CN102134244A - Medical photosensitizer and preparation method thereof - Google Patents
Medical photosensitizer and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a medical photosensitizer and a preparation method thereof. The photosensitizer is tetra(trifluoroethoxy) phthalocyaninate. The preparation method comprises: synthesizing an intermediate 4-trifluoroethoxybenzenedicarbonitrile by reacting 4-nitro-2-benzenedicarbonitrile with trifluoroethanol in dry dimethyl sulfoxide (DMSO) in the presence of lithium hydroxide; and reacting the intermediate and anhydrous metal chloride in dry n-amyl alcohol in the presence of 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) which is a strong organic alkali to obtain the tetra(trifluoroethoxy) phthalocyaninate. In the method, the conditions are mild, the reaction temperature is only about 70 DEG C, and the yield is up to 78 percent. In-vitro cell experiments prove that the tetra(trifluoroethoxy) phthalocyaninate has high ability of killing HL-60 and SW-1116 cells. The results of in-vivo photodynamic therapy (PDT) tests show that ZnPcF has PDT effect on U14 transplantable tumor in mice and that the U14 transplantable tumor inhibition rate of the ZnPcF reaches 79.1 percent.
Description
Technical field
The present invention relates to a kind of medical photosensitive agent and preparation method thereof, this kind photosensitizers can be used as the optical dynamic therapy that medicine is used for tumour.
Background technology
According to the World Health Organization, annual have 9,000,000 new cancer ratios to take place in the world, and 5,000,000 people die from cancer, and cancer replaces cardiovascular and cerebrovascular disease becomes the No.1 killer who threatens the human life.Tumour particularly malignant tumour is human 21st century to expect one of main difficult problem of capturing.Therefore, the research of tumor prevention medicine has become at present one of research focus of oncology and pharmacy both at home and abroad.
Photodynamic therapy (photodynamic therapy is called for short PDT) is to begin to be used for clinical a kind of new therapy the eighties of last century later stage seventies.Photodynamic therapy claims photoradiation therapy (Photoradiation Therapy) or photochemotherapy (Photochemotherapy) again
[1,2]This methods of treatment is based on the use of photosensitizers and control, and these photosensitizerss can optionally be trapped in the cancer cells, after the enrichment, and with the optical excitation generation photodynamics reaction of certain wavelength, thus kill cancer cell.Compare with traditional remedies such as surgical operation, chemotherapy, radiotherapy etc., the photodynamic therapy biggest advantage is to carry out selective destruction to cancerous tissue, and side effect is less.Porphyrin-Based Sensitizer is to be applied to clinical anti-tumor photosensitizer at present, and its main drawback is a maximum absorption wavelength, not at the red light district preferable to the tissue transmitance, so drug effect is not ideal enough, and the speed that it is got rid of in the skin automatically is slow, and phototoxicity is big, and its clinical application is restricted
[3]Therefore development of new efficiently anticancer photosensitizer be the focus of domestic and international PDT research always.
The ideal photosensitizers should have following characteristic: (1) tumor-selective uptake ratio height, and be easy to metabolism; (2) by π-π
*The maximum absorption wavelength of the Q band that transition causes should be positioned at the strong red light district of penetrate tissue ability (670-850nm); (3) excite triplet state quantum yield height down at ruddiness, the life-span is long; (4) to a little less than the natural light absorption, little to the phototoxicity of skin; (5) chemical property is stable, low toxicity
[4]Therefore meeting above-mentioned requirements as s-generation photosensitizers phthalocyanine-like compound, is ideal photosensitizers comparatively.But the phthalocyanines photosensitizers all has a common shortcoming, and promptly its solvability in water-soluble solvent and fat-soluble solvent is not high, and this has influenced its transhipment in vivo and the accumulation ability on tumor tissues.
From Ben-Hur in 1985 etc.
[5]Reported at first since the photoinactivation of aluminum phthalocyanine to tumour cell that phthalocyanine-like compound has become a focus as the research of anticancer photosensitizer.The more attention of domestic and international research is having sulfonic Phthalocyanine Zinc and aluminium (MPcSn), has synthesized sulfonic group phthalimidomethyl Phthalocyanine Zinc as Liu Ersheng etc.
[6], and Svetlanakudievich synthetic trisulfonic acid base substituted phthalocyanine title complex etc.
