KR20170105851A - Bio imaging composition containing cyclometalated transition metal complex - Google Patents
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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Abstract
The present invention relates to a bioimaging composition comprising a cyclometallated transition metal complex, and more particularly to a bioimaging composition comprising a cyclometallated transition metal complex of iridium or rhodium, which is a luminescent metal complex, To bio-imaging compositions.
Description
The present invention relates to a bioimaging composition comprising a cyclometallated transition metal complex, and more particularly to a bioimaging composition comprising a cyclometallated transition metal complex of iridium or rhodium, which is a luminescent metal complex, To bio-imaging compositions.
The endoplasmic reticulum (ER) is one of the cell organs and has received a great deal of attention due to its various metabolic processes of protein synthesis, post-translation modification, and pro-apoptotic signaling have. When some balance of the various protein synthesis processes in the ER is broken, an ER stress response such as an unfolded protein response (UPR) results. However, overexpression of this ER stress response in cancer cells destroys cancer cells. Indeed, conventional cancer therapies have shown that an intensive strategy for ER and mitochondria is an effective cancer therapy compared to other methods. Therefore, the combination of spontaneous ER cell imaging and photodynamic therapy seems to be a step toward efficient cancer cell therapy: specifically, ER visualization in real-time, and the use of both oxidative and aggregation by some photo- , It is expected that effective cancer treatment will be possible.
Much research has been conducted on ER probes for ER visualization. Unfortunately, however, there are not many successful ER target probes compared to other cellular organs such as mitochondria, nuclei and lysosomes. Although successful ER probes have been proposed based on organic molecules, the limitations of fluorescence images are limited because of the use of fluorescent molecules, such as auto-fluorescence, self-quenching and low optical stability. It could not be prevented.
For example, lanthanide metal ions such as europium (Eu 3+ ) and terbium (Tb 3+ ) are used for luminescence in the visible light region, large stoke shifts (excitation and emission) Wavelength difference]. Thus, a light emitting material using such a material has been developed. However, the lanthanide metal ions have a disadvantage in that their luminescence intensity is very weak due to their small cross-sectional area of absorption. To overcome this, lanthanum ions are chemically combined with organic photosensitive molecules, And methods for improving the luminous efficiency have been widely studied [Y. Wada et al., Angew. Chem. Int. Ed., 45: 1925, 2006; JCG Bunzli, Acc. Chem. Res., 39:53, 2006]. However, most of the luminescent materials developed so far have a problem that it is difficult to utilize them in various fields such as bio-imaging and biosensing due to lack of biocompatibility of the material itself.
Accordingly, an object of the present invention is to provide a bioimaging composition capable of imaging an endoplasmic reticulum with minimized cytotoxicity using an iridium or rhodium-based cyclometallated transition metal complex which is a luminescent metal complex.
In order to achieve the above object,
The present invention provides a biomedical composition comprising a cyclometallated transition metal complex represented by the following
[Chemical Formula 1]
(2)
In the
M is iridium or rhodium,
R 1 to R 16 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxyl, thiol, alkylthiol, urea, alkylthiol, cyano, alkyl, alkoxy, An amino group, an alkylamino group, an arylamino group, a hydroxyamino group, an alkylammonium group, a carboxy group, a carbamoyl group, a sulfanyl group, a sulfonyl group, a sulfo group, a sulfonate group , A sulfonamide group, a phosphate group, a phosphonate group, and a phosphinate group,
Ring A and ring B are each independently a substituted or unsubstituted 5-membered aromatic ring, a substituted or unsubstituted 6-membered aromatic ring, a substituted or unsubstituted 5-membered aromatic heterocycle, and a substituted or unsubstituted 6-membered aromatic ring, Aromatic heterocyclic group.
According to one embodiment of the present invention, the endoplasmic reticulum can be visualized with strong phosphorescence by using only iridium or rhodium-based cyclic metallization transition metal complexes.
In addition, the bioimaging composition according to one embodiment of the present invention avoids toxicity by an exogenous additive and can be used in living cells.
1 shows the results of photochemical analysis of a cyclometallated transition metal complex according to an embodiment of the present invention.
