Versatile Strategy To Generate a Rhodamine Triplet State as

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Biological and Medical Applications of Materials and Interfaces

A Versatile Strategy to Generate Rhodamine Triplet State as MitochondriaTargeting Visible Light Photosensitizers for Efficient Photodynamic Therapy Chuangjun Liu, Lihua Zhou, Fangfang Wei, Ling Li, Shunan Zhao, Ping Gong, Lintao Cai, and Keith Man-Chung Wong ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b20224 • Publication Date (Web): 07 Feb 2019 Downloaded from http://pubs.acs.org on February 8, 2019

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ACS Applied Materials & Interfaces

A Versatile Strategy to Generate Rhodamine Triplet State as Mitochondria-Targeting Visible Light Photosensitizers for Efficient Photodynamic Therapy Chuangjun Liu,‡a,c Lihua Zhou,‡b Fangfang Wei,a Ling Li,a Shunan Zhao,a Ping Gong,*b Lintao Caib and Keith Man-Chung Wong*a a Department of Chemistry, Southern University of Science and Technology, 1088 Xueyuan Blvd., Shenzhen 518055, China b Guangdong Key Laboratory of Nanomedicine, Shenzhen, engineering Laboratory of nanomedicine and nanoformulations, CAS Key Lab for Health Informatics, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China c College of Chemistry and Pharmaceutical Engineering, Huanghuai University, 463000, Zhumadian, China KEYWORDS: Luminescent Transition Metal Complex; Photosensitizer; Photodynamic Therapy; Triplet state; Rhodamine

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ABSTRACT

Through the use of a rhodamine appended chelate, bpy-Rho, a versatile strategy has been demonstrated to readily form mitochondria-targeting photosensitizers via the incorporation of a variety of luminescent transition metal systems, M-Rho, such as Re(I), Ir(III), Pt(II) and Rh(III). The emission from the rhodamine singlet excited state as well as the transition metal triplet excited state are partially quenched by the depopulation of them into the dark rhodamine triplet excited state. The generation of the triplet excited state of rhodamine moiety endows the complexes with mitochondria-targeting photosensitizing ability to form singlet oxygen (1O2) for use as photodynamic therapy (PDT) agent upon visible light irradiation. The combination of rhodamine organic dye and luminescent transition metal centers in such hybrid systems exhibits the synergistic merits for the biological applications, including low dark cytotoxicity, selective tumor cell uptake, high molar absorptivity suitable for low-energy excitation in the visible region, and high photostability. The corresponding in vitro photocytotoxicity and in vivo photo antitumor efficacy have also been studied to demonstrate the potential PDT application of M-Rho.


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INTRODUCTION Photodynamic therapy (PDT), which is regarded as a less invasive tumor treatment, is a clinically approved technique to eradicate a variety of tumor cells by simultaneously applying a photosensitizer, molecular oxygen, and light.1-3 Upon photo-excitation, the photosensitizer with a triplet excited state from an intersystem crossing (ISC) pathway is able to generate reactive oxygen species (ROS) in the presence of molecular oxygen (3O2), such as singlet oxygen (1O2), which is cytotoxic to tumor cells and immediately induces cell apoptosis.2,3 In order to fulfill the criteria of a large molar extinction coefficient, high ISC efficiency and good photostability, lots of attention has been put in the development of ideal photosensitizers.2,3 Meanwhile, the exploration of photosensitizers, with high tumor selectivity represents another big challenge as it can significantly increase tumor ablation accuracy and efficiency. Rhodamine, one of the most common organic dyes, has been widely applied in chemosensing4-7 and biomolecular labelling,8 in view of its great photostability, low excitation and emission energies, large molar extinction coefficient and high fluorescence quantum yield, as well as good water solubility.9 Because tumor cells with higher mitochondria activity typically show higher net negative charge than normal cells,10 the cationic rhodamine can be attracted and accumulated onto the mitochondria,11 facilitating its rapid migration towards the organelle.12 Singlet oxygen has a short lifetime and its subcellular diffusion radius is short, therefore, localization of the photosensitizer is crucial for its PDT performance. In order to circumvent the limitations caused by the short lifetime ( Rh-Rho > bpy-Rho, as indicated by their 1O2 emission intensities and ΦΔ as well as intracellular and mitochondria-localized ROS yield (vide infra). Difference in cellular uptake of M-Rho in DMEM cell cultures in such in vitro cytotoxicity studies, as well as another solvent (MeCN) used in singlet oxygen quantum yield measurement, are ascribed to the reversed order of PDT performance for Pt-Rho and Re-Rho with their ΦΔ values. Among these complexes M-Rho, the best PDT performance is found in Ir-Rho, which shows the strongest ability to populate the rhodamine triplet state (T1) and hence to produce 1O2, which is considered to trigger the apoptotic cell death.47


