CN114045045B - Single-photon up-conversion pentamethine cyanine photosensitive dye, and preparation method and application thereof - Google Patents
Single-photon up-conversion pentamethine cyanine photosensitive dye, and preparation method and application thereof Download PDFInfo
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- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 title claims abstract description 24
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/083—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines five >CH- groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
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Abstract
The invention provides a single-photon up-conversion pentamethine cyanine photosensitive dye, a preparation method and application thereof, wherein the photosensitive dye has a structure shown in a general formula I. The pentamethine cyanine photosensitive dye without heavy atom modification and with single photon up-conversion property has high singlet oxygen generation capability under the excitation of light at the wavelength longer than the maximum absorption wavelength of the dye. Can effectively carry out photodynamic killing on cancer cells under deep tissues under the excitation of the up-conversion light, can be used for photodynamic therapy of solid tumors in vivo, and has good application prospect for inhibiting the growth of deep tumors.
Description
Technical Field
The invention relates to the technical field of fine chemical engineering, in particular to a single-photon upconversion pentamethine cyanine photosensitive dye, and a preparation method and application thereof.
Background
Photodynamic Therapy (PDT) is a method of applying principles of photochemistry, photophysics and photobiology to diagnosis and treatment of diseases, is a fourth Therapy following surgery, chemotherapy and radiotherapy, and has great application potential in treating malignant diseases such as cancer and various benign diseases.
The three elements of photodynamic therapy are: a light source, a photosensitizer, and oxygen. Wherein the wavelength of the light emitted by the light source largely determines the treatment depth of the solid tumor through photodynamic therapy. Therefore, the development of photosensitizing dyes that can be excited by long wavelength light has been a focus of research. Although increasing the conjugation degree of organic molecules by chemical modification to extend the excitation wavelength of photosensitive molecules is the most direct and effective method, the design and development of near-infrared photosensitizers by researchers are always plagued by complex, cumbersome synthetic means, reduced chemical and photostability, and reduced solubility and biosafety.
Photon up-conversion mediated photosensitizer activation is a type of technological approach that does not sacrifice the photophysical, chemical properties, solubility and biocompatibility of the target photosensitizer. The low-energy long-wavelength exciting light is used for exciting the photosensitizer through intermolecular and intramolecular energy conversion, and the photosensitizer emits high-energy short-wavelength fluorescence and generates active oxygen to destroy cancer cells. The current technology for realizing photon up-conversion activation photosensitizer mainly relies on rare earth up-conversion nano particles and two-photon excitation materials. However, the activation process by multi-photon excitation is limited, the activation of the photosensitizer by the above two means requires the use of a high-power laser, especially a two-photon excitation material, and the laser used is a high-energy femtosecond laser, which is not favorable for clinical application. The phenomenon of up-conversion of the absorption frequency of the tropical zone is present in organic fluorophore molecules, which are generally characterized by a large molar extinction coefficient, a bright fluorescence emission and a small stokes shift. Electrons in the fluorophores are distributed at a ground state high vibration energy level and a rotation energy level, and the electrons at the high vibration energy level are excited by selecting light with a specific long wavelength, so that a large anti-Stokes displacement is formed, and the interference of the excitation light on fluorescence emission capture in conventional fluorescence imaging is favorably reduced. More importantly, the process of inducing such up-conversion to occur is a single photon excitation process. This greatly reduces the light dose of the excitation light, reducing the damage of the excitation light itself to the tissue and cells.
The currently reported fluorescent indicators with single-photon up-conversion properties include hemicyanine dyes, BODIPY dyes, heptamethine cyanine dyes, rhodamine dyes and phenoxazine dyes. To enhance its photosensitizing active oxygen generating capacity, the current mainstream strategy is to utilize the heavy atom effect. However, heavy atom modifications induce enhanced dark toxicity, reduced light and chemical stability, poor solubility and low economy are detrimental to its transformation to the clinic.
Unlike the typical photosensitizer parent structure, cyanine dyes, which naturally have a cationic structure, are a class of chemical sensors widely used in the biological field, and can simultaneously satisfy challenging requirements, including: 1. the extinction coefficient in the near infrared region is large to ensure the excitation wavelength of further up-conversion; 2. a clear subcellular localization, the photosensitizer targeting important organelles (e.g., mitochondria or endoplasmic reticulum), effective in enhancing therapeutic efficacy; 3. the cation flexible structure has good solubility and biocompatibility and can be effectively enriched in a tumor area. However, the existing PDT photosensitizer has the defect of limited yield of active oxygen molecules generated by depending on heavy atoms and upconversion excitation. Therefore, the development of heavy atom-free single photon up-conversion photosensitizers based on cyanine dyes is of great interest and challenging.