FIG. 2 shows a 1-photon / 2-photon image of a U2OS cell labeled with a cyclometallated transition metal complex according to an embodiment of the present invention and a FLIM analysis on the lifetime according to cell condition.
Figure 3 shows the cytotoxicity of the cyclometallated transition metal complex according to one embodiment of the present invention.
Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, which will be readily apparent to those skilled in the art. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In order to clearly illustrate the present invention, parts not related to the description are omitted, and similar parts are denoted by like reference characters throughout the specification.
It is to be understood that the terms or words used in the specification and claims are not to be construed in a conventional or dictionary sense and that the inventor may properly define the concept of a term in order to best describe its invention And should be construed in accordance with the principles and meanings and concepts consistent with the technical idea of the present invention.
In the specification of the present invention, when a component is referred to as "comprising ", it means that it can include other components as well as other components, .
In the specification of the present invention, "A and / or B" means A or B, or A and B.
Throughout the specification of the present invention, the bonding lines between atoms and atoms in chemical formulas, reaction schemes and schemes are not only covalent bonds, ionic bonds but also weak noncovalent bonds such as bonds by unshared electron pairs, Van der Waals forces, For convenience sake, and is shown to a degree that can be easily understood by a person skilled in the art. In particular, a coupling line indicated by an arrow means a coordinate combination in which two electrons present in one element are donated to the other element. As a result, the number of valence electrons may not match the number of electrons in each of the elements represented by the formulas, the formulas, and the schemes, but this is easily understood by those skilled in the art. In addition, carbon and hydrogen are omitted, except as otherwise indicated.
Throughout the specification, the term "aromatic ring" or "aryl" means containing at least one aromatic hydrocarbon group and the term "aromatic heterocycle" means containing at least one aromatic hydrocarbon group and at least one heteroatom , Wherein at least one carbon atom of the aromatic hydrocarbon group is substituted by a hetero atom. When the aromatic ring (aryl) or the aromatic heterocyclic ring contains plural rings, the aromatic ring or the aromatic heterocyclic ring may include one aromatic ring and include an aromatic ring or a non-aromatic ring as an additional ring have. The plurality of rings may include, but are not limited to, one in which at least one aromatic ring and an additional ring are bonded through one atom or a fused structure through two or more atoms.
For the purposes of the present specification, the term "hetero" means containing atoms other than carbon and hydrogen atoms. For example, the atoms other than the carbon and hydrogen atoms may be Si, Se, N, O, S, P, As , F, Cl, Br and I, but the present invention is not limited thereto.
Throughout this specification, the term "alkyl group" or "alkyl" typically includes 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 5 carbon atoms, Refers to a linear or branched alkyl group having one or more carbon atoms and includes, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, Pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosanyl, or all possible isomers thereof. When the alkyl group is substituted with an alkyl group, it is also used interchangeably as a "branched alkyl group ". Substituents which may be substituted on the alkyl group include halo (for example, F, Cl, Br, I), haloalkyl (for example, CC1 3 or CF 3 ), alkoxy, alkylthiol, -C (O) -OH), alkyloxycarbonyl (-C (O) -OR), alkylcarbonyloxy (-OC (O) -R), amino (-NH 2), carbamoyl (-NHC (O) OR- or -OC (O) NHR-), urea (-NH-C (O) -NHR-) and thiol (-SH). .
Throughout this specification, the term " halogen "or" halo " means that the halogen atom belonging to group 17 of the periodic table is included in the compound as a form of a functional group, and may be, for example, chlorine, bromine, fluorine or iodine , But may not be limited thereto.
Hereinafter, the present invention has been specifically described with reference to the accompanying drawings, but the present invention is not limited thereto.
The present invention provides a biomedical composition comprising a cyclometallated transition metal complex represented by the following
[Chemical Formula 1]
(2)
In the
M is iridium or rhodium,
R 1 to R 16 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxyl, thiol, alkylthiol, urea, cyano, alkyl, alkoxy, aryl, A sulfonyl group, a sulfonate group, a sulfonamide group, a sulfonyl group, a sulfonyl group, a sulfonyl group, a sulfonyl group, a sulfonyl group, a sulfonyl group, a sulfonyl group, , A phosphate group, a phosphonate group, and a phosphinate group,
Ring A and ring B are each independently a substituted or unsubstituted 5-membered aromatic ring, a substituted or unsubstituted 6-membered aromatic ring, a substituted or unsubstituted 5-membered aromatic heterocycle, and a substituted or unsubstituted 6-membered aromatic ring, Aromatic heterocyclic group.