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Figure 6. In vitro cell viability of MCF-7 cells treated with different concentrations of bpy-Rho and M-Rho (a) in the dark and (b) after irradiation with 11-W lamp. (c) Fluorescence images of MCF-7 cells treated with blank, bpy-Rho and M-Rho (5 μM) irradiated with 11-W lamp for 30 min. Viable cells were stained green with calcein-AM, and dead cells were stained red with PI. (Scale bar =100 μm) The intracellular ROS generation ability of bpy-Rho and M-Rho in MCF-7 cells has also been examined after irradiation with the 11-W lamp for 30 min by using DCFH-DA assay. The nonfluorescent and cell-permeable H2DCFH-DA dye will be oxidized into strongly fluorescent and cell membrane-impermeable DCF dye by ROS. Both confocal fluorescence microscopic images (Fig. 7a) and flow cytometry analysis (Fig. 7b) indicate that intracellular ROS is significantly generated by the evaluation of DCF fluorescence. In line with the photophysical results, Ir-Rho is found to have the highest ROS generation ability, while the blank and bpy-Rho can only generate negligible or a small amount of ROS under the same condition.


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Figure 7. DCFH-DA assay for the evaluation of intracellular ROS production of bpy-Rho and MRho (5 μM) in DMEM; incubation with MCF-7 cells in the dark for 30 min followed by 30 min irradiation with 11-W lamp (a) Confocal fluorescence microscopy images and (b) flow cytometry analysis (n=10000 cells) with mean fluorescence intensity per cell. In order to investigate the intracellular localization of bpy-Rho and M-Rho, MCF-7 cells have been co-stained with the mitochondria-specific probe, MitoTracker Green. Confocal microscopy shows that most of them are specifically localized in the mitochondria (Fig. 8), suggesting that the modified rhodamine ligand and metal complexes retain the mitochondria-targeting ability of rhodamine. According to the overlapping of fluorescence signals between the compounds and MitoTracker Green, the metal complexes M-Rho are essentially localized in the mitochondria whereas the ligand bpy-Rho is relatively less mitochondria-localized as revealed from their Pearson’s colocalization coefficients. It is interesting to note that the incorporation of transition metal systems into the rhodamine-tethered ligand results in stronger mitochondria-targeting properties, probably due to the balanced interplay between the cationic charge and lipophilicity.


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Figure 8. Confocal fluorescence microscopic images of MCF-7 cells treated with 5 μM bpy-Rho and M-Rho and MitoTracker Green. On the basis of the results of intracellular ROS production and colocalization study, it is reasonable to anticipate that the ROS is essentially generated within the mitochondria. MitoSOX Red reagent, a mitochondrial ROS indicator, is also used to probe specifically the generation of mitochondria-localized ROS. Intense red fluorescence from the oxidation of MitoSOX is observed in both confocal fluorescence microscopy images (Fig. 9a) and flow cytometry analysis (Fig. 9b) of MCG-7 cells incubated with MitoSOX and M-Rho. In contrast, with the same treatment of bpyRho or in the untreated control, only very weak red fluorescence has been detected. This experiment indicates that remarkable mitochondria-localized ROS is generated with the treatment of M-Rho. In view of all these results, both the mitochondria-targeting and enhanced photosensitizing properties are unique to M-Rho, showing the synergistic effect between the rhodamine unit and transition metal system.