Disclosure of Invention
The invention aims to provide a novel PDT photosensitizer which has single-photon up-conversion property and is positioned in mitochondria without depending on heavy atoms.
The invention firstly provides a single-photon upconversion pentamethyl cyanine photosensitive dye which has the following structural general formula I:
in formula I:
R 1 and R 2 Each independently selected from one of H, cl, F, carboxyl, sulfonic group, etc.;
R 3 and R 4 Each independently selected from one of methyl, ethyl, propyl, long alkyl chain, benzyl and the like;
Ar 1 one selected from the group consisting of those described by formulas i to iv:
x is selected from one of iodine, chlorine or bromine.
In another aspect, the invention provides a preparation method of the pentamethylcyanine photosensitive dye with single-photon up-conversion property, which comprises the step of reacting the compound of formula II with the compound of formula III in the presence of zero-valent palladium,
the pentamethine cyanine photosensitive material with single-photon up-conversion property prepared by the synthesis method has the following remarkable characteristics: 1. large molar extinction coefficient (>200000M -1 cm -1 ) The maximum absorption wavelength is in the near infrared region (>650 nm), capable of being excited by near infrared light; 2. the cation structure can be localized to mitochondria; 3. can be excited by near infrared up-conversion light (760 nm, the maximum fluorescence emission wavelength is 670 nm) to generate singlet oxygen and destroy cancer cells; 4. the biocompatibility is good, and the tumor can be rapidly enriched and metabolized; 5. can inhibit solid tumor in deep tissue.
Based on the above, the invention further provides application of the single-photon up-conversion pentamethine cyanine photosensitizing dye in preparation of PDT photosensitizers, preparation of photodynamic therapy medicines and preparation of medicines for inhibiting growth of cancer cells and tumors under deep tissues. The prepared PDT photosensitizer can be used for photodynamic therapy, is excited by converting light on near infrared, and obviously has stronger photodynamic therapy effect on tumor cells under deep tissues compared with the common photosensitizer.
More specific discussion of PDT photosensitizers is related to the enhanced photophysical properties of the compounds of the present invention relative to unmodified pentamethine cyanine dyes. For the reported cyanine photosensitizer, the single-photon up-conversion pentamethyl cyanine photosensitive dye can improve the singlet oxygen generation capability of the dye under the excitation of up-conversion light without losing excellent photo-physical properties. The photosensitizer provided by the invention has specific subcellular organelle localization and stronger treatment effect, and can be excited by near infrared light (760 nm) with the maximum absorption wavelength being more than 100nm, so that the treatment depth is increased to a certain extent. Based on this, the PDT photosensitizer in the above application is preferably used for fluorescence imaging of cancer cells, solid tumors, and inducing death of cancer cells, tumors under deep tissues in the presence of the upconversion photoluminescence light.
Drawings
The invention is shown in the following drawings:
FIG. 1 is a graph showing a singlet oxygen generating ability test of the photosensitizer XAN-Cy5 of the present invention. In FIG. 1: the dye is a normalized quantitative curve of the absorption attenuation of DPBF at 415nm under 760nm light irradiation by respectively unmodified pentamethine cyanine dye Cy5, and mixed solution of benzene ring modified pentamethine cyanine dyes Ph-Cy5, XAN-Cy5 and DPBF (3-diphenyl isobenzofuran).
FIG. 2 is a graph showing up-conversion fluorescence excitation of the photosensitive molecule XAN-Cy 5.
Fig. 3 is a graph of confocal imaging cellular uptake of photosensitive molecules XAN-Cy5 of the invention into 4T1 cells. In fig. 3: the A diagram is a confocal imaging diagram of XAN-Cy5, and the B diagram is a data quantification diagram of fluorescence imaging.
FIG. 4 is a graph of the subcellular organelle localization of the photosensitive molecule XAN-Cy5 of the invention in 4T1 cells. In fig. 4: a, B, C and D are respectively shown in a commercial cell nucleus dye staining, XAN-Cy5 staining, staining superposition and superposed positioning coefficient map; e, F, G and H are respectively a commercial lysosomal dye staining, XAN-Cy5 staining, staining superposition and a mapping coefficient map; panels I, J, K and L represent commercial mitochondrial dye staining, XAN-Cy5 staining, overlay of localization coefficients, respectively.