The M is preferably iridium, but may not be limited thereto.
When R 1 to R 16 and ring A and ring B are substituted, the substituent described in the above definition is F, Cl, Br, I, a hydroxyl group, a thiol group, an alkylthiol group, a urea group, a cyano group, An aryl group, an aryl group, an aryl group, a vinyl group, an acyl group, an azido group, a nitro group, an amino group, an alkylamino group, an arylamino group, a hydroxyamino group, an alkylammonium, a carboxy group, a carbamoyl group, A sulfonate group, a sulfonamide group, a phosphate group, a phosphonate group, and a phosphinate group.
The bioimaging composition may target an endoplasmic reticulum, particularly an endoplasmic reticulum in cancer cells. In one embodiment of the present invention, the cancer cell to which the bioimaging composition is applied may be at least one selected from the group consisting of an ovarian cancer cell line, a breast cancer cell line, and a cancer cell line, but may not be limited thereto.
The cyclometallated transition metal complex which may be included in the bioimaging composition according to one embodiment of the present invention may be a complex having iridium as a central metal, for example, a compound of the following formulas (7) to (10) .
(7)
[Chemical Formula 8]
[Chemical Formula 9]
[Chemical formula 10]
The bioimaging composition according to an embodiment of the present invention may emit phosphorescence in response to light at room temperature, for example, emit phosphorescence within a wavelength range of about 480 to 750 nm, . For example, the bioimaging composition comprising the compound of Formula 7 may emit blue phosphorescence within a wavelength range of about 480 to 550 nm, and the bioimaging composition comprising the compound of Formula 8 may have a fluorescence spectrum of greater than about 500 nm to about 630 nm wavelength range, and the bioimaging composition comprising the compound of Formula 9 can emit orange phosphorescence within a wavelength range of about 550 nm to 650 nm, and the bioimaging composition containing the compound of
Here, the phosphorescent quantum efficiency of the bioimaging composition may be from about 0.01 to about 1, for example, from about 0.4 to about 0.99, or from about 0.5 to about 0.7, but is not limited thereto. The phosphorescent lifetime of the bioimaging composition may be greater than about 200 ns, for example, greater than about 400 ns, or from about 400 to about 1000 ns, but is not limited thereto.
The bioimaging composition according to one embodiment of the present invention has good phosphorescence quantum efficiency and good imaging efficiency. The fact that the phosphorescence quantum efficiency is good means that the efficiency of using light is good, and when the molecule absorbs light, the radiative decay becomes much larger than the non-radiative decay. It is. Such quantum efficiency has a great effect on the biomedical imaging, and the larger the quantum efficiency, the better the brightness and sharpness of the image.
The bioimaging composition may further comprise reactive oxygen species (ROS) such as superoxide anion radical (O 2 - ) and / or singlet oxygen ( 1 O 2 ) in response to light, Can be generated. The excess oxide anion radical can be produced through electron transfer from the cyclomethalized transition metal complex represented by formula (I) or (II) to oxygen as the
In one embodiment of the invention, the bioimaging composition may be prepared by forming a cyclometallated transition metal complex represented by formula (I) or (II) via two steps, as shown in
[Reaction Scheme 1]
[Reaction Scheme 2]
In the above equations,
M, R 1 to R 16 , ring A, and ring B are each as defined above.
Specifically,
[Chemical Formula 1]
(3)
[Chemical Formula 4]
In the above equations,
M, and R 9 to R 16 are each the same as defined above.
Scheme 2 also shows a process for preparing an intermediate complex represented by the following formula (6) by reacting IrCl 3 .nH 2 O with a starting material compound represented by the following formula (5), and reacting the intermediate material with 2,2'-bipyridine To form a cyclometallated transition metal complex represented by the following formula (2): < EMI ID =
(2)
[Chemical Formula 5]
[Chemical Formula 6]
In the above equations,
M, R 9 to R 12 , ring A, and ring B are each as defined above.