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Figure 9. (a) Confocal fluorescence microscopic images of MCF-7 cells treated with MitoSOX (1.0 μM) and bpy-Rho and M-Rho (10 μM), 11 W lamp irradiation for 10 min.(b) Flow cytometry analysis of MCF-7 cells (n=10000 cells) after treatment with MitoSox and bpy-Rho and M-Rho mean fluorescence intensity per cell. In order to confirm that the mechanism of cell death is arising from the photo-cytotoxicity of MRho, a flow-cytometry-based JC-1 assay was adopted to investigate the change in mitochondrial membrane potential (ΔΨm). Mitochondrial depolarization occurs as a result of mitochondrial dysfunction and is commonly regarded as a hallmark of apoptosis.48 As a lipophilic and cationic dye, JC-1 can selectively translocate into mitochondria. The J-aggregate form of JC-1 with intense red fluorescence is formed in healthy cells with high ΔΨm, while green fluorescent monomeric form exists in the apoptotic cells with low ΔΨm.49,50 No obvious change in the ΔΨm of MCF-7 cells is found in the vehicle control, as evident from dominant red J-aggregates (94.8%) with minimal green JC-1 monomers (1.69%). In contrast, a dramatic increase in the green fluorescence with a concomitant drop in red fluorescence is observed for the MCF-7 cells treated with increasing concentration of Ir-Rho upon irradiation (Fig. S17). This strongly indicates an increase in mitochondrial depolarization and hence apoptosis, which are responsible for the photocytotoxicity. Parallel experiments for bpy-Rho and M-Rho at the same concentration suggest that Ir-Rho results in significantly higher mitochondrial dysfunction and eventually increased


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apoptosis (Fig. 10). On the basis of the decreased ratio of JC-1 aggregates/JC-1 monomers in the cells with 1O2 generated, the lowest ratio of 1.79 for Ir-Rho shows the enhanced effect of PDT on the mitochondrial-regulated apoptosis, relative to the others (bpy-Rho, 14.23; Rh-Rho, 11.28; PtRho, 8.16; Re-Rho, 3.48).

Figure 10. Flow-cytometry-based JC-1 assay as a measure of mitochondrial depolarization induced by bpy-Rho and M-Rho.

Tumor Cell Selectivity. We envisioned that the mitochondria-targeting bpy-Rho and M-Rho would exhibit good selectivity towards tumor cells that possess more active mitochondria. Flow cytometry has been used to evaluate the tumor cell selectivity of bpy-Rho and M-Rho by incubation in different cell lines, including tumor cells (MCF-7, human breast cancer cells; A549, human lung cancer cells; 4T1, mouse breast cancer cells) and normal cells (MCF-10A, human breast cells; 293T, human kidney cells; bEnd3, mouse microvascular endothelial cells). The results indicate that Ir-Rho possessed the highest uptake efficiency and affinity to tumor cells (Fig. 11).


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Based on the previous studies, a contrast index (CI) higher than 2.5 is considered as substantial accumulation in a tumor,51 and therefore Ir-Rho is found to be selective towards tumor cells from their CI values of greater than 2.5 to 4T1, A549, and MCF-7.

