本研究成功合成出一體化介孔奈米球mPDA-TPZ-MoS2 ( mPTM )，以介孔聚多巴胺( Mesoporous Polydopamine, mPDA )為載體，披覆厭氧性還原藥物替拉扎明( Tirapazamine, TPZ )及二硫化鉬量子點( Molybdenum disulfide quantum dots, MoS2 QD )。mPDA奈米粒子具有良好的光熱療效；而TPZ在缺氧環境下有顯著殺死細胞效果，MoS2 QD則可實現類芬頓反應以及氣體治療，利用π-π interaction負載於mPDA上，接著以EDC/Sulfo NHS與MoS2 QD進行共價交聯反應，合成出一體化介孔奈米球mPTM。
mPTM奈米球在近紅外光照射下，表現出良好的光熱轉換效率，在腫瘤微環境中，mPTM 奈米球的Mo(Ⅳ) 通過與內源性H2O2進行類芬頓反應產生 •OH，同時，透過Mo(Ⅵ) 與穀胱甘肽反應氧化為穀胱甘肽二硫化物，藉由消耗穀胱甘肽強化化學動力療法；於氣體治療上，mPTM 奈米球釋放之H2S氣體，與腫瘤細胞蛋白質結合後，誘導細胞死亡；最後，TPZ•可在腫瘤缺氧區產生BTZ• 和 •OH毒殺腫瘤細胞，實現化學療法，因此，mPTM奈米球結合光熱治療、化學動力療法、氣體治療及化療的協同作用，為一多功能複合奈米材料。
材料鑑定方面由TEM、SEM、FTIR與UV-Vis等儀器進行奈米材料組成及光學性質分析。於生物應用上，確認mPTM奈米球為高生物相容性材料後，使用共軛聚焦顯微鏡驗證材料可於細胞內產生ROS以及細胞經由多重治療後凋亡情形，最後以流式細胞儀計算細胞存活率，相較單一療法，經由多重治療後療效顯著提升，證明mPTM奈米球具有優異的癌細胞治療效果。

In this study, an integrated mesoporous nanospheres mPDA-TPZ-MoS2 (mPTM) was successfully synthesized, using mesoporous polydopamine (mPDA) as a carrier, loaded with drug tirapazamine (TPZ) and Molybdenum disulfide quantum dots (MoS2 QD). mPDA is a outstanding photothermal agent; while TPZ has a significant effect on killing cells in hypoxia and MoS2 QD can trigger Fenton-like reaction and gas therapy.
mPTM nanospheres show excellent photothermal effect, and in the tumor microenvironment ( TME ), the Mo( IV ) of mPTM nanospheres undergoes a Fenton-like reaction to generate •OH ; S2- releasing can form H2S gas; TPZ• can produce BTZ• and •OH. Therefore, by combining the synergistic effects of PTT, CDT, GT, and CT, mPTM nanospheres are a multifunctional composite nanomaterial.
In terms of material characterization, TEM, SEM, FTIR, and UV-Vis instruments are used to analyze the composition and optical properties of materials. For biological applications, firstly, confirm that mPTM nanospheres are highly biocompatible materials. Additionally, CLSM is used to verify the apoptosis of cells after multiple treatments. Finally, the cell survival rate is calculated by Flow Cytometry, which proves that mPTM nanospheres have excellent therapeutic effects on cancer cells.

1 LEE, Haeshin, et al. Mussel-inspired surface chemistry for multifunctional coatings. science, 2007, 318.5849: 426-430.
2 ASHA, Anika Benozir; CHEN, Yangjun; NARAIN, Ravin. Bioinspired dopamine and zwitterionic polymers for non-fouling surface engineering. Chemical Society Reviews, 2021, 50.20: 11668-11683.
3 LI, Jing-an, et al. Enhancing biocompatibility and corrosion resistance of biodegradable Mg-Zn-Y-Nd alloy by preparing PDA/HA coating for potential application of cardiovascular biomaterials. Materials Science and Engineering: C, 2020, 109: 110607.
