembly of supramolecular photosensitizers enhanced photothermal therapy through aggregation-caused quenching. Moreover, glutathione triggered disulfide bond cleavage, and consequently Ergosterol (ET) and Chlorin e6 release. Therefore, chemotherapy and photodynamic therapy achieved synergistic anticancer effects. Ce6 cavities were also used to chelate high valence Au and Bi metal ions for computed tomography. The ETSCe6@Au, Bi NPs demonstrated remarkable efficacy in vitro and in vivo, achieving complete tumor elimination after treatment. This integrated approach combining imaging, chemotherapy, photodynamic, and photothermal therapies has substantial promise for clinical applications, and may provide an innovative strategy for developing intelligent nanomedicines with promising prospects.

Keywords

Natural small molecules / Aggregation-caused quenching / Photodynamic therapy / Photothermal therapy / Synergistic cancer treatment

References

[1] Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, et al.: Cancer Treatment and Survivorship Statistics. CA: A Cancer Journal for Clinicians 2019, 69: 363-385.

[2] Feng E, Jiao L, Tang S, Chen M, Lv S, Liu D, et al.: Antiphotobleaching Cyanine-based Nanoparticles with Simultaneous PET and ACQ Effects for Improved Tumor Photothermal Therapy. Chemical Engineering Journal 2022, 432: 134355.

[3] Yu Y, Tang D, Liu C, Zhang Q, Tang L, Lu Y, et al.: Biodegradable Polymer with Effective Near-Infrared-II Absorption as a Photothermal Agent for Deep Tumor Therapy. Advanced Materials 2022, 34: e2105976.

[4] Wan Y, Fu LH, Li C, Lin J, Huang P: Conquering the Hypoxia Limitation for Photodynamic Therapy. Advanced Materials 2021, 33: 2103978.

[5] Li L, Shao C, Liu T, Chao Z, Chen H, Xiao F, et al.: An NIR-II-Emissive Photosensitizer for Hypoxia-tolerant Photodynamic Theranostics. Advanced Materials 2020, 32: e2003471.

[6] Fu Z, Williams GR, Niu S, Wu J, Gao F, Zhang X, et al.: Functionalized Boron Nanosheets as an Intelligent Nanoplatform for Synergistic Low-temperature Photothermal Therapy and Chemotherapy. Nanoscale 2020, 12: 14739-14750.

[7] Wang L, Gao C, Liu K, Liu Y, Ma L, Liu L, et al.: Cypate-conjugated Porous Upconversion Nanocomposites for Programmed Delivery of Heat Shock Protein 70 Small Interfering RNA for Gene Silencing and Photothermal Ablation. Advanced Functional Materials 2016, 26: 3480-3489.

[8] Feng S, Lu J, Wang K, Di D, Shi Z, Zhao Q, et al.: Advances in Smart Mesoporous Carbon Nanoplatforms for Photothermal-enhanced Synergistic Cancer Therapy. Chemical Engineering Journal 2022, 435: 134886.

[9] Wang C, Cao F, Ruan Y, Jia X, Zhen W, Jiang X: Specific Generation of Singlet Oxygen Through the Russell Mechanism in Hypoxic Tumors and GSH Depletion by Cu-TCPP Nanosheets for Cancer Therapy. Angewandte Chemie (International ed. in English) 2019, 58: 9846-9850.

[10] Sun J, Du K, Diao J, Cai X, Feng F, Wang S: GSH and H₂O₂ Co-activatable Mitochondria-targeted Photodynamic Therapy under Normoxia and Hypoxia . Angewandte Chemie (International ed. in English) 2020, 59: 12122-12128.

[11] Lan JS, Liu L, Zeng RF, Qin YH, Hou JW, Xie SS, et al.: Tumor-specific Carrier-free Nanodrugs with GSH Depletion and Enhanced ROS Generation for Endogenous Synergistic Anti-tumor by a Chemotherapy-photodynamic Therapy. Chemical Engineering Journal 2021, 407: 127212.