FIG. 5 is a test of the photo-dark toxicity of the photosensitive molecule XAN-Cy5 of the invention on 4T1 cells in normal and deep tissues (5 mm). In fig. 5: the exciting light is 760nm near infrared light source, and the light dose is 500mW cm -2 ,15min。
FIG. 6 shows fluorescence imaging experiments of the photosensitive molecule XAN-Cy5 of the invention in a living subcutaneous tumor model. In fig. 6: a is a fluorescence imaging diagram of XAN-Cy5 in a living subcutaneous tumor model; the B diagram is the data quantization diagram of the A diagram.
FIG. 7 shows photodynamic tumor inhibition experiments of photosensitive molecule XAN-Cy5 in a deep in vivo antitumor model. In FIG. 7: panel A shows dissected tumors after 14 days of XAN-Cy5 photodynamic therapy; panel B is the change in tumor volume in vivo following XAN-Cy5 photodynamic therapy; panel C is the change in body weight in vivo following XAN-Cy5 photodynamic treatment.
Detailed Description
The pentamethyl cyanine photosensitive dye with the single-photon up-conversion property has the following structural general formula I:
R 1 and R 2 Each independently selected from one of H, cl, F, carboxyl, sulfonic group, etc.;
R 3 and R 4 Each independently selected from one of methyl, ethyl, propyl, long alkyl chain, benzyl and the like;
Ar 1 one selected from the group consisting of those described by formulas i to iv:
x is selected from one of iodine, chlorine or bromine.
Preferably, R is 1 、R 2 Are each hydrogen.
Preferably, said R is 3 And R 4 Are each an ethyl group.
Preferably, X is iodine.
Preferably, ar is 1 One selected from the group consisting of those described by formulas i, ii, iii, iv.
The combination of the above preferred features results in preferred compounds of the invention, with a representative most preferred compound being XAN-Cy5:
on the other hand, the invention provides a preparation method of the single-photon upconversion pentamethyl cyanine photosensitive dye, which comprises the step of reacting the compound of the formula II with the compound of the formula III in the presence of zero-valent palladium,
wherein, the molar ratio of the compound of formula II to the compound of formula III may be 1 to 10, preferably 1 to 4, more preferably 1 to 2 to 3, and most preferably 1.
Preferably, the zero-valent palladium is one selected from palladium tetratriphenylphosphine, palladium tris dibenzylideneacetone and palladium acetate matched phosphorus ligand;
preferably, the molar ratio of the zero-valent palladium to the compound of formula II is 1.
Preferably, the solvent for the reaction is selected from 1, 4-dioxane or dimethyl sulfoxide to facilitate the dissolution of the reactants.
In actual production operations, it is preferred to add the compound of formula III in a slight excess over intermediate II to facilitate the completion of the reaction of intermediate II.
On the other hand, this step is preferably carried out under an inert gas atmosphere, which results in a higher yield.
Whether the reaction has reached the end point is judged by Thin Layer Chromatography (TLC), and the usual reaction time is preferably 4 to 12 hours.
After the reaction, the solvent was distilled off. The product is preferably purified by column chromatography using dichloromethane/methanol as eluent. The product was characterized by nuclear magnetic and high resolution mass spectrometry.
The resulting photosensitizer can be recovered by separation and purification techniques well known in the art to achieve the desired purity.
On the other hand, the invention provides the application of the single-photon upconversion pentamethine cyanine photosensitizing dye in preparing PDT photosensitizers, preparing photodynamic therapy medicines and preparing medicines for inhibiting the growth of cancer cells and tumors under deep tissues.
Preferably, the PDT photosensitizer has subcellular organelle (mitochondrion) localization characteristics, and/or has the characteristics of large molar extinction coefficient in a near infrared region, and/or has single-photon up-conversion luminescence performance, and/or has the generation capacity of converting light to excite singlet oxygen in a near infrared region longer than autofluorescence emission.
