CN115650964A - Xanthene-heptamethine cyanine photosensitive dye and preparation method and application thereof - Google Patents
Xanthene-heptamethine cyanine photosensitive dye and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH, preparation method and application thereof, and photosensitive dye OxCy 7 the-COOH comprises two high-performance fluorophores of heptamethine cyanine and xanthene and a plurality of carboxyl groups, has dual-band fluorescence and subcellular organelle mitochondrion positioning characteristics, and is soluble in water. The photosensitizing dye OxCy 7 -COOH under near infrared laser irradiation of more than 700nm, oxCy 7 the-COOH can rapidly generate singlet oxygen through intersystem crossing and light-controlled energy transfer, induce tumor cell apoptosis, inhibit cancer cell migration, and realizePhotodynamic therapy of tumor cells. OxCy 7 the-COOH contains a plurality of mitochondrial subcellular organelle positioning groups, is soluble in water, has good biocompatibility, has near-infrared absorption and dual-band fluorescence emission, can be used as a near-infrared photosensitive dye with excellent performance, and has wide application in the aspects of dual-band fluorescence imaging, fluorescence labeling and near-infrared dynamic therapy.
Description
Technical Field
The invention belongs to the technical field of photosensitive dyes, and particularly relates to a xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH and a preparation method and application thereof.
Background
Under the excitation of light, the photosensitive dye sensitizes oxygen molecules to generate active oxygen through light-controlled energy transfer or electron transfer to induce the damage or apoptosis of tumor cells, thereby realizing the photodynamic therapy of the tumor cells. Mitochondria is an important organelle in cells, and the targeting property of the mitochondria can promote the photosensitizer to be enriched at a tumor part, thereby having remarkable advantages for the precise photodynamic therapy of tumor cells. However, most of the photosensitive dyes used for photodynamic therapy in the prior art are located in a visible light region, are insoluble in water, have poor biocompatibility, lack targeting groups, are difficult to meet the requirements of photodynamic therapy of a biological system, and greatly limit the application range of the dyes.
The near-infrared photosensitive dye can effectively reduce photodamage, has strong penetrating power in biological tissues, and is safe and reliable; the mitochondrion targeted photosensitizer can be enriched at tumor positions, improve the killing efficiency of cancer cells, reduce toxic and side effects and enhance the photodynamic therapy effect.
Therefore, designing and preparing a near-infrared photosensitive dye which has excellent performance, is soluble in water and has an organelle targeting group is a recent research hotspot.
Disclosure of Invention
The invention aims to: the invention aims to solve the technical problem of providing a near-infrared photosensitive dye xanthene-heptamethine cyanine OxCy which is soluble in water, contains a plurality of mitochondrion targets and has the characteristic of double-channel fluorescence imaging 7 -COOH。
The invention also aims to solve the technical problem of providing the xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH in the presence of a catalyst.
The invention also aims to solve the technical problem of providing the xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH for use as a photosensitizer for near infrared photodynamic therapy.
The invention also aims to solve the technical problem of providing the xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH for use in two-channel fluorescence imaging or fluorescence labeling.
The invention finally solves the technical problem of providing a photosensitizer for near infrared photodynamic therapy.
The technical scheme is as follows: in order to solve the technical problem, the invention provides a xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH, said xanthene-heptamethine cyanine dye OxCy 7 -COOH has the formula:
wherein the photosensitizing dye OxCy 7 -COOH by chloroheptamethine cyanine Cl-Cy 7 With piperazine-xanthene M 1 Prepared from the chloro heptamethine cyanine Cl-Cy 7 With piperazine-xanthene M 1 The structural formula is as follows:
the invention also comprises a xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH preparation process comprising the following steps: under the protection of inert gas and at the temperature of 80 ℃, taking triethylamine as a catalyst, and using chloroheptamethine cyanine Cl-Cy 7 With piperazine-xanthene M 1 And (3) reacting in anhydrous DMF for 6-8 h in a dark place, and purifying by column chromatography to obtain the near-infrared photosensitive dye.
The xanthene-heptamethine cyanine photosensitive dye OxCy prepared by the preparation method of the invention 7 The yield of-COOH is 21% -32%.
