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Upconversion NIR-II Fluorophores for Mitochondria-Targeted Cancer

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Upconversion NIR-II Fluorophores for Mitochondria-Targeted Cancer ARTICLE https://doi.org/10.1038/s41467-020-19945-w OPEN Upconversion NIR-II fluorophores for mitochondria-targeted cancer imaging and photothermal therapy Hui Zhou 1,2,7, Xiaodong Zeng 1,3,7, Anguo Li1, Wenyi Zhou1,3, Lin Tang1, Wenbo Hu 4, Quli Fan 4, ✉ ✉ Xianli Meng5, Hai Deng 6, Lian Duan1, Yanqin Li1, Zixin Deng1, Xuechuan Hong 1,2 & Yuling Xiao 1,3 fl 1234567890():,; NIR-II uorophores have shown great promise for biomedical applications with superior in vivo optical properties. To date, few small-molecule NIR-II fluorophores have been dis- covered with donor-acceptor-donor (D-A-D) or symmetrical structures, and upconversion- mitochondria-targeted NIR-II dyes have not been reported. Herein, we report development of D-A type thiopyrylium-based NIR-II fluorophores with frequency upconversion luminescence (FUCL) at ~580 nm upon excitation at ~850 nm. H4-PEG-PT can not only quickly and effectively image mitochondria in live or fixed osteosarcoma cells with subcellular resolution at 1 nM, but also efficiently convert optical energy into heat, achieving mitochondria-targeted photothermal cancer therapy without ROS effects. H4-PEG-PT has been further evaluated in vivo and exhibited strong tumor uptake, specific NIR-II signals with high spatial and temporal resolution, and remarkable NIR-II image-guided photothermal therapy. This report presents the first D-A type thiopyrylium NIR-II theranostics for synchronous upconversion- mitochondria-targeted cell imaging, in vivo NIR-II osteosarcoma imaging and excellent photothermal efficiency. 1 State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE), Hubei Provincial Key Laboratory of Developmentally Originated Disease, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China. 2 College of Science, Innovation Center for Traditional Tibetan Medicine Modernization and Quality Control, Tibet University, Lhasa 850000, China. 3 Shenzhen Institute of Wuhan University, Shenzhen 518057, China. 4 Key Laboratory for Organic Electronics and Information Displays & Institute of Advanced Materials, Nanjing University of Posts and Telecommunications, Nanjing 210023, China. 5 Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Wenjiang, Chengdu, Sichuan 611137, China. 6 Department ✉ of Chemistry, University of Aberdeen, Aberdeen, UK. 7These authors contributed equally: Hui Zhou, Xiaodong Zeng. email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2020) 11:6183 | https://doi.org/10.1038/s41467-020-19945-w | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19945-w luorescence imaging in the second near-infrared window or high-energy laser excitation. Therefore, the exploitation of new (NIR-II, 1000–1700 nm) has been widely used in biological mitochondria-targeted NIR-II fluorophores with a more bio- F 41 and biomedical research, because the light in this wave- compatible upconversion strategy is greatly desired . length region is capable of deep penetration, and cellular auto- As useful and versatile heterocyclic luminescent compounds fluorescence is minimal1–17. Our initial progress toward the with a positive charge, pyrylium salts are widely utilized as photo- first small-molecule organic NIR-II dye entailed the formation of sensitizers, Q-switchers, and NIR dyes for proteins and oligo- the fluorophore CH1055 from benzo-bis(1,2,5-thiadiazole) saccharide labeling42,43. Thiopyrylium is analogous to the pyr- (BBTD), which absorbed light at ~750 nm and fluoresced at ylium cation with the oxygen atom replaced by a sulfur atom. ~1055 nm18–20. The LUMO of CH1055 showed a strong con- Notably, thiopyrylium salts display physical and chemical prop- tribution at the electron-accepting moiety BBTD with a typical erties typical of aromatic compounds and are much less reactive optical bandgap (Egap) smaller than 1.5 eV, which was beneficial than analogous pyrylium salts due to the lower electronegativity for bathochromic shift and large Stokes shift. Despite a panel of of the sulfur atom44,45. As is clearly seen in Supplementary NIR-II emissive contrasts have been explored, the majority of Table 1, the Egap of thiopyrylium is much lower than that of them had a BBTD core or were symmetrical fluorophores with a pyrylium, suggesting that thiopyrylium salts may become novel D–A–D structure (Fig. 1a)21–29. It is imperative to search for new NIR acceptors. In the current work, we utilized thiopyrylium types of small-molecule NIR-II probes with desirable chemical heterocycle 2 as a building block to construct a series of novel and physical properties, minimal cellular toxicity, and clinical red-shifted thiopyrylium dyes 3 with donor–acceptor (D–A) translation ability (Fig. 1). structures (Fig. 