The single-photon up-conversion pentamethine cyanine photosensitive dye prepared by the synthesis method has the following remarkable characteristics: 1. large molar extinction coefficient (>200000M -1 cm -1 ) The maximum absorption wavelength is in the near infrared region (>650 nm); 2. the cationic structure can be localized to mitochondria; 3. can be excited by near infrared light (760 nm) longer than the maximum absorption wavelength of the near infrared light (100 nm) and generate singlet oxygen and destroy cancer cells; 4. the biocompatibility is good, and the tumor can be rapidly enriched and metabolized; 5. can inhibit deep solid tumor in vivo.
The various starting materials used in the present invention are commercially available or can be simply prepared from starting materials known in the art by methods known to those skilled in the art or disclosed in the prior art.
The following non-limiting examples are presented to enable those of ordinary skill in the art to more fully understand the present invention and its advantages, but are not intended to limit the invention in any way.
Example 1 synthesis of photoactive molecule XAN-Cy5:
(1) Synthesis of intermediate compound 3:
a solution of compound 2 (0.34g, 1mmol), quaternary ammonium salt 1 (0.63g, 2mmol) and anhydrous sodium acetate (0.2 g, 2.5 mmol) in anhydrous ethanol was stirred under reflux for 2h. After cooling, ethanol was spin-dried by a rotary evaporator, and then the crude product was purified by silica gel column chromatography (dichloromethane/methanol =10, 1,v/v) to give compound 3 as a blue powder (0.53g, 71.8%). 1 H NMR(400MHz,MeOD):8.41(d,J＝13.3Hz,2H,CH),7.56 (d,J＝7.4Hz,2H,ArH),7.46(t,J＝7.6Hz,2H,ArH),7.40(d,J＝7.8Hz,2H,ArH),7.33(t,J＝ 7.4Hz,2H,ArH),6.49(d,J＝13.3Hz,2H,CH),4.24(q,J＝7.2Hz,4H,CH 2 ),1.76(s,12H,CH 3 ), 1.45(t,J＝7.2Hz,6H,CH 3 ).ESI-MS(C 29 H 34 BrN 2 I)m/z:[M–I] - calcd.489.19；found,489.28.
(2) Synthesis of photosensitive molecule XAN-Cy5:
3 (0.1g, 0.16mmol), 4 (0.084g, 0.25mmol) and tetratriphenylphosphine palladium (0.0092g, 0.008mmol), potassium carbonate (0.066 g, 0.48mmol) were dissolved in 10mL of 1, 4-dioxane and stirred at 90 ℃ for 8 hours. Finally the solvent was evaporated and the mixture was purified by silica gel column chromatography (dichloromethane/methanol =100, 0.8, v/v) to give XAN-Cy5 as a blue black solid powder (17%). 1 H NMR(400MHz,MeOD)δ(ppm):8.61(d,J＝14.1Hz,2H), 8.49(d,J＝14.1Hz,2H),8.30(d,J＝8.7Hz,1H),8.10–8.04(m,2H),7.57–7.53(m,4H),7.43 (ddd,J＝21.6,11.6,4.1Hz,4H),7.29(t,J＝7.3Hz,2H),7.23(d,J＝7.9Hz,2H),5.94(d,J＝14.1 Hz,2H),3.76(q,J＝7.1Hz,4H),1.84(s,12H),1.11(t,J＝7.2Hz,6H). 13 C NMR(126MHz, MeOD)δ(ppm):174.51,154.57,142.91,133.73,133.11,132.38,130.83,130.46,129.80,129.29, 128.84,127.46,127.00,126.53,123.53,111.85,102.29,50.71,39.94,27.81,12.13.ESI-MS (C 43 H 43 IN 2 )m/z:[M–I] - calcd 587.34,found 587.47.
Example 2 singlet oxygen Performance test of photosensitive molecule XAN-Cy5
Adding 2 μ M photosensitive molecule XAN-Cy5 into test quartz dish containing 3mL dichloromethane solution, adjusting absorbance at 415nm to about 1 by DPBF solution, placing dish at 760nm,500mW/cm 2 Was irradiated under a light source, and the absorption spectrum of the solution was recorded every 120 seconds. The results of the tests are collated in FIG. 1, and the absorption of the solution decays equally with increasing exposure time at a certain value, indicating that the solution produces singlet oxygen under exposure to light of this wavelength.