Figure 11. Flow cytometry analysis (n = 10 000 cells) of bpy-Rho and M-Rho in normal cells (bEnd3, 293T, MCF-10A) and tumor cells (4T1, A549, MCF-7) with normalized fluorescence intensity. It is known that the selectivity toward tumor cells is not only because of the enhanced mitochondrial membrane potential in typical tumor cells, but also highly dependent on the lipophilic/hydrophilic character of the photosensitizers.10,52 Octanol-water partition coefficients (log Po/w)53 of bpy-Rho and M-Rho have been measured in order to study their lipophilic/hydrophilic characters. The higher is the log Po/w value associated with the dye, the higher is its lipophilic character. The log Po/w values of bpy-Rho, Ir-Rho, Re-Rho, Pt-Rho and Rh-Rho are determined to be 0.49, ‒0.39, 0.41, 1.26, and ‒1.05, respectively. This result indicates that the more hydrophilic (negative log Po/w values) dyes show a high degree of tumor cell selectivity. Previous studies demonstrated that the tumor cell selectivity is more likely to occur


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when the lipophilic/hydrophilic character of any cationic mitochondrial drug falls within a narrow range of Po/w values close to that of the prototypical mitochondrial dye rhodamine 123 (log Po/w = ‒0.62).52 Our data show that the log Po/w value of Ir-Rho is very close and the closest among other compounds to rhodamine 123. The best tumor cell selectivity of Ir-Rho is consistent with this prediction. Other factors, including OTAP1B3 subtype of organic anion transporter peptides (OATPs),48-56 affecting the tumor cell selectivity cannot be precluded. The tumor cell selectivity of Ir-Rho has been further evaluated by in vivo near-infrared fluorescence (NIRF) imaging by monitoring the in vivo biodistribution and tumor accumulation of Ir-Rho. The in vivo NIRF images demonstrate a steady increase of tumor uptake of Ir-Rho, which peaks at 24 h (Fig. 12a and Fig. S18) after intravenous (i.v.) injection into MCF-7 tumor-bearing mice via the tail vein. At 24 h post-injection, tumors and major organs were excised for ex vivo NIRF imaging to determine the tissue distribution of Ir-Rho (Fig. 12b and 12c). As shown in Fig. 12, Ir-Rho exhibits good tumor accumulation and relatively low liver uptake, further indicating its good selectivity towards tumor cells.

Figure 12. (a) In vivo NIFR images of MCF-7 tumor-bearing nude mice from 0 to 48 h after injection of Ir-Rho (200μM, 150μl). (b) Ex vivo NIR images and (c) fluorescence intensity of dissected organs and tumor at 24 h post injection.


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In vivo Antitumor Efficacy Studies. The in vivo study for anticancer efficacy of bpy-Rho and M-Rho has been evaluated on MCF-7 tumor-bearing nude mice. The samples of bpy-Rho, M-Rho and PBS (as a control) were individually administered into the mice via i.v. injection. Upon 30- min irradiation with a Xenon lamp light source for two times at 24 and 48 hours after injection, the tumor volume was measured every 2 or 3 days to monitor the rate of tumor growth. As shown in Fig. S19a, tumor volume in the mice with the injection of bpy-Rho or PBS and with irradiation was found to grow rapidly, and no mouse was survived in these two groups at the end of observation period (Fig. S19b). Whereas, the rate of tumor growth in the mice treated with MRho after irradiation was significantly slower, indicative of pronounced anticancer efficacy in such treatment with M-Rho (Fig. S19a). Furthermore, the tumors in the mice treated with Ir-Rho and with irradiation exhibited remarkable ablation, with low probability tumor recurrence after 21-day treatment (Fig. S19b). These results indicate that the tumor was eradicated by the light-triggering PDT effect of M-Rho. No obvious variation in the mice weight for all treated groups was observed, suggesting of well tolerance in the experimental treatments of M-Rho (Fig. S19c). CONCLUSION In summary, we have established a versatile strategy to combine a rhodamine unit with a variety of transition metal centers to afford mitochondria-targeting photosensitizers. Facile generation of rhodamine triplet excited states, which are involved in 1O2 formation, can be achieved. M-Rho, receiving the synergistic effects of large molar extinction coefficients in the visible region, low dark cytotoxicity, high photostability as well as selective tumor cell uptake, has been demonstrated as a promising candidate in PDT application. More importantly, this work opens up a new avenue for the potential application of the rhodamine system through the efficient population of triplet state in photocatalytic reactions, DSSC, solar cells and so on. Extension of this strategy to other


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organic chromophores, such as fluorescein, Si-rhodamine and Si-fluorescein, as well as the exploration of other applications of this system are ongoing in our laboratory.