[7]But but the metal phthalocyanine photosensitizers poor stability after the sulfonation, intermolecular easy polymerization, weakened the ability of light power killing tumor cell, and product is the mixture that sulfonation degree differs, be difficult to separate the separation and purification that needs the high performance liquid phase preparative column, these defectives are restricted this class title complex exploitation and application clinically.But some scholar begins the synthetic and photosensitive lethal effect of the reasonable polyfluoro alkoxyl group of solubility property substituted metal phthalocyanine title complex is studied both at home and abroad in recent years.Four-(Halothane oxygen base) Phthalocyanine Zinc have been synthesized as Gao Lindong etc.
[8]Wesley M.Sharman etc. has synthesized the polyfluoro substituted phthalocyanine
[9]Document according to Gao Lindong etc.
[10]The report four-(Halothane oxygen base) Phthalocyanine Zinc be miscible among the emulsifying agent Pluronic F68, ruddiness (＞610nm) radiation under the effect of anti-myeloma is preferably arranged.This product has bright prospect and great potential as the clinical treatment that photosensitizers is applied to tumour.
Reference
[1]Hofman?J，Zeeland?F，Tutker?S，et?al.Peripheral?and?axial?substitution?of?phthalocyanines?with?solketal?groups：synthesis?and?in?vitro?evaluation?for?photodynamic?therapy[J].J.Med.Chem.，2007；50：1485-1494.
[2]Liu?W，Jensen?T，Fronczek?F，et?al.Synthesis?and?cellular?studies?of?nonaggregated?water-soluble?phthalocyanines[J].J.Med.Chem，2005；48：1033-1041.
[3] Zhou Jinlan, Cheng Hong, woman's bow are virtuous. the preparation of novel tetraamido aluminium phthalocyanine and in body light power Anticancer Activities [J]. Chinese laser, 2005; 32 (8): 1155-1160.
[4] Yu Kaichao, Cheng Hong, Jin Ling etc. optical dynamic therapy makes progress [J] with the study on the synthesis of phthalocyanines photosensitizers. photographic science and photochemistry, 2003; 21 (2): 138-146.
[5]Ben-Hur，Rosenthal?I.Photosensitized?inactivation?of?Chinese?hamster?cells?by?phthalocyanines[J].Photochem?Photobiol，1985；42(2)：129-133.
[6] Liu Ersheng, Huang Jiandong, Dai Zhi fly etc. the synthetic and light power anti-tumor activity research [J] of sulfonic group phthalimidomethyl Phthalocyanine Zinc. and Chinese Journal of Inorganic Chemistry, 1997; 12 (4): 167-172.
[7]Svetlana?k.Synthesis?and?photodynamic?activities?of?novel?trisulfonate?zinc?phthalocyanines[J].Journal?of?Medicinal?Chemistry，1997；40：24.
[8]Gao?L?D，Qian?X?H，Zhang?Y?X.Soluble?fluoroalkoxyl?metal?phthalocyanate：novel?photosensitizer?for?photodynamic?for?tumor?therapy[J].Photographic?Science?and?Photochemistry，2001；19(4)：244-249.
[9]Wesley?M，Johan?E.Synthesis?and?photodynamic?activity?of?novel?asymmetrically?substituted?fluorinated?phthalocyanines[J].Bioconjugate?Chem.，2005；16：1166-1175.
[10]Gao?L?D，Qian?X?H，Zhang?Y?X.Soluble?fluoroalkoxyl?metal?phthalocyanate：novel?photosensitizer?for?photodynamic?for?tumor?therapy.Photographic?Science?and?Photochemistry，2001，19(4)：244-249.
Summary of the invention
Main purpose of the present invention is to provide a kind of new method to synthesize four-(Halothane oxygen base) metal phthalocyanine zinc, and its synthesis condition is more gentleer than existing method, and the synthetic productive rate improves.This method provides a kind of favorable solubility, and compares novel medical photosensitive agent four-(the Halothane oxygen base) metal phthalocyanine that is easier to separation and purification with sulfonated phthalocyanine.
Second purpose of the present invention be to provide this four-(Halothane oxygen base) novel metal phthalocyanines as medical photosensitive agent in the application aspect the optical dynamic therapy.
Medical photosensitive agent of the present invention is the phthalocyanine derivates of following formula (I):
In the formula: four Halothane oxygen base (F are arranged on the phthalocyanine ring
3CH
2CO-) substituting group, and lay respectively at 2 or 3 positions on the phthalocyanine ring, 9 or 10 positions, 16 or 17 positions, 23 or 24 positions.