Example 3 upconversion excitation fluorescence assay of XAN-Cy5
mu.M of compound XAN-Cy5 was placed in 3mL of dichloromethane solution. Fluorescence emission at 630-700nm was captured using 760nm excitation. FIG. 2 is a graph showing up-conversion fluorescence excitation of photosensitive molecule XAN-Cy5
Example 4 cellular uptake assay for photosensitive molecule XAN-Cy5
4T1 cells were cultured in DMEM (invitrogen) with 10% FCS (invitrogen). mu.M of the compound XAN-Cy5 was added to a culture solution containing 4T1 cells, incubated at 37 ℃ and then the amount of uptake was determined by confocal imaging. The excitation wavelength of the photosensitive molecules was 640nm and the emission wavelength of the probes was 675nm, and the results of the tests are shown in the graphs A and B of FIG. 3. As can be seen from the figure, the uptake of the photosensitive compound XAN-Cy5 in 4T1 cells reached saturation after 60min of incubation. Indicating that the photosensitive compound XAN-Cy5 is easily taken up by cells.
Example 5 subcellular organelle localization experiments for photosensitive molecule XAN-Cy5
4T1 cells were cultured in DMEM (invitrogen) with 10% FCS (invitrogen). One day prior to confocal fluorescence imaging experiments, cells were seeded in a cell confocal culture dish. FIG. 5 is a commercial dye counterstain experiment of the localization of photosensitive molecules to different subcellular organelles. The concentration of the photosensitive molecule XAN-Cy5 was 1. Mu.M, and the concentrations of the commercial dyes Hochest 33342 (nucleus), MTG (mitochondria), LTG (lysosome) were 100nM, respectively. mu.M of the photosensitive molecule XAN-Cy5 was added to 3 dishes containing 4T1 cells and incubated for 2 hours, followed by 100nM of 3 commercial dyes added to the dishes and incubated for 5min, 30min and 20min, respectively, followed by confocal laser imaging. The excitation wavelength of the photosensitive molecule XAN-Cy5 is 640nm and the emission is 670-710nm. The excitation wavelength of Hochest 33342 is 405nm, and the acceptance band is 460-490 nm. The excitation wavelength of MTG and LTG is 488nm, and the receiving band is 515-545nm. It can be seen from FIG. 4 that XAN-Cy5 is well localized in the mitochondria of 4T1 cells.
Example 6 cellular light dark toxicity test of photosensitive molecule XAN-Cy5 on 4T1 cells
4T1 cells to be detected were digested with 0.25% trypsin, and a single cell suspension was prepared using DMEM medium containing 10% fetal bovine serum at 10 wells 3 ～10 4 Inoculating each cell in 96-hole culture plate with volume of 100 μ L; transferring the plates into an incubator at 37 ℃ and 5% CO 2 And after culturing for 24 hours under saturated humidity, adding photosensitive molecules with different concentrations respectively, and continuously culturing for 2 hours; then, 760nm,500mW/cm are adopted 2 Irradiating each hole by using the near-infrared light source, and continuously placing the 96-hole plate in an incubator for 24 hours after the irradiation is finished. mu.L of MTT solution (5 mg/mL) was added to each well, incubated for 4 hours, the culture was terminated, and the culture supernatant in the well was carefully aspirated. Then, 100 μ L of DMSO was added to each well, and shaken for 10 minutes to sufficiently dissolve the crystals; the absorbance at 490nm of each well was measured on a microplate reader and the cell viability was calculated: test group absorbance/control group absorbance value x 100%.
As can be seen from fig. 5, the photosensitive molecule XAN-Cy5 possesses significant light-induced killing toxicity to 4T1 cells, whether or not under deep tissues.
Example 7: fluorescence imaging of photosensitive molecule XAN-Cy5 under living subcutaneous tumor model
Will be 1 × 10 6 The 4T1 cells were injected subcutaneously into the axilla of BALB/c female mice and examined once every other day. The tumor volume is up to 150mm 3 Then, 100 μ M of photosensitive molecule XAN-Cy5 was injected into mice by intravenous injection, and fluorescence in vivo was detected in real time by a small animal fluorescence imager. The dye XAN-Cy5 was excited at 650nm and the 670-700nm band was collected.
As can be seen in fig. 6, the photosensitive molecule XAN-Cy5 can be rapidly enriched at the tumor site and rapidly metabolize from the body, and has good biocompatibility.
Example 8: tumor inhibition experiment of photosensitive molecule XAN-Cy5 under living body metastatic tumor model
The photosensitive molecule XAN-Cy5 was injected into mice at 100. Mu.M by intravenous injection, and after 10min of injection, 760nm light (500 mW/cm) was applied to the tumor site 2 ) Irradiating for 15min. The same experiment was performed again 3 days after the first treatment. Starting on the first day of treatment, the body weight and tumor volume of the mice were recorded every other day. The mice were dissected to remove tumor and lung tissue 14 days after the first treatment and the analysis experiment was performed.