EXPERIMENTAL SECTION Materials and Reagents. All the solvents for synthesis were of analytical grade. Iridium(III) chloride hydrate and 4,4’-dimethyl-2,2’-bipyridine were purchased from Aldrich Chemical Company. Re2(CO)10 was purchased from Stream. Rhodium(III) chloride hydrate was purchased from Innochem. Re(CO)5Br,57 4'-methyl-[2,2'-bipyridine]-4-carbaldehyde,58 {Ir(ppy)2Cl}2,59 cis[(DMSO)2PtCl2],60

and

{Rh(ppy)2Cl2}2,61

Re(bpy)(CO)3Br,62

[Ir(ppy)2(bpy)]PF663

and

[Rh(ppy)2(bpy)]PF663 were synthesized according to the literature methods. Synthesis. For bpy-Rho, a mixture of 4'-methyl-[2,2'-bipyridine]-4-carbaldehyde (1g, 5 mmol), 3-(diethylamino)phenol (1.7 g, 10 mmol), p-TsOH (0.129 g, 0.75 mmol) and acetic acid (50 mL) was heated to 70 °C and stirred for 7 h. The reaction mixture was cooled to r.t., and the pH was adjusted to above 7 with a 10% NaOH solution. The precipitate was filtered and washed with water (50 mL). The solid was dissolved in CH2Cl2 (50 mL), to which chloranil (0.615 g, 2.5 mmol) was added. The mixture was stirred for 2 h, and then evaporated to dryness. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH, 10:1, v/v) to give a purple solid; yield 860 mg (27 %). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.92 (d, J = 4.8, 1H), 8.46 (d, J = 4.9, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 7.35 (dd, J = 4.9, 1.6, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 7.17 (d, J = 4.2, 1H), 6.92 (dd, J = 12.3, 2.4, 4H), 3.72 – 3.59 (m, 8H), 2.47 (s, 3H), 1.31 (t, J = 7.1, 12H). 13C NMR (101 MHz, CDCl3) δ (ppm): 158.01, 157.26, 155.89, 154.74, 153.77, 150.00, 149.31, 148.73, 141.29, 131.57, 125.70, 123.68, 122.58, 121.29, 114.92, 112.74, 96.90, 46.53, 21.45, 12.88. HRMS (ESI). Calcd for C32H35N4O ([M + H]+): m/z 491.2805; found: m/z 491.2794.