1b). The electronic structure calculations and Among all the fluorescent dyes, frequency upconversion experimental evaluation of the optical properties of 3a–3k and H4 luminescence (FUCL) materials can convert low-energy excita- were carried out to elucidate the structure–property relationship. tion to high-energy emission with large anti-Stokes shift, limited Furthermore, the synthesized NIR-II fluorophores 3k-PEG, H4- auto-fluorescence from biological samples, high signal-to-noise PEG, and H4-PEG-PT were highly resistant to photobleaching ratio, and tunable excitation and emission30–32. Mitochondria are and well retained within the mitochondria even after osteo- vital organelles responsible for the energy production and pro- sarcoma cell fixation and permeabilization at 1 nM based on gramed cell death such as apoptosis33–35. Despite the develop- FUCL strategy with a short-wavelength luminescence at 580 nm ment of mitochondria-targeted therapeutics, imaging of upon excitation at ~850 nm, which is among the most favorable mitochondria is also crucial for providing important information characteristics of fluorescent dyes. Moreover, H4-PEG-PT about disease presence, progression, and pathways for early dis- exhibited potent photothermal therapy effect toward osteo- ease diagnosis and treatment36–39. To date, limited examples of sarcoma both in vitro and in vivo. To the best of our knowledge, mitochondria-targeted FUCL organic dyes have been reported this report presents the first D–A type thiopyrylium NIR-II and used for deep-seated tumor treatment40. Furthermore, no theranostics for synchronous FUCL mitochondria-targeted cell research based on the FUCL and mitochondria-targeted NIR-II imaging with subcellular resolution, deeper tissue NIR-II osteo- imaging technology has been developed for tumor imaging and sarcoma imaging in vivo and excellent photothermal efficiency. antitumor therapy. Many small-molecule mitochondria-targeted agents have been developed, including alkyltriphenylpho- Results sphonium cations, rhodamine, and both natural and synthetic Synthesis and rational design.Wefirst designed and synthesized 38 mitochondria-targeted peptides . However, most currently 3a–3f (R = H) to confirm our hypothesis that these dyes fol- fl 2 available mitochondria-targeted uorescent dyes emit only one lowed the D–A rather than D–A–D structure46,47. The chemical color in the visible or NIR-I window. Their applications are structures of 3 are shown in Fig. 1b. The synthetic route for 3 is somewhat limited due to poor photostability, small Stokes shifts, shown in Fig. 2a. The key intermediate thiopyrylium a Acceptor unit Spacer unit D s A s D Functional Acceptor Donor group unit unit BBTD b 808 nm NIR-II Light 1 2 3, H4 (R = H, alkoxy group, n = 0 or 1) c 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k H4 Fig. 1 Structural design and bright-filed images of 3a–3k, H4. a Traditional NIR-II small-molecule dyes based on the BBTD core with D–A–Dor symmetrical structures. b A new strategy for the construction of D–A type thiopyrylium mitochondria-targeted NIR-II dyes with FUCL and photothermal properties, n = 0, 1. c Bright field images of a series of new thiopyrylium-based probes 3a–3k and H4 in dichloromethane. 2 NATURE COMMUNICATIONS | (2020) 11:6183 | https://doi.org/10.1038/s41467-020-19945-w | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19945-w ARTICLE a 4a: R = H; 4b: R = OH 1 1 5a: R2 = H; 5b: R2 = OCH2CCH 6a: R2 = H; 6b: R2 = OCH2CCH Phenyl ring A Phenyl ring B Phenyl ring C 7a: R2 = H; 7b: R2 = OCH2CCH 3a-3k, H4 3a: n = 0, R2 = H, R3 = H, 50%; 3b: n = 0, R2 = H, R3 = OCOMe, 54% 3c: n = 0, R2 = H, R3 = OME, 60%; 3d: n = 0, R2 = H, R3 = SMe, 58% 3e: n = 0, R2 = H, R3 = NMe2, 54%; 3f: n = 1, R2 = H, R3 = NMe2, 51% 3g: n = 0, R2 = OCH2CCH, R3 = H, 48%; 3h: n = 0, R2 = OCH2CCH, R3 = OCOMe, 50% 3i: n = 0, R2 = OCH2CCH, R3 = OMe, 58%; 3j: n = 0, R2 = OCH2CCH, R3 = SMe, 52% 3k: n = 0, R2 = OCH2CCH, R3 = NMe2, 51%; H4: n = 1, R2 = OCH2CCH, R3 = NMe2, 47% b 48° 49° 37° 34° 0.9° 0.1° 0.4° 0.1° 3e-Geometry (S ) 0 3f-Geometry (S0) 48° 48° 37° 33° 0.6° 0.7° 0.3° 0.4° 3k-Geometry (S0) H4-Geometry (S0) Fig. 2 Synthetic route of 3a–3k, H4 and the calculated optimized geometries of 3e–3k, H4. a Reagents and conditions: a (i) acetophenone, benzaldehyde, 3 M aqueous KOH, EtOH, 25 °C, 14 h, 5a: 80%; 1-(4-hydroxyphenyl)ethan-1-one: 82%; (ii) K2CO3, 3-bromoprop-1-yne, acetone, reflux 4 h, 5b: 97%; b (i) cyclopentanone, pyrrolidine, benzene, 100 °C, 4 h; (ii) compound 5, dioxane, reflux, 6 h, 6a: 68%; 6b: 66%; c thioacetic acid, boron trifluoride ether, ether, 60 °C, 2 h, 7a: 62%; 7b: 50%; d aldehydes, acetic anhydride, 70 °C, under microwave irradiation, 75 °C, 2 h, 47–60%. b Calculated optimized ground state (S0) geometries of the molecules at the B3LYP/6-31 G (d) level (Gaussian 09, Revision D.09).
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