[12] Li W, Wang S, Ren C, Liu P, Lu Q, Yang L, et al.: Exo/Endogenous Dual-augmented Chemodynamic Therapy Based on Bio-reducible and Bio-breakable Copper (II)-Based Truncated Octahedron. Chemical Engineering Journal 2020, 396: 125280.

[13] Hu K, Xie L, Zhang Y, Hanyu M, Yang Z, Nagatsu K, et al.: Marriage of Black Phosphorus and Cu²⁺ as Effective Photothermal Agents for PET-guided Combination Cancer Therapy . Nature Communications 2020, 11: 2778.

[14] He T, Jiang C, He J, Zhang Y, He G, Wu J, et al.: Manganese-Dioxide-Coating-Instructed Plasmonic Modulation of Gold Nanorods for Activatable Duplex-Imaging-Guided NIR-II Photothermal-chemodynamic Therapy. Advanced Materials 2021, 33: e2008540.

[15] Zhou Y, Liang X, Dai Z: Porphyrin-loaded Nanoparticles for Cancer Theranostics. Nanoscale 2016, 8: 12394.

[16] Song F, Peng X, Lu E, Wang Y, Zhou W, Fan J: Tuning the Photoinduced Electron Transfer in Near-infrared Heptamethine Cyanine Dyes. Tetrahedron Letters 2005, 46: 4817-4820.

[17] Zou Q, Abbas M, Zhao L, Li S, Shen G, Yan X: Biological Photothermal Nanodots Based on Self-assembly of Peptide-porphyrin Conjugates for Antitumor Therapy. Journal of the American Chemical Society 2017, 13: 1921-1927.

[18] Gao S, Wei G, Zhang S, Zheng B, Xu J, Chen G, et al.: Albumin Tailoring Fluorescence and Photothermal Conversion Effect of Near-Infrared-II Fluorophore with Aggregation-induced Emission Characteristics. Nature Communications 2019, 10: 2206.

[19] Xing R, Zou Q, Yuan C, Zhao L, Chang R, Yan X: Self-assembling Endogenous Biliverdin as a Versatile Near-infrared Photothermal Nanoagent for Cancer Theranostics. Advanced Materials 2019, 31: e1900822.

[20] Du W, Chong Y, Hu X, Wang Y, Zhu Y, Chen J, et al.: Increasing Photothermal Efficacy by Simultaneous Intra- and Intermolecular Fluorescence Quenching. Advanced Functional Materials 2020, 30: 1908073.

[21] Nel A, Xia T, Mädler L, Li N: Toxic Potential of Materials at the Nanolevel. Science 2006, 311: 622-627.

[22] Li J, Rao J, Pu K: Recent Progress on Semiconducting Polymer Nanoparticles for Molecular Imaging and Cancer Phototherapy. Biomaterials 2018, 155: 217-235.

[23] Yang X, Ma C, Chen Z, Liu J, Liu F, Xie R, et al.: Single Small Molecule-assembled Nanoparticles Mediate Efficient Oral Drug Delivery. Nano Research 2019, 12: 2468-2476.

[24] Bag BG, Majumdar R: Self-assembly of Renewable Nano-sized Triterpenoids. Chemical Record 2017, 17: 841-873.

[25] Paterson I, Anderson EA: The Renaissance of Natural Products as Drug Candidates. Science 2005, 310: 451-453.

[26] Rodrigues T, Reker D, Schneider P, Schneider G: Counting on Natural Products for Drug Design. Nature Chemistry 2018, 8: 531-541.

[27] Fu S, Yang X: Recent Advances in Natural Small Molecules as Drug Delivery Systems. Journal of Materials Chemistry B 2023, 11: 4584-4599.

[28] Wang J, Zhao H, Zhi K, Yang X: Exploration of the Natural Active Small-molecule Drug-loading Process and Highly Efficient Synergistic Antitumor Efficacy. ACS Applied Materials & Interfaces 2020, 12: 6827-6839.

[29] Wang J, Zhao H, Qiao W, Cheng J, Han Y, Yang X: Nanomedicine-Cum-Carrier by Co-assembly of Natural Small Products for Synergistic Enhanced Antitumor with Tissues Protective Actions. ACS Applied Materials & Interfaces 2020, 12: 42537-42550.