It is a kind of under comparatively gentle condition that this invention provides, the technology of synthesizing new antineoplaston medical photosensitive agent four-(Halothane oxygen base) metal phthalocyanine and its intermediate.This method is: with 4-nitro phthalic nitrile and and trifluoroethanol in the presence of lithium hydroxide, synthetic intermediate 4-Halothane oxygen base phthalic nitrile in exsiccant DMSO.Use this intermediate and anhydrous metal muriate then, exist down at strong organic bases DBU (1,8-diazabicylo [5,4,0] 7-hendecene), reaction obtains photosensitizers four-(Halothane oxygen base) metal phthalocyanine in dry Pentyl alcohol.
According to technique scheme, when also comprising synthetic described intermediate 4-Halothane oxygen base phthalic nitrile in the method for synthetic such phthalocyanine photosensitizers of the present invention, temperature of reaction is 20-30 ℃, and preferred 25 ℃, the reaction times is 48-72h.
According to technique scheme, after also comprising reaction in the method for synthetic such phthalocyanine photosensitizers intermediate of the present invention and finishing, in mixed reaction solution, slowly splash in the deionized water, obtain turbid liquid, take out freezing back.After it is left standstill for some time, filter, be washed till neutrality with deionized water, suction filtration gets solid, uses recrystallizing methanol, to obtain the intermediate of purifying.
According to technique scheme, when also comprising in the method for synthetic such phthalocyanine photosensitizers of the present invention with synthetic described four-(the Halothane oxygen base) metal phthalocyanines of intermediate, reaction mixture reacts under 60-80 ℃ of temperature, preferred 70 ℃ temperature, feed nitrogen simultaneously, condensing reflux 24-48h.
According to technique scheme, after also comprising reaction in the method for synthetic such phthalocyanine photosensitizers of the present invention and finishing, in mixed reaction solution, slowly splash into deionized water, obtain turbid liquid, filter mixed reaction solution and get blackish green solid.Place vacuum freeze drier dry blackish green solid, get crude product.
According to technique scheme, also comprise in the method for synthetic such phthalocyanine photosensitizers of the present invention then dried crude product neutral alumina chromatography column, with methyl alcohol: chloroform=1: 100 is that moving phase is further purified.
This invention is to have adopted new method synthetic novel medical photosensitive agent four-(Halothane oxygen base) Phthalocyanine Zinc.With Gao Lindong
[10]Synthetic method compare, its synthesis condition is more gentle, the top temperature of reaction is reduced to 70 ℃ by 200 ℃ because the reduction of temperature of reaction, the by product in the building-up reactions reduces, the synthetic productive rate is promoted to 78% by 11%.The solubility property of synthetic product is greatly improved, and compares its product with sulfonated phthalocyanine and be easier to separation and purification.
Application in the photosensitizer drug that the phthalocyanine derivates of formula of the present invention (I)---four-(Halothane oxygen base) Phthalocyanine Zinc are used as the optical dynamic therapy of tumour.In the experiment in vitro, described tumour behaviour acute myeloid leukaemia clone HL-60 cell, colon cancer cell SW-1116, breast cancer cell MCF-17, liver cancer cell HepG2; In the body experiment, described tumour is a cervical cancer U14 transplanted tumor.
Advantage of the present invention: this method is a kind of new simple and convenient preparation method for preparing the novel medical photosensitive agent of antineoplaston.This method adopts gentle condition, and temperature of reaction needs only about 70 ℃, and productive rate is higher, reaches 78%, easy handling.Simultaneously, it is few that the product that synthesizes and such Sulfonated phthalocyanine photosensitizers are compared isomer, and material is easy to purifies and separates, and the product solvability is better.Experimental results show that through cell in vitro four-(Halothane oxygen base) Phthalocyanine Zinc (ZnPcF) are strong to HL-60 and SW-1116 cell killing ability, and to a little less than breast cancer cell MCF-17, the photosensitive kill capability of liver cancer cell HepG2, and effect is concentration dependence effect.The optical dynamic therapy test-results shows in vivo, and ZnPcF has the effect of PDT to mouse U14 transplanted tumor, and during dosage 2mg/kg, it reaches 79.1% to U14 transplanted tumor inhibiting rate.This product has bright prospect and great potential as the clinical treatment that photosensitizers is applied to tumour.
Embodiment
The present invention is described in detail below in conjunction with embodiment:
The present invention has adopted new condition, the comparatively novel medical photosensitive agent intermediate 4-Halothane oxygen base phthalic nitrile of Wen He method synthetic antineoplaston, and photosensitizers four-(Halothane oxygen base) metal phthalocyanine.Being characterized as of this compound: on the big ring of Phthalocyanine Zinc, introduce four Halothane oxygen bases, increased the solvability of phthalocyanine, help photosensitizers transhipment in vivo, and have the selectivity uptake ratio that is beneficial to the raising tumor tissues.