For example, the iridium complex, which is a compound of the above general formulas (7) to (10), can be prepared by the same method as in the above-mentioned
Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following Examples are given for the purpose of helping understanding of the present invention, but the present invention is not limited to the following Examples.
[Example]
Example: Synthesis of iridium-based cyclometallated transition metal complexes
The synthesis process of the iridium-based cyclometallated transition metal complex (hereinafter, an iridium complex or an Ir (III) complex) is as shown in the following schemes:
In the course of the synthesis, chloridized iridium dimers (intermediate complexes) were prepared using 2 equivalents of IrCl 3 .nH 2 O (Strem Chemicals, USA) and 4 equivalents of C ^ N ligand (Sigma Aldrich, USA) . 1 equivalent of the chlorine-linked iridium dimer prepared above was added to a mixed solvent (DCM: MeOH = 1: 1, volume ratio) of dichloromethane (DCM: Samcheon Chemical Co., '-Bipyridine (Sigma Aldrich, USA) was dissolved and then subjected to a reflux reaction in an inert gas atmosphere of N 2 for 12 hours. Then, precipitation was carried out using DCM and n-hexane (Samseong Chemical Co., Korea), and an additional washing process using hexane was conducted to obtain the compound represented by Chemical Formula 7 (abbreviated as ER-Ir-B) (Abbreviated as Ir-G), 9 (abbreviated as ER-Ir-O), and 10 (abbreviated as ER-Ir-R).
The 2,2'-pyridine ligand was used as an auxiliary ligand to make the cationic species. This leads to high solubility in water and good quantum efficiency.
Experimental Example 1: Cell Imaging
Cell culture, 1-photon / 2-photon imaging and fluorescence lifetime imaging microscopy (FLIM) after transfection,
HEK-293T or U2OS cells are the cell culture plate (cell culture plate) in 10% FBS, 50 units / mL penicillin and temperature 37 ℃ in MEM a buffer (Gibco) containing 50 mg / mL streptomycin, 5% CO 2 conditions For 16 hours. Particularly, for the bioimaging experiment, glass coated with fibronectin was used in the cell culturing process. Plasmids were then transfected into cells grown with Lipofectamine 2000 (Life Technologies). Transfected cells were treated with 30 μM each of ER-Ir-B, ER-Ir-G, ER-Ir-O and ER-Ir-R in 10 μM of each MEM in clean MEM buffer. After washing three times with DPBS buffer, cells were fixed with 4% formaldehyde solution for 15 min. And washed twice more with DPBS buffer. 1-photon imaging and 2-photon imaging were then performed using a confocal microscope (Carl Zeiss LSM780NLO), and fluorescence lifetime imaging microscopy was performed using a time-resolved fluorescence spectrometer in the Korea Basic Science Institute (KBSI) Using a confocal microscope (Pico Quant MicroTime 200). Each 1-photon image and 2-photon image was processed through the Carl Zeiss ZEN2012 software (UNIST Olympus Biomed Imaging Center, Ulsan, Republic of Korea).
Experimental Example 2: Cytotoxicity
For cytotoxicity analysis, human embryonic kidney (HEK-293) was used. All cells were 5% (v / v) FBS (Sigma Aldrich) and 1% (v / v) penicillin (penicillin: GIBCO) is added DMEM (Dulbecco Modified Eagle Medium: GIBCO ) in the culture medium 37 ℃ and 5% CO 2 It was raised in the environment. Cell viability of iridium complexes having PF 6 - anions instead of Cl - anions in the structures of the respective iridium complexes of formulas 7 to 10 and the complexes of these complexes were determined by MTT [3- (4,5-dimethylthiazol-2 -yl) -2,5-diphenyltetrazolium bromide] analysis.