Wherein the chloro heptamethine cyanine Cl-Cy 7 The molar ratio of the piperazine to the xanthene is 1: 1-1: 1.5.
The invention also comprises a xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH for use as a photosensitizer for near infrared photodynamic therapy.
Wherein, the application is photodynamic therapy of tumor cells.
The invention also comprises the xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH for use in dual channel fluorescence imaging and fluorescence labeling.
The invention also comprises a near-infrared photodynamic therapy photosensitizer, and the near-infrared photodynamic therapy photosensitizer comprises the xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH。
Has the beneficial effects that: compared with the prior art, the invention has the following remarkable advantages: the xanthene-heptamethine cyanine OxCy 7 the-COOH is a high-performance near-infrared photosensitive dye, structurally comprises two high-performance fluorophores of heptamethine cyanine and xanthene and a plurality of carboxyl groups, has the characteristics of dual-band fluorescence imaging and organelle mitochondrion positioning, is soluble in water and has good biocompatibility. Under the irradiation of near infrared laser of 700-1400nm, xanthene-heptamethine cyanine photosensitive dye OXCy 7 the-COOH can rapidly generate singlet oxygen through intersystem crossing and light-controlled energy transfer, induce tumor cell apoptosis, inhibit cancer cell migration and realize photodynamic therapy on the tumor cells. Photosensitizing dye OxCy 7 the-COOH has near infrared absorption and dual-band fluorescence emission, is soluble in water, has good biocompatibility, can be used as a near infrared photosensitive dye with excellent performance, and has wide application in the aspects of dual-band fluorescence imaging, fluorescence labeling and near infrared light dynamic treatment.
Drawings
FIG. 1 shows xanthene-heptamethine cyanine dye OxCy 7 Two-channel fluorescence imaging of COOH co-incubation with a549 cells. Wherein OxCy 7 The concentration of-COOH was 2 μ M, and the scale bar was 50 μ M.
FIG. 2 shows a photosensitive dye OxCy containing xanthene-heptamethine cyanine 7 Co-localization fluorescence imaging of-COOH a549 cells in orange/red light dual channel mitochondria. Wherein the concentration of OxCy7-COOH is 2 μ M and the scale bar is 50 μ M.
Detailed Description
Example 1
(1) Xanthene-heptamethine cyanine photosensitive dye OxCy 7 Preparation of-COOH:
to which 0.21g of piperazine-xanthene M was dissolved at room temperature 1 0.29g of chloroheptamethine cyanine Cl-Cy is slowly added dropwise to 5mL of the dry DMF solution 7 0.09g of triethylamine catalyst is added, and the mixture is reacted for 8 hours under the protection of nitrogen and at 80 ℃ in the dark. After the reaction is finished, the reaction is carried outReduced pressure distillation and column chromatography purification to obtain the photosensitive dye OxCy 7 -COOH, yield 32%.
Xanthene-heptamethine cyanine photosensitive dye OxCy 7 The synthetic route for-COOH is as follows:
chloro heptamethine cyanine Cl-Cy 7 Prepared according to literature methods (Syed Muhammad Usmaa, sopida Thavornplate, and Kevin Burgess, optimized Heaptametine Cyanines for Photodynamic Therapy, ACS Applied Biomaterials 2018,1 (4): 1195-1205).