[30] Cheng J, Zhao H, Wang J, Han Y, Yang X: Bioactive Natural Small Molecule-tuned Coassembly of Photosensitive Drugs for Highly Efficient Synergistic and Enhanced Type I Photochemotherapy. ACS Applied Materials & Interfaces 2020, 12: 43488-43500.

[31] Cheng J, Li X, Wang S, Han Y, Zhao H, Yang X: Carrier-free Triterpene Prodrugs with Glutathione Response and Biosafety for Synergistically Enhanced Photochemotherapy. ACS Applied Materials & Interfaces 2021, 13: 245-256.

[32] Cheng J, Zhao H, Yao L, Li Y, Qi B, Wang J, et al.: Simple and Multifunctional Natural Self-assembled Sterols with Anticancer Activity-mediated Supramolecular Photosensitizers for Enhanced Antitumor Photodynamic Therapy. ACS Applied Materials & Interfaces 2019, 11: 29498-29511.

[33] Cheng J, Fu S, Qin Z, Han Y, Yang X: Self-assembled Natural Small Molecule Diterpene Acids with Favorable Anticancer Activity and Biosafety for Synergistically Enhanced Antitumor Chemotherapy. Journal of Materials Chemistry B 2021, 9: 2674-2687.

[34] Lovell JF, Jin CS, Huynh E, Jin H, Kim C, Rubinstein JL, et al.: Porphysome Nanovesicles Generated by Porphyrin Bilayers for use as Multimodal Biophotonic Contrast Agents. Nature Materials 2011, 10: 324-332.

[35] Zhang HY, Firempong CK, Wang YW, Xu WQ, Wang MM, Cao X, et al.: Ergosterol-loaded Poly(lactide-co-glycolide) Nanoparticles with Enhanced in vitro Antitumor Activity and Oral Bioavailability. Acta Pharmacologica Sinica 2016, 37: 834-844.

[36] Liu Y, Wang H, Li S, Chen C, Xu L, Huang P, et al.: In Situ Supramolecular Polymerization-enhanced Self-assembly of Polymer Vesicles for Highly Efficient Photothermal Therapy. Nature Communications 2020, 11: 1724.

[37] Fu S, Wang M, Li B, Li X, Cheng J, Zhao H, et al.: Bionic Natural Small Molecule Co-assemblies Towards Targeted and Synergistic Chemo/PDT/CDT. Biomaterials Research 2023, 27: 43.

[38] Zhang L, Jiang C, Li B, Liu Z, Gu B, He S, et al.: A Core-shell Au@Cu_2-xSe Heterogeneous Metal Nanocomposite for Photoacoustic and Computed Tomography Dual-Imaging-Guided Photothermal Boosted Chemodynamic Therapy . Journal of Nanobiotechnology 2021, 19: 410.

[39] Li X, Li Y, Yu C, Bao H, Cheng S, Huang J, et al.: ROS-responsive Janus Au/Mesoporous Silica Core/Shell Nanoparticles for Drug Delivery and Long-term CT Imaging Tracking of MSCs in Pulmonary Fibrosis Treatment. ACS Nano 2023, 17: 6387-6399.

[40] Jin L, Jia G, Hao Q, Jun JS: Simultaneous Realization of Persistent Luminescence and CT Dual-mode Imaging by X-ray Recharged Bi₂Ga₄O₉:Cr Nanoprobes in Depth-independent Tumors . Chemical Engineering Journal 2020, 406: 126008.

[41] Meng N, Xu P, Wen C, Liu H, Gao C, Shen XC, et al.: Near-Infrared-II-Activatable Sulfur-deficient Plasmonic Bi₂S_3-x-Au Heterostructures for Photoacoustic Imaging-guided Ultrasound Enhanced High Performance Phototherapy . Journal of Colloid and Interface Science 2023, 644: 437-453.

[42] Long R, Guo M, Liu L, Fang W: Nonradiative Relaxation of Photoexcited Black Phosphorus is Reduced by Stacking with Mos₂: A Time Domain Ab Initio Study . The Journal of Physical Chemistry Letters 2016, 7: 1830-1835.