Cells were plated on 96-well plates (150,000 cells in 100 mL per well) and then loaded with iridium complexes at each concentration (1, 5, 10 μM; final 1% v / v DMSO). After incubation at 37 ° C for 24 hours in the absence of light, 25 mL of MTT (BioWorld, Korea) [concentration of 5 mg / mL in PBS (phosphate buffered saline), pH 7.4; GIBCO] in each well. After treatment, the cells were incubated at 37 DEG C for 4 hours in a state where the light was blocked again. A formazan solution was prepared by adding a solution of a solubilization buffer containing DMF (N, N-dimethylformamide: 50% v / v aqueous solution, pH 4.5) and SDS (sodium dodecyl sulfate: 20% w / v) And dissolved by addition overnight. Absorbance of dissolved formazan was measured using a SpectraMax M5 microplate reader (Molecular Devices, Sunnyvale, Calif., USA). A small amount of light could be applied to the cells during the sampling for analysis, but care was taken to ensure that the cells were not exposed to light as much as possible. Cell viability was determined by placing cells with the same amount of DMSO (dimethylsulfoxide) in a comparative group. The error bars were calculated as the standard error from three independent experiments. The cell viability of HEK-293 treated with the compound of formula (9) (containing Cl - cation) and the iridium complex with PF 6 - anion coordination as shown in the following formula (11) :
(11)
<Results and Analysis>
Synthesis and Photochemical Analysis of Four ER Targeted Iridium (III) Complexes
The compounds of formulas (7) to (10), four cyclometallated Ir (III) complexes were prepared by way of example and were investigated in order to determine if these four Ir (III) complexes are suitable emitters with potential for target ER .
FIG. 1 shows the results of a photochemical analysis using a UV-vis fluorescent system and a cyclic voltammetry. The results are shown in Table 1. The UV-vis absorption / emission spectra of the four Ir (III) complexes were measured in H 2 O solution.
Referring to Figure 1 and Table 1, the four Ir (III) complexes showed strong peaks for spin-tolerant π-π ligands of the central transition metal at 350 nm or less. The weak absorption peaks between 350 and 450 nm correspond to mono and tri-metal-to-ligand charge transfer ( 1 MLCT and 3 MLCT): ER-Ir-B 354 nm, ER- Ir-G 374 nm, ER-Ir-O 432 nm, ER-Ir-R 437 nm. Emission peaks from radiative relaxation in the triplet state due to strong spin-orbital coupling were observed at 531 nm, 590 nm, 562 nm, and 592 nm. The Ir (III) complex was prevented from self extinguishing and showed a large Stokes shift exceeding 130 nm. In addition, the quantum efficiencies for phosphorescence were in the order of ER-Ir-O (0.58), ER-Ir-B (0.43), ER-Ir-R (0.097) and ER-Ir-G (0.011). Furthermore, the energy levels of HOMO and LUMO were analyzed by cyclic voltammetry using Bu 3 NPF 6 0.1 M MeCN solution as the supporting electrolyte. As a result, a color adjustment effect on major ligand exchange was confirmed.
ER imaging and fluorescence lifetime imaging microscopy (FLIM) analysis to determine the lifespan of U2OS cells
Figure 2 shows the 1-photon / 2-photon image of U2OS cells labeled with ER-Ir-O (10 [mu] M, 0.5 h) and the results of FLIM analysis on lifetime according to cell conditions: a, ER-Ir-O 1-photon excitation image (the iridium distribution in U2OS cells is labeled with red: RFP Channel (560 - 615 nm)); b, a two-photon excitation image of ER-Ir-O (the iridium distribution in U2OS cells is labeled in red: λ ex = 860 nm, RFP Channel); c, transfected KDEL-BFP image (DAPI Channel (distribution of BFP in U2OS cells blue labeled: 417-477 nm)); d, image overlap of 1-photon excitation image of ER-Ir-O and KDEL-BFP image (coexistence) (coexistence of iridium and BFP in the same position is labeled purple); Confocal laser scanning microscope (CLSM) images transfected with e, mCherry (nuclear) and subsequently treated with ER-Ir-O (ER); The fluorescence for mCherry is located in the nucleus and the phosphorescence for ER-Ir-O is located in the endoplasmic reticulum (FLIM) image combined with f, mCherry (fluorescence) and ER-Ir-O (phosphorescence).