4 PU, Yiyao, et al. A Gd-doped polydopamine (PDA)-based theranostic nanoplatform as a strong MR/PA dual-modal imaging agent for PTT/PDT synergistic therapy. Journal of Materials Chemistry B, 2021, 9.7: 1846-1857.
5 WU, Wenna, et al. Formation and degradation tracking of a composite hydrogel based on UCNPs@ PDA. Macromolecules, 2020, 53.7: 2430-2440.
6 ZHU, Menglu, et al. Recent developments in mesoporous polydopamine-derived nanoplatforms for cancer theranostics. Journal of Nanobiotechnology, 2021, 19.1: 1-22.
7 PENG, Liang, et al. Versatile nanoemulsion assembly approach to synthesize functional mesoporous carbon nanospheres with tunable pore sizes and architectures. Journal of the American Chemical Society, 2019, 141.17: 7073-7080.
8 WANG, Haijun, et al. Dimeric Her2-specific affibody mediated cisplatin-loaded nanoparticles for tumor enhanced chemo-radiotherapy. Journal of Nanobiotechnology, 2021, 19.1: 138.
9 SHU, Gaofeng, et al. Sialic acid-engineered mesoporous polydopamine nanoparticles loaded with SPIO and Fe3+ as a novel theranostic agent for T1/T2 dual-mode MRI-guided combined chemo-photothermal treatment of hepatic cancer. Bioactive materials, 2021, 6.5: 1423-1435.
10 WANG, Nan, et al. Two-dimensional interface engineering of mesoporous polydopamine on graphene for novel organic cathodes. ACS Applied Energy Materials, 2019, 2.8: 5816-5823.
11 MA, Hualin, et al. Frontiers in Preparations and Promising Applications of Mesoporous Polydopamine for Cancer Diagnosis and Treatment. Pharmaceutics, 2022, 15.1: 15.
12 LI, Jiali, et al. A comparison between mesoporous and nonporous polydopamine as nanoplatforms for synergistic chemo-photothermal therapy. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2022, 653: 130005.
13 ZHANG, Liren, et al. Multifunctional mesoporous polydopamine with hydrophobic paclitaxel for photoacoustic imaging-guided chemo-photothermal synergistic therapy. International journal of nanomedicine, 2019, 8647-8663.
14 WANG, Huajuan, et al. Photothermal Therapy with Ag Nanoparticles in Mesoporous Polydopamine for Enhanced Antibacterial Activity. ACS Applied Nano Materials, 2023, 6.6: 4834-4843.
15 LIU, Yingying, et al. Construction of a mesoporous polydopamine@ GO/cellulose nanofibril composite hydrogel with an encapsulation structure for controllable drug release and toxicity shielding. ACS Applied Materials & Interfaces, 2020, 12.51: 57410-57420.
16 LIU, Yingying, et al. Construction of nanocellulose-based composite hydrogel with a double packing structure as an intelligent drug carrier. Cellulose, 2021, 28.11: 6953-6966.
17 GAO, Minjie, et al. Construction of Double-Shelled Hollow Ag2S@ Polydopamine Nanocomposites for Fluorescence-Guided, Dual Stimuli-Responsive Drug Delivery and Photothermal Therapy. Nanomaterials, 2022, 12.12: 2068.
18 LIN, Ai Jeng, et al. Potential bioreductive alkylating agents. 1. Benzoquinone derivatives. Journal of medicinal chemistry, 1972, 15.12: 1247-1252.
19 ZEMAN, Elaine M., et al. SR-4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. International Journal of Radiation Oncology* Biology* Physics, 1986, 12.7: 1239-1242.
20 HICKS, Kevin O., et al. Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic cell killing in tumors. Clinical Cancer Research, 2010, 16.20: 4946-4957.
21 BEDIKIAN, A. Y., et al. Phase II trial of tirapazamine combined with cisplatin in chemotherapy of advanced malignant melanoma. Annals of oncology, 1997, 8.4: 363-367.