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For Re-bpy, bpy-Rho (100 mg, 0.16 mmol) and Re(CO)5Br (65 mg, 0.16 mmol) were refluxed in toluene overnight in the dark under nitrogen. The solution was cooled to room temperature, and then evaporated to dryness. The crude was purified by neutral Al2O3 column chromatography (CH2Cl2/MeCN). Subsequent recrystallization of the complex by diffusion of diethyl ether vapor into a solution of the complex in acetonitrile. Yield: 126 mg (80%). 1H NMR (400 MHz, CD3CN) δ (ppm): 9.25 (d, J = 5.7, 1H), 8.93 (d, J = 5.7, 1H), 8.45 (d, J = 1.0, 1H), 8.26 (s, 1H), 7.64 (dd, J = 5.6, 1.7, 1H), 7.52 (d, J = 4.9, 1H), 7.34 (d, J = 9.6, 1H), 7.16 (s, 1H), 7.08 – 6.99 (m, 2H), 6.90 (d, J = 2.0, 2H), 3.65 (dd, J = 7.1, 4.3, 8H), 2.53 (s, 3H), 1.35 – 1.21 (m, 12H). 13C NMR (126 MHz, CD3CN) δ (ppm): 7.45, 189.22, 157.87, 156.75, 155.96, 154.75, 153.58, 152.80, 152.65, 150.87, 144.02, 131.32, 130.95, 128.75, 127.45, 125.41, 124.26, 114.94, 112.50, 96.42, 45.92, 20.60, 11.91. HRMS (ESI). Calcd for C35H35BrN4O4Re ([M – PF6]+): m/z 841.1394; found: m/z 841.1385. Elemental analysis (%) calcd for C35H35BrF6N4O4PRe·CH3OH·3CH3COCH3 (found): C 45.30 (45.65), H 4.82 (4.66), N 4.70 (4.98). For Ir-bpy, a mixture of {Ir(ppy)2Cl}2 (86 mg, 0.08 mmol) and bpy-Rho (100 mg, 0.16 mmol) in 20 mL of methanol/dichloromethane (1:1 v/v) was refluxed under an inert atmosphere of nitrogen in the dark for 12 h. The solution was then cooled to room temperature, and KPF6 (30 mg, 0.16 mmol) was added to the solution. The mixture was stirred for 30 min at room temperature and then evaporated to dryness. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH). Yield 152 mg (74 %). 1H NMR (400 MHz, CD3CN) δ (ppm): 8.67 (s, 1H), 8.47 (s, 1H), 8.21 (d, J = 5.6, 1H), 8.11 (t, J = 7.4, 2H), 7.88 (m, , 6H), 7.69 (d, J = 5.7, 1H), 7.50 (t, J = 7.2, 2H), 7.39 (d, J = 5.5, 1H), 7.11 (m, 6H), 7.00 – 6.81 (m, 5H), 6.36 (d, J = 7.4, 1H), 6.26 (d, J = 7.5, 1H), 3.65 (dq, J = 14.3, 7.0, 8H), 2.51 (s, 3H), 1.37 – 1.18 (m, 12H). 13C NMR (126 MHz, CD3CN) δ (ppm): 167.43, 157.87, 156.91, 155.88, 154.91, 152.11, 151.20, 150.12, 150.06, 149.55,


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144.29, 144.03, 143.28, 138.67, 131.63, 131.39, 131., 130.43, 129.58, 128.63, 126.00, 124.91, 123.65, 122.67, 1.94, 114.62, 112.46, 96.40, 45.84, 20.43, 11.87. HRMS (ESI). Calcd for C54H51ON6F6IrP ([M – PF6]+): m/z 1137.3390; found: m/z 1137.3392. Elemental analysis (%) calcd for C54H51ON6F12IrP2·2CH3OH·2CH3COCH3 (found): C 50.92 (50.66), H 4.89 (4.66), N 5.75 (5.44). For Pt-bpy, bpy-Rho (100 mg, 0.16 mmol), cis-[Pt(DMSO)2Cl2] (68 mg, 0.16 mmol), and CH2Cl2 (20 mL) were stirred at room temperature. overnight under an atmosphere of nitrogen, during which time a deep purple precipitate appeared. The product was collected by filtration and washed with diethyl ether (2 × 3 mL), which was used in next step without further purification. The crude product obtained in the previous step were sonicated with 5 mg of CuI, 0.1 ml (1.0 mmol) of phenylacetylene in 2 ml of DMF and 1.5 ml of diethylamine for 4 h. The flask was chilled, and the precipitate was collected by filtration and washed with ether. Yield: 77 mg (68%). 1H

NMR (400 MHz, CD3CN) δ (ppm): 9.93 (d, J = 5.5, 1H), 9.48 (d, J = 6.0, 1H), 8.35 (s, 1H),

8.15 (s, 1H), 7.75 (s, 1H), 7.60 (s, 2H), 7.43 (d, J = 9.1, 3H), 7.39 (d, J = 7.0, 2H), 7.32 – 7.25 (m, 3H), 7.20 (d, J=8.6, 3H), 6.99 (d, J = 9.6, 2H), 6.87 (d, J = 2.4, 2H), 3.64 (dd, J=14.3, 7.1, 8H), 2.46 (s, 3H), 1.38 – 1.21 (m, 12H).