As can be seen from fig. 7 (a represents tumor tissue dissected from a mouse treated with the photosensitizer molecule XAN-Cy5 for 14 days; B represents change in volume of a living tumor after XAN-Cy5 photodynamic treatment; and C represents change in body weight after XAN-Cy5 photodynamic treatment), the photodynamic treatment effect of the photosensitizer XAN-Cy5 significantly inhibited tumor growth. In the whole treatment process, the body weight of each group of mice is not changed, which shows that XAN-Cy5 has high-efficiency tumor treatment effect, no toxic or side effect and good biocompatibility.
Comparative example 1 singlet oxygen Performance testing of unmodified pentamethylcyanine dye molecules
Adding 2 μ M of reference unmodified pentamethine cyanine dye Cy5 into a test quartz dish containing 3mL of dichloromethane solution, adjusting the absorbance at 415nm to about 1 by using DPBF solution, placing the quartz dish at 760nm and 500mW/cm 2 Was irradiated under a xenon lamp light source, and the absorption spectrum of the solution was recorded every 120 seconds. The test results are shown in fig. 1. By analyzing the figure 1, the target compound XAN-Cy5 can be shown to improve the singlet oxygen generation performance of the conventional pentamethyl cyanine dye molecule under the excitation of upconversion light.
Comparative example 2 singlet oxygen Performance testing of phenyl-modified pentamethylcyanine dye molecules
Adding 2 mu M of pentamethyl cyanine dye Ph-Cy5 with reference meso position modified by phenyl into a test quartz dish containing 3mL of dichloromethane solution, adjusting the absorbance at 415nm to about 1 by using DPBF solution, placing the quartz dish at 760nm and 500mW/cm 2 Was irradiated under a xenon lamp light source, and the absorption spectrum of the solution was recorded every 120 seconds. The test results are shown in fig. 1. The analysis of FIG. 1 shows that the target compound XAN-Cy5 has relative specificity for improving the upconversion singlet oxygen generation performance of the pentamethylcyanine dye molecule.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and those skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. A single-photon up-conversion pentamethine cyanine photosensitive dye has the following structural general formula I:
in the general formula I:
R 1 and R 2 Each independently selected from one of H, cl, F, carboxyl and sulfonic group;
R 3 and R 4 Each is independently selected from one of methyl, ethyl, propyl, long alkyl chain and benzyl;
Ar 1 one selected from the group consisting of those described by formulas i to iv:
x is selected from one of iodine, chlorine or bromine.
2. The photosensitizing dye according to claim 1, wherein R is 1 、R 2 Are each H.
3. The photosensitive dye according to claim 1, wherein R is 3 And R 4 Are each an ethyl group.
4. The photosensitizing dye according to claim 1, wherein X is iodine.
5. The photosensitive dye according to claim 1, wherein Ar 1 One selected from the group consisting of those described by formulas i, ii, iii, iv.
6. The method for preparing a single photon upconversion pentamethyl cyanine photosensitive dye of claim 1, which comprises the step of reacting a compound of formula II with a compound of formula III in the presence of zero-valent palladium,
7. the preparation method according to claim 6, wherein the molar ratio of the compound of formula II to the compound of formula III is 1 to 10;
the molar ratio of the zero-valent palladium to the compound shown in the formula II is 1.01-0.10;
the reaction also uses a solvent which is selected from 1, 4-dioxane or dimethyl sulfoxide.
8. The method according to claim 6, wherein the zero-valent palladium is selected from the group consisting of palladium tetratriphenylphosphine and palladium tris-dibenzylideneacetone.
9. The use of the single-photon upconversion pentamethylcyanine photosensitizing dyes of claim 1 in the preparation of upconversion PDT photosensitizers, in the preparation of photodynamic therapy drugs, and in the preparation of drugs for inhibiting the growth of cancer cells in deep tissues.
10. The use of claim 9, wherein said up-conversion PDT photosensitizer has subcellular organelle localization properties, and/or has a near infrared region with large molar extinction coefficient properties, and/or single photon up-conversion luminescence properties, and/or has a high singlet oxygen generating capacity under near infrared excitation longer than autofluorescence emission.
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