22 ZHANG, Kailiang, et al. Two dimensional hexagonal boron nitride (2D-hBN): synthesis, properties and applications. Journal of Materials Chemistry C, 2017, 5.46: 11992-12022.
23 LI, Dengfeng, et al. 2D boron sheets: structure, growth, and electronic and thermal transport properties. Advanced Functional Materials, 2020, 30.8: 1904349.
24 MALDONADO, Melissa E., et al. Nonlinear optical interactions and relaxation in 2D layered transition metal dichalcogenides probed by optical and photoacoustic Z-scan methods. ACS Photonics, 2020, 7.12: 3440-3447.
25 RADISAVLJEVIC, Branimir, et al. Single-layer MoS2 transistors. Nature nanotechnology, 2011, 6.3: 147-150.
26 XU, Mingsheng, et al. Graphene-like two-dimensional materials. Chemical reviews, 2013, 113.5: 3766-3798.
27 ALI, Luqman, et al. Exfoliation of MoS2 Quantum Dots: Recent Progress and Challenges. Nanomaterials, 2022, 12.19: 3465.
28 VIDYA, C., et al. A multifunctional nanostructured molybdenum disulphide (MoS2): an overview on synthesis, structural features, and potential applications. Materials Research Innovations, 2023, 27.3: 177-193.
29 ZHOU, Kai, et al. As-prepared MoS2 quantum dot as a facile fluorescent probe for long-term tracing of live cells. Nanotechnology, 2016, 27.27: 275101.
30 GUO, Yongming; LI, Jianwei. MoS2 quantum dots: synthesis, properties and biological applications. Materials Science and Engineering: C, 2020, 109: 110511.
31 WANG, Xiaojie, et al. One-step synthesis of water-soluble and highly fluorescent MoS2 quantum dots for detection of hydrogen peroxide and glucose. Sensors and Actuators B: Chemical, 2017, 252: 183-190.
32 CAO, Haiyan, et al. Quantification of gold (III) in solution and with a test stripe via the quenching of the fluorescence of molybdenum disulfide quantum dots. Microchimica Acta, 2017, 184: 91-100.
33 WANG, Yong, et al. Label-free fluorescence sensing of lead (II) ions and sulfide ions based on luminescent molybdenum disulfide nanosheets. ACS Sustainable Chemistry & Engineering, 2016, 4.5: 2535-2541..
34 FAHIMI-KASHANI, Nafiseh, et al. MoS 2 quantum-dots as a label-free fluorescent nanoprobe for the highly selective detection of methyl parathion pesticide. Analytical Methods, 2017, 9.4: 716-723.
35 GU, Wei, et al. One-step synthesis of water-soluble MoS2 quantum dots via a hydrothermal method as a fluorescent probe for hyaluronidase detection. ACS applied materials & interfaces, 2016, 8.18: 11272-11279.
36 WANG, Zhuosen, et al. Two optically active molybdenum disulfide quantum dots as tetracycline sensors. Materials Chemistry and Physics, 2016, 178: 82-87.
37 CHEN, Shih‐Chiang, et al. 6‐Mercaptopurine‐Induced Fluorescence Quenching of Monolayer MoS2 Nanodots: Applications to Glutathione Sensing, Cellular Imaging, and Glutathione‐Stimulated Drug Delivery. Advanced functional materials, 2017, 27.41: 1702452.
38 QI, Xiating; YE, Pengkun; XIE, Meng. MoS2 quantum dots based on lipid drug delivery system for combined therapy against Alzheimer's disease. Journal of Drug Delivery Science and Technology, 2023, 82: 104324..
39 ZHOU, Jun, et al. Engineering of a nanosized biocatalyst for combined tumor starvation and low-temperature photothermal therapy. ACS nano, 2018, 12.3: 2858-2872.
40 HUANG, Xiaohua, et al. Plasmonic photothermal therapy (PPTT) using gold nanoparticles. Lasers in medical science, 2008, 23: 217-228.