Embodiment 1:
(1) 4-Halothane oxygen base phthalic nitrile is synthetic
4-nitro phthalic nitrile and the exsiccant dimethyl sulfoxide (DMSO) (DMSO) of 240ml and the trifluoroethanol adding band CaCl of 40mmol with 40mmol
2In the three-necked flask of drying tube, keep 25 ℃ and carry out stirring reaction, in 2h, divide 3 batches of lithium hydroxides that add 2.4g, (the preferred lithium hydroxide that added 0.8g every 40 minutes in the actual tests operation).Slowly splash in the deionized water behind the reaction 72h, obtain turbid liquid, put into refrigerator, take out freezing back.After it is left standstill for some time, filter, be washed till neutrality with deionized water, suction filtration gets solid.Use recrystallizing methanol, obtain the intermediate of the 4-Halothane oxygen base phthalic nitrile of purifying.Productive rate 81%.Survey the infrared spectrum of 4-Halothane oxygen base phthalic nitrile, IR (cm
-1): 3075 (Ar, H), 2230 (C ≡ H), 1920,1590,1485,1450,1420,1400 (C-F), 1320 (C-F), 1600,1563,1480,1286,1250 (R-O-Ar).
Synthesizing of (two) four-(Halothane oxygen base) Phthalocyanine Zinc
Wherein: MX=ZnCl
2
The strong organic bases DBU of 35mmol (3-Halothane oxygen base) adjacent benzene two eyeballs and 15mL (1,8-diazabicylo [5,4; 0] 7-hendecene) and the dry Pentyl alcohol of 25mL be mixed in the reaction flask; feed nitrogen protection, be heated with stirring to 70 ℃, add the 10mmol Zinc Chloride Anhydrous.The reaction 24h after, reaction solution is chilled to 60 ℃, slowly splash into deionized water, obtain turbid liquid, filter blackish green solid.Place vacuum freeze drier dry blackish green solid, the dry crude product that gets.Then with dried solid crude product alumina chromatographic column, with methyl alcohol: chloroform=be further purified at 100: 1 four-(Halothane oxygen base) the pure product of Phthalocyanine Zinc, productive rate 78%.
The UV, visible light scanning spectrogram and fluorescent scanning spectrum data: Uv-vis (THF) λ=349nm of four-(Halothane oxygen base) Phthalocyanine Zinc, 609nm, 671nm; Fluorescence (THF) λ ex=698nm, λ em=710nm.
The infrared scan spectral data of four-(Halothane oxygen base) Phthalocyanine Zinc: IR (KBr, cm
-1) v3430,2925,2854,1624,1350,860,700,679.1160,1220cm
-1(C-F) 1077 (Ar-C-O);
The hydrogen nuclear magnetic resonance spectrum data of four-(Halothane oxygen base) Phthalocyanine Zinc:
1HNMR
1HNMR δ=8.866 (m, 12H, H-PC), 7.808 (m, 12H, H-PC), 5.360 (s, 2H ,-CH
2-O) 3.306 (s, 2H, H
2O), 2.508 (s, 6H, DMSO);
The mass spectrum data of four-(Halothane oxygen base) Phthalocyanine Zinc: MSm/z:971[M+H]
+, 819[M+H-CF
3-(CF
3CH
2)]
+, 808[M+H-(CF
3CH
2)
2]
+, 789[M+H-CF
3CH
2-(CF
3CH
2O)]
+, 575[M+H-(CF
3CH
2O)
4]
+
The ultimate analysis data of four-(Halothane oxygen base) Phthalocyanine Zinc: w (C) 49.35%, w (H) 2.08%, w (N) 11.55%; Found 49.05%, w (H) 2.00%, w (N) 11.15%.
Embodiment 2:
(1) external optical dynamic therapy test
The preparation of four-(Halothane oxygen base) Phthalocyanine Zinc (ZnPcF) emulsions: (a) ZnPcF (67.85mg) is dissolved in ethanol (2mL) earlier.This ethanolic soln slowly add Pu Luonike F68 (Pluronic F68, F68) aqueous solution (10%, 50mL) in, violent stirring simultaneously, the concentration of the ZnPcF in the final solution is 1.3mgmL
-1(1.34mmolL
-1), F68 concentration is 9.6% (w/v).(b) simultaneously 2mL ethanol is added in the F68 aqueous solution (50mL), as solvent control solution.Above-mentioned solution through the membrane filtration degerming of 0.45 μ m after lucifuge be stored in refrigerator.F68 refers to Pu Luonike F68.