The four cyclomated Ir (III) complexes were treated with U2OS cell lines and their cell images were collected using a 1-photon / 2-photon microscope (Fig. The targeting motions of the proposed Ir (III) complexes with different major ligands were coexisted in U2OS cells using a BFP coupled with a KDEL tetrapeptide sequence that positions the blue fluorescent protein (BFP) in the ER -localization. The results of the coexistence of Ir (III) complexes show the location of the dye. The targeted motions of the Ir (III) complexes in the coexistence results were the same in both 1-photon and 2-photon microscopes. After identifying the targeted motions of the four compounds for ER, a clear phosphorescent image was revealed through the distinction between phosphorescence and fluorescence. Nuclear-targeted H2B-mCherry fusion proteins and ER-Ir-O of ER were used for this explanation. H2B-mCherry and ER-Ir-O emit fluorescence and phosphorescence, respectively. In a simple cell image using H2B-mCherry and ER-Ir-O, a major problem is the difficulty of distinguishing between fluorescence and phosphorescence in the cellular environment due to color similarity (Fig. 2e). Therefore, fluorescence lifetime microscopy (FLIM) analysis was observed to be able to block ambient fluorescence interference by the long lifetime of phosphorescence. The visualization of lifetime through FLIM characterizes fluorescence (1.571 ns, blue region) and phosphorescence (498.575 ns, yellow region) in the cell image (Fig. 2F). This 498.575 ns lifetime exhibits an approximately four-fold increase in photochemical properties compared to the previously reported iridium-based lysosome tracker, which exhibits a lifetime of about 40-180 ns. In addition, such an increase will cause an improvement in light stability. As a result, a proven phosphorescent image was provided according to the corresponding lifetime.
Cytotoxicity
Referring to Figure 3, according to the type of the anion coordinated to the iridium complex to check that there is a difference in cytotoxicity, PF 6 - as the iridium complex according to the present embodiment compared to the compound which is the anion is coordinated to Cl - It can be seen that the cell survival rate is higher when the cation-coordinated compound is treated. Most of the cytotoxicity of the iridium complexes according to this example is due to the 2,2'-pyridine ligand.
In summary, the iridium complexes of the general formulas (7) to (10) according to this embodiment have a Cl - anion bonded to the central metal, minimizing cytotoxicity and enabling application in living cells. ROS generation, long lifetime and quantum efficiency Lt; RTI ID = 0.0 > ER < / RTI > probe as an iridium-based phosphorescent ER probe.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the present invention. You will understand. It is therefore to be understood that the embodiments described above are illustrative in all aspects and not restrictive. For example, each component described as a single entity may be distributed and implemented, and components described as being distributed may also be implemented in a combined form.
The scope of the present invention is defined by the appended claims rather than the detailed description and all changes or modifications derived from the meaning and scope of the claims and their equivalents are to be construed as being included within the scope of the present invention do.
Claims (5)
[Chemical Formula 1]
(2)
In the above Formulas 1 and 2,
M is iridium or rhodium,
R 1 to R 16 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxyl, thiol, alkylthiol, urea, cyano, alkyl, alkoxy, aryl, A sulfonyl group, a sulfonate group, a sulfonamide group, a sulfonyl group, a sulfonyl group, a sulfonyl group, a sulfonyl group, a sulfonyl group, a sulfonyl group, a sulfonyl group, , A phosphate group, a phosphonate group, and a phosphinate group,
Ring A and ring B are each independently a substituted or unsubstituted 5-membered aromatic ring, a substituted or unsubstituted 6-membered aromatic ring, a substituted or unsubstituted 5-membered aromatic heterocycle, and a substituted or unsubstituted 6-membered aromatic ring, Aromatic heterocyclic group.
Wherein M is iridium.
A biomedical composition targeted to an endoplasmic reticulum.
Wherein the composition emits phosphorescence in response to light.
Wherein the phosphorescence has a quantum efficiency of 0.01 to 0.9 and a lifetime of 400 ns or more.
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| CN109293705A (en) * | 2018-11-08 | 2019-02-01 | 云南大学 | A kind of preparation method of complex of iridium and the application in two-photon mitochondrial dye |
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| CN109293705B (en) * | 2018-11-08 | 2021-04-20 | 云南大学 | Preparation method of iridium complex and application of iridium complex in two-photon mitochondrial dye |
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