41 HAN, Hwa Seung; CHOI, Ki Young. Advances in nanomaterial-mediated photothermal cancer therapies: toward clinical applications. Biomedicines, 2021, 9.3: 305.
42 LI, Jie, et al. Near infrared photothermal conversion materials: Mechanism, preparation, and photothermal cancer therapy applications. Journal of Materials Chemistry B, 2021, 9.38: 7909-7926.
43 JAQUE, Daniel, et al. Nanoparticles for photothermal therapies. nanoscale, 2014, 6.16: 9494-9530.
44 ZHAROV, Vladimir P.; GALITOVSKY, Valentin; VIEGAS, Mark. Photothermal detection of local thermal effects during selective nanophotothermolysis. Applied Physics Letters, 2003, 83.24: 4897-4899.
45 WANG, Yawen; LIU, Tongtong; LIU, Juewen. Synergistically boosted degradation of organic dyes by CeO2 nanoparticles with fluoride at low pH. ACS Applied Nano Materials, 2019, 3.1: 842-849.
46 KUMAR, Achalla Vaishnav Pavan, et al. Recent advances in nanoparticles mediated photothermal therapy induced tumor regression. International journal of pharmaceutics, 2021, 606: 120848.
47 LI, Jie, et al. Near infrared photothermal conversion materials: Mechanism, preparation, and photothermal cancer therapy applications. Journal of Materials Chemistry B, 2021, 9.38: 7909-7926.
48 SONG, Jibin, et al. Rational design of branched nanoporous gold nanoshells with enhanced physico-optical properties for optical imaging and cancer therapy. ACS nano, 2017, 11.6: 6102-6113.
49 HE, Wenya, et al. Plasmonic titanium nitride nanoparticles for in vivo photoacoustic tomography imaging and photothermal cancer therapy. Biomaterials, 2017, 132: 37-47.
50 ZHANG, Ming, et al. Multifunctional nanocomposites for targeted, photothermal, and chemotherapy. Chemistry of Materials, 2018, 31.6: 1847-1859.
51 GENG, Shinan, et al. Injectable in situ forming hydrogels of thermosensitive polypyrrole nanoplatforms for precisely synergistic photothermo-chemotherapy. ACS applied materials & interfaces, 2020, 12.7: 7995-8005.
52 HE, Yue, et al. Multifunctional polypyrrole‐coated mesoporous TiO2 nanocomposites for photothermal, sonodynamic, and chemotherapeutic treatments and dual‐modal ultrasound/photoacoustic imaging of tumors. Advanced healthcare materials, 2019, 8.9: 1801254.
53 TIAN, Qiwei, et al. Tumor pH‐Responsive Albumin/Polyaniline Assemblies for Amplified Photoacoustic Imaging and Augmented Photothermal Therapy. Small, 2019, 15.42: 1902926.
54 JANA, Jayasmita; GANGULY, Mainak; PAL, Tarasankar. Enlightening surface plasmon resonance effect of metal nanoparticles for practical spectroscopic application. RSC advances, 2016, 6.89: 86174-86211.
55 REPASKY, Elizabeth A.; EVANS, Sharon S.; DEWHIRST, Mark W. Temperature matters! And why it should matter to tumor immunologists. Cancer immunology research, 2013, 1.4: 210-216.
56 LI, Shu‐Lan, et al. Recent advances in nanomaterial‐based nanoplatforms for chemodynamic cancer therapy. Advanced Functional Materials, 2021, 31.22: 2100243.
57 TIAN, Qiwei, et al. Recent advances in enhanced chemodynamic therapy strategies. Nano Today, 2021, 39: 101162.
58 TIAN, Yilong, et al. Automatic-degradable Mo-doped W18O49 based nanotheranostics for CT/FL imaging guided synergistic chemo / photothermal/chemodynamic therapy. Chemical Engineering Journal, 2023, 462: 142156.