13C

NMR (101 MHz, CD3CN) δ (ppm): δ 157.86, 157.80,

155.86, 155.75, 131.87, 131.47, 131.47, 131.33, 131.28, 128.67, 128.65, 128.62, 128.12, 128.12, 127.98, 127.91, 127.91, 125.77, 125.62, 124.73, 124.26, 123.09, 123.07, 122.29, 122.24, 117.34, 114.77, 114.70, 114.70, 112.60, 112.22, 96.21, 96.21, 96.16, 45.80, 45.80, 20.94, 11.91. HRMS (ESI). Calcd for C48H45ON4Pt ([M – PF6]+): m/z 888.3241; found: m/z 888.3254. For Rh-bpy, the synthetic procedure was similar to that of complex bpy-Rho except that [{Rh(ppy)2Cl}2] was used instead of {Ir(ppy)2Cl}2. Yield: 70%. 1H NMR (400 MHz, CD3CN) δ (ppm): 8.52 (s, 1H), 8.32 (s, 1H), 8.23 (d, J = 5.4, 1H), 8.12 (dd, J = 7.9, 4.7, 2H), 8.02 – 7.95 (m,


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2H), 7.89 (dd, J = 9.8, 6.7, 3H), 7.80 (d, J = 5.2, 1H), 7.66 (d, J = 5.3, 1H), 7.52 (d, J = 5.4, 1H), 7.44 (d, J = 9.6, 1H), 7.39 (d, J = 5.3, 1H), 7.21 – 7.08 (m, 5H), 7.04 – 6.98 (m, 3H), 6.92 – 6.86 (m, 3H), 6.38 (d, J = 7.7, 1H), 6.29 (d, J = 7.7, 1H), 3.65 (dq, J = 14.5, 7.1, 8H), 2.47 (s, 3H), 1.26 (dt, J=14.3, 7.1, 12H). 13C NMR (101 MHz, CD3CN) δ (ppm): δ 167.34, 167.29, 167.01, 166.96, 164.78, 164.70, 157.90, 157.87, 155.93, 155.85, 155.45, 153.63, 152.29, 151.30, 150.70, 149.63, 149.55, 149.49, 144.17, 143.96, 143.82, 138.79, 138.74, 132.68, 132.50, 131.61, 131.16, 130.17, 129.02, 127.85, 125.35, 124.70, 124.24, 123.69, 123.60, 123.55, 120.13, 120.11, 114.61, 112.47, 112.45, 96.39, 96.35, 45.88, 45.83, 20.44, 11.83. HRMS (ESI). Calcd for C54H51ON6F6RhP ([M – PF6]+): m/z 1047.2821; found: m/z 1047.2818.

ASSOCIATED CONTENT Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org. Experimental details of X-ray crystallography, photophysical measurement and biological studies. 1H and 13C NMR spectra of bpy-Rho and M-Rho and other spectroscopic results.

AUTHOR INFORMATION Corresponding Author * [email protected] * [email protected] ORCID


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Keith Man-Chung Wong: 0000-0001-5551-7806 Author Contributions ‡ C. Liu and L. Zhou contributed equally to this work. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT K.M.C.W. acknowledges the “Young Thousand Talents Program” award and the start-up fund administered by the Southern University of Science and Technology. This project is also supported by National Scientific Foundation of China (grant no. 21471074 and 21771099) and Shenzhen Technology

and

Innovation

Committee

(grant

no.

JCYJ20170307110203786

and

JCYJ20170817110721105).


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Versatile Strategy To Generate a Rhodamine Triplet State as

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