Piperazine-xanthene M 1 Prepared according to literature methods (hanging Liu, lingfeng Wang, ronghua Shen, jie Zhao, ying Qian. A novel peptide cysteine cyanine photosensizer for FRET-amplified photosensibility therapy and two-photosensing in A-549 cells. Spectrochima Acta Part A
(2) Xanthene-heptamethine cyanine photosensitive dye OxCy 7 Structural characterization of-COOH:
hydrogen spectrum of nuclear magnetic resonance 1 H NMR(600MHz，CDCl 3 )：δ8.52(d，J＝16.3Hz，1H)，8.30(d，J＝7.4Hz，1H)，8.09(s，1H)，7.84(s，1H)，7.71-7.69(m，1H)，7.62(s，1H)，7.54-7.52(m，1H)，7.50-7.48(m，2H)，7.44-7.40(m，2H)，7.39(s，2H)，7.36-7.34(m，2H)，7.33-7.30(m，2H)，7.22-7.19(m，2H)，7.04(t，J＝7.5Hz，2H)，6.85(d，J＝7.8Hz，1H)，4.69(s，2H)，4.59(s，2H)，4.31(t，J＝6.6，2H)，4.22-4.18(m，2H)，3.78(s，4H)，2.86-2.82(m，4H)，2.60-2.58(m，2H)，2.53(s，4H)，2.38(t，J＝7.1Hz，4H)，2.00-1.94(m，4H)，1.83(s，6H)，1.75-1.71(m，4H)，1.35(s，12H)。
High resolution mass spectrometry HRMS: m/z calcd for C 68 H 76 N 5 O 7 - [M-H] - ：1074.5750，found：1074.5795。
Thereby confirming that obtainedXanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH has the formula:
example 2
Xanthene-heptamethine cyanine photosensitive dye OxCy 7 Preparation of-COOH As in example 1, 0.25g of piperazine-xanthene M was dissolved in water at room temperature 1 0.29g of chloroheptamethine cyanine Cl-Cy is slowly added dropwise to 5mL of the dry DMF solution 7 0.09g of triethylamine catalyst is added, and the mixture is reacted for 6 hours under the protection of nitrogen and at 80 ℃ in a dark place. After the reaction is finished, carrying out reduced pressure distillation and column chromatography purification to obtain the photosensitive dye OxCy 7 COOH, yield 21%.
Example 3 xanthene-heptamethine cyanine photosensitive dye OxCy 7 Application of-COOH in high-resolution dual-channel fluorescence imaging
The xanthene-heptamethine cyanine photosensitive dye OxCy prepared in example 1 was used 7 -COOH (added at a concentration of 2. Mu. Mol.L) -1 ) The cells were incubated with A549 cells (commercially available) for 2 hours for confocal laser fluorescence imaging. FIG. 1 shows a xanthene-heptamethine cyanine dye OxCy 7 Graph of fluorescence images of-COOH incubated with a549 cells. Xanthene-heptamethine cyanine photosensitive dye OxCy 7 the-COOH can rapidly enter the A549 cells, and bright orange and red fluorescence is presented for high-resolution two-channel fluorescence imaging.
Xanthene-heptamethine cyanine photosensitive dye OxCy prepared in example 1 7 -COOH (concentration 2. Mu.M) was added to a confocal dish containing zebrafish for staining for 1 hour, and then subjected to laser confocal fluorescence imaging experiments. Xanthene-heptamethine cyanine photosensitive dye OxCy 7 the-COOH quickly enters the zebra fish body, and the orange light/red light double-channel fluorescence imaging in the zebra fish body is realized.
Xanthene-heptamethine cyanine photosensitive dye OxCy 7 the-COOH can realize high-resolution double-channel fluorescence imaging and can be used for photodynamic therapy guided by the high-resolution fluorescence imaging.
Example 4 xanthene-heptamethine cyanine photosensitive dye OxCy 7 Application of-COOH as near infrared photodynamic therapy photosensitizer
Xanthene-heptamethine cyanine photosensitive dye OxCy prepared in examples 1 to 3 7 The UV-visible maximum absorption of-COOH was at 769nm, the maximum emission was at 796nm, both absorption and emission were above 700nm. Under the excitation of 730nm laser, taking indocyanine green as a reference, 1,3-diphenyl isobenzofuran (DPBF) as a singlet oxygen capture agent, and determining xanthene-heptamethine cyanine photosensitive dye OxCy through experiments 7 The singlet oxygen quantum yield of-COOH was 31%.
Measurement of xanthene-heptamethine cyanine photosensitive dye OxCy prepared in examples 1 to 3 by MTT method 7 -toxicity of COOH to a549 cells. In dark environment, tumor cells A549 and xanthene-heptamethine cyanine photosensitive dye OxCy 7 Cell viability of over 85% after 24h incubation with-COOH (1. Mu.M), indicating that the photosensitizer OxCy 7 -COOH has lower dark toxicity. Under the laser irradiation of 730-1400nm, the cell survival rate is remarkably reduced, and along with the OXCy 7 The cell viability decreased with increasing-COOH concentration and light exposure time. Maximum half maximal Inhibitory Concentration (IC) of A549 cells after 20min of 730nm near-infrared laser irradiation 50 ) The values were 4.73. Mu.M, respectively.