59 HE, Yaling, et al. Photoregulated plasmon enhanced controllable hydrogen sulfide delivery for photothermal augmented gas therapy. Applied Materials Today, 2022, 26: 101313.
60 HUANG, L. Eric, et al. Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide: implications for oxygen sensing and signaling. Journal of Biological Chemistry, 1999, 274.13: 9038-9044.
61 BONAVIDA, Benjamin, et al. Novel therapeutic applications of nitric oxide donors in cancer: roles in chemo-and immunosensitization to apoptosis and inhibition of metastases. Nitric oxide, 2008, 19.2: 152-157.
62 SUNG, Yun-Chieh, et al. Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies. Nature nanotechnology, 2019, 14.12: 1160-1169.
63 YAO, Xianxian, et al. Zwitterionic polymer coating of sulfur dioxide‐releasing nanosystem augments tumor accumulation and treatment efficacy. Advanced Healthcare Materials, 2020, 9.5: 1901582.
64 SZABO, Csaba. Gasotransmitters in cancer: from pathophysiology to experimental therapy. Nature reviews Drug discovery, 2016, 15.3: 185-203.
65 OLSON, Nels; VAN DER VLIET, Albert. Interactions between nitric oxide and hypoxia-inducible factor signaling pathways in inflammatory disease. Nitric oxide, 2011, 25.2: 125-137.
66 CHEN, Jiajie, et al. Palladium Nanocrystals‐Engineered Metal–Organic Frameworks for Enhanced Tumor Inhibition by Synergistic Hydrogen/Photodynamic Therapy. Advanced Functional Materials, 2021, 31.4: 2006853.
67 HU, Fang, et al. Metal–organic framework as a simple and general inert nanocarrier for photosensitizers to implement activatable photodynamic therapy. Advanced Functional Materials, 2018, 28.19: 1707519.
68 HARRIS, Lyndsay, et al. Liposome‐encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first‐line therapy of metastatic breast carcinoma. Cancer, 2002, 94.1: 25-36.
69 DUNCAN, Ruth. Polymer therapeutics as nanomedicines: new perspectives. Current opinion in biotechnology, 2011, 22.4: 492-501.
70 WU, Ming‐Xue; YANG, Ying‐Wei. Metal–organic framework (MOF)‐based drug/cargo delivery and cancer therapy. Advanced Materials, 2017, 29.23: 1606134.
71 MENG, Jin, et al. A multistage assembly/disassembly strategy for tumor-targeted CO delivery. Science Advances, 2020, 6.20: eaba1362.
72 HE, Ting, et al. Tumor pH-responsive metastable-phase manganese sulfide nanotheranostics for traceable hydrogen sulfide gas therapy primed chemodynamic therapy. Theranostics, 2020, 10.6: 2453.
73 LIU, Furong, et al. A glutathione-activatable nanoplatform for enhanced photodynamic therapy with simultaneous hypoxia relief and glutathione depletion. Chemical Engineering Journal, 2021, 403: 126305.
74 JIN, Zhaokui, et al. Intratumoral H 2 O 2-triggered release of CO from a metal carbonyl-based nanomedicine for efficient CO therapy. Chemical Communications, 2017, 53.40: 5557-5560.
75 GUO, Ranran, et al. Near‐infrared laser‐triggered nitric oxide nanogenerators for the reversal of multidrug resistance in cancer. Advanced Functional Materials, 2017, 27.13: 1606398.
76 ZHENG, Di‐Wei, et al. Photocatalyzing CO2 to CO for enhanced cancer therapy. Advanced Materials, 2017, 29.44: 1703822.
77 YAO, Xianxian, et al. Novel gas‐based nanomedicines for cancer therapy. View, 2022, 3.1: 20200185.
78 HARRIS, Lyndsay, et al. Liposome‐encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first‐line therapy of metastatic breast carcinoma. Cancer, 2002, 94.1: 25-36.
79 DUNCAN, Ruth. Polymer therapeutics as nanomedicines: new perspectives. Current opinion in biotechnology, 2011, 22.4: 492-501.
80 WU, Ming‐Xue; YANG, Ying‐Wei. Metal–organic framework (MOF)‐based drug/cargo delivery and cancer therapy. Advanced Materials, 2017, 29.23: 1606134.
81 MENG, Jin, et al. A multistage assembly/disassembly strategy for tumor-targeted CO delivery. Science Advances, 2020, 6.20: eaba1362.
82 HE, Ting, et al. Tumor pH-responsive metastable-phase manganese sulfide nanotheranostics for traceable hydrogen sulfide gas therapy primed chemodynamic therapy. Theranostics, 2020, 10.6: 2453.
83 LIU, Furong, et al. A glutathione-activatable nanoplatform for enhanced photodynamic therapy with simultaneous hypoxia relief and glutathione depletion. Chemical Engineering Journal, 2021, 403: 126305.
84 JIN, Zhaokui, et al. Intratumoral H 2 O 2-triggered release of CO from a metal carbonyl-based nanomedicine for efficient CO therapy. Chemical Communications, 2017, 53.40: 5557-5560.
85 GUO, Ranran, et al. Near‐infrared laser‐triggered nitric oxide nanogenerators for the reversal of multidrug resistance in cancer. Advanced Functional Materials, 2017, 27.13: 1606398.
86 ZHENG, Di‐Wei, et al. Photocatalyzing CO2 to CO for enhanced cancer therapy. Advanced Materials, 2017, 29.44: 1703822.
87 MU, Jing, et al. Cascade reactions catalyzed by planar metal–organic framework hybrid architecture for combined cancer therapy. Small, 2020, 16.42: 2004016.
88 LIU, Tianzhi, et al. Endogenous catalytic generation of O2 bubbles for in situ ultrasound-guided high intensity focused ultrasound ablation. ACS nano, 2017, 11.9: 9093-9102.
89 CHEN, Jiajie, et al. Palladium Nanocrystals‐Engineered Metal–Organic Frameworks for Enhanced Tumor Inhibition by Synergistic Hydrogen/Photodynamic Therapy. Advanced Functional Materials, 2021, 31.4: 2006853.
90 XU, Jiating, et al. Tumor microenvironment‐responsive mesoporous MnO2‐coated upconversion nanoplatform for self‐enhanced tumor theranostics. Advanced Functional Materials, 2018, 28.36: 1803804.
91 LU, Sen, et al. GYY4137, a hydrogen sulfide (H2S) donor, shows potent anti-hepatocellular carcinoma activity through blocking the STAT3 pathway. International journal of oncology, 2014, 44.4: 1259-1267.
92 EGHBAL, Mohammad A.; PENNEFATHER, Peter S.; O’BRIEN, Peter J. H2S cytotoxicity mechanism involves reactive oxygen species formation and mitochondrial depolarisation. Toxicology, 2004, 203.1-3: 69-76.
93 YAO, Xianxian, et al. Novel gas‐based nanomedicines for cancer therapy. View, 2022, 3.1: 20200185.
94 CHEN, Xiaobo, et al. Semiconductor-based photocatalytic hydrogen generation. Chemical reviews, 2010, 110.11: 6503-6570.
95 FAN, Wenpei, et al. Nanotechnology for multimodal synergistic cancer therapy. Chemical reviews, 2017, 117.22: 13566-13638.
96 SHEN, Bo, et al. Topotecan‐loaded mesoporous silica nanoparticles for reversing multi‐drug resistance by synergetic chemoradiotherapy. Chemistry–An Asian Journal, 2015, 10.2: 344-348.
97 YANG, Zebin, et al. Photothermo‐promoted nanocatalysis combined with H2S‐mediated respiration inhibition for efficient cancer therapy. Advanced Functional Materials, 2021, 31.8: 2007991.
98 L. Wang et al., "Fe-doped copper sulfide nanoparticles for in vivo magnetic resonance imaging and simultaneous photothermal therapy," Nanotechnology, vol. 30, no. 41, p. 415101, 2019.