FIG. 2 shows a photosensitive dye OxCy containing xanthene-heptamethine cyanine 7 Co-localization fluorescence imaging of a-COOH a-549 cells in orange/red light dual channel mitochondria. Wherein the concentration of OxCy7-COOH is 2 μ M and the scale bar is 50 μ M. OxCy 7 -COOH has multiple mitochondrial targeting groups with a mitochondrial co-localization coefficient of up to 0.94.
Xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH had low dark toxicity and high phototoxicity, and the xanthene-heptamethine cyanine photosensitive dyes OxCy prepared in examples 1 to 3 were irradiated with near-infrared laser light of 730 to 1400nm 7 the-COOH can rapidly generate singlet oxygen in A-549 cells and zebra fish bodies, can effectively kill tumor cells, inhibits the migration of the tumor cells, promotes the apoptosis of the tumor cells, and realizes near infrared light dynamic treatment on the tumor cells.
In conclusion, the xanthene-heptamethine cyanine photosensitive dye OxCy prepared by the invention 7 -COOHComprises a xanthene and heptamethine cyanine double-fluorophore structure and a plurality of mitochondrion targeting groups. Under the irradiation of near-infrared laser, the near-infrared photosensitive dye OxCy 7 the-COOH can efficiently release singlet oxygen, inhibit cancer cell migration and promote tumor cell apoptosis, thereby realizing photodynamic therapy on the tumor cells. Xanthene-heptamethine cyanine photosensitive dye OxCy 7 the-COOH is soluble in water, contains a plurality of mitochondrial subcellular organelle positioning groups, has good biocompatibility, can be used as a near infrared waveband photosensitizer and a fluorescent dye with excellent performance, and has wide application in the aspects of double-channel fluorescence imaging, fluorescence labeling and near infrared light dynamic treatment.
Claims (8)
1. Xanthene-heptamethine cyanine photosensitive dye OxCy 7 -COOH, characterized in that said xanthene-heptamethine cyanine dye OxCy 7 The structural formula of-COOH is as follows:
2. the xanthene-heptamethine cyanine photosensitive dye OxCy of claim 1 7 -COOH, characterized in that said photosensitizing dye OxCy 7 -COOH by chloroheptamethine cyanine Cl-Cy 7 With piperazine-xanthene M 1 Prepared from the chloro heptamethine cyanine Cl-Cy 7 With piperazine-xanthene M 1 The structural formula is as follows:
3. the xanthene-heptamethine cyanine photosensitive dye OxCy of claim 1 or 2 7 -COOH, characterized in that it comprises the following steps: under the protection of inert gas and at the temperature of 80 ℃, taking triethylamine as a catalyst, and using chloroheptamethine cyanine Cl-Cy 7 With piperazine-xanthene M 1 Reacting in DMF for 6-8 h in dark, and performing column chromatographyPurifying to obtain the photosensitive dye.
4. The xanthene-heptamethine cyanine photosensitive dye OxCy as claimed in claim 3 7 -COOH, characterized in that it is a chloroheptamethine cyanine Cl-Cy 7 Piperazine-xanthene M 1 The molar ratio of (A) to (B) is 1: 1-1: 1.5.
5. The xanthene-heptamethine cyanine photosensitive dye OxCy of claim 1 or 2 7 -COOH for use as a photosensitizer for near infrared photodynamic therapy.
6. Use according to claim 5, wherein the use is photodynamic therapy of tumour cells, and the use does not relate to methods of diagnosis and treatment of disease.
7. Use of the xanthene-heptamethine cyanine dye OxCy7-COOH as claimed in claim 1 or 2 in dual-channel fluorescence imaging or fluorescence labeling, which does not relate to methods of diagnosis and treatment of diseases.
8. A near-infrared photodynamic therapy photosensitizer, characterized in that the photosensitizer comprises the xanthene-heptamethine cyanine photosensitizing dye OxCy of claim 1 or 2 7 -COOH。
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| CN117169182B (en) * | 2023-08-30 | 2024-03-15 | 广州沙艾生物科技有限公司 | In-vitro efficacy detection method for stem cell therapeutic preparation and application thereof |
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