Cell strain and cultivation: breast cancer cell MCF-17, liver cancer cell HepG2, HL-60 cell and SW-1116 cell strain are available from Shanghai cell institute, be incubated at and contain 10% calf serum, penicillin 100IU/mL, in the RPMI1640 nutrient solution of Streptomycin sulphate 100IU/mL, cell cultures is in 37 ℃, 5%CO2, in the CO2gas incubator of saturated humidity, the cell in the vegetative period of taking the logarithm experimentizes.
The F68 aqueous solution (the 1.34mmolL of ZnPcF
-1), with the membrane filtration of 0.45 μ M, the dosing final concentration is (90,60,44.5,23,11.5 μ M).With the RPMI medium RPMI-1640 cultivator acute myeloid leukaemia clone HL-60 cell, colon cancer cell SW-1116, breast cancer cell MCF-17, the liver cancer cell HepG2 that contain 10% deactivation calf serum.Cell inoculation is in 96 well culture plates, every porocyte number 6 * 10
3, in 37 ℃, the CO of humidity 5%
2Incubated overnight in the gas.After allow cell cultures 24h in the above-mentioned concentration phthalocyanine solution of 200 μ L under the same conditions.Cell places illumination under the room temperature then with PBS solution flushing and the cultivation liquid that adds 180 μ L
[4]Illumination condition is the halogen tungsten lamp illumination of the 100W of lasting 2h, and light cools off through a tank, and (λ=650nm) filter, light intensity is 280mWcm to a spectral filter
-2
After the illumination, cell cultures is in 37 ℃, 5%CO
2Condition under place an evening, cell inhibitory rate detects with mtt assay, with PBS solution (20 μ l, the 5mgml of MTT
-1) join in each hole, cultivated under the same conditions 4 hours.At room temperature, plate is placed on reading of data on the microplate reader, every hole exciting light is 492nm.The hole that does not add cell only to add substratum 200 μ L is a blank well, and other hole readings deduct this blank well numerical value, medicine to the method for calculation of cancer cells inhibiting rate as shown in the formula:
In: A: tested sample group absorbancy mean value; A
0: solvent control group absorbancy mean value.
Formula ZnPcF pair cell phototoxicity the results are shown in Table 12.To breast cancer cell MCF-17, liver cancer cell HepG2, HL60 cell and SW-1116 cell inhibiting rate are respectively 51.2%, 42.2%, 64.3% and 72.1% when recording the ZnPcF adding consistency and being 90 μ M.Calculate ZnPcF to breast cancer cell MCF-17,, the IC of HL60 cell and three kinds of cells of SW-1116 cell
50Be respectively 78.35,41.4 and 31.05 μ M.
ZnPcF all has obvious lethal effect to breast cancer cell MCF-17, liver cancer cell HepG2, HL-60 and SW-1116 cell and along with drug level increases progressively, the killer cell ability strengthens, show HL-60 and SW-1116 cell killing ability strong, and to a little less than breast cancer cell MCF-17, the photosensitive kill capability of liver cancer cell HepG2, liver cancer cell especially.Vitro culture finds that ZnPcF is the strongest to drug susceptibility to the SW-1116 tumour cell.Its mechanism may be because the plasmalemma of MPcF and cell interacts, generation high density singlet oxygen under the illumination (
1O
2), cause that thus the cell biological molecule produces the peroxidation killing tumor cell.
Mechanism may be because the plasmalemma of ZnPcF and cell interacts, generation high density singlet oxygen under the illumination (
1O
2), cause that thus the cell biological molecule produces the peroxidation killing tumor cell.
Table 1. different concns ZnPcF is to HL60 and the phototoxic action of SW-1116 cell
(2) the dark toxicity inspection of cell
Four-(Halothane oxygen base) Phthalocyanine Zinc (ZnPcF)) the Pu Luonike F68 aqueous solution (1.34mmolL
-1), filtering with the strainer of 0.45 μ M, the dosing final concentration is (90,60,44.5,23,11.5 μ M).Cultivate breast cancer cell MCF-17, liver cancer cell HepG2 with the RPMI medium RPMI-1640 that contains 10% deactivation calf serum, HL60 cell and SW-1116 cell, cell inoculation be in 96 well culture plates, every porocyte number 6 * 10
3, in 37 ℃, the CO of humidity 5%
2Incubated overnight in the gas.After allow cell cultures 24h in the phthalocyanine solution of above-mentioned each concentration of 200 μ L under the same conditions.Cell is with PBS solution flushing and add the cultivation liquid of 180 μ L, after continue to place and cultivate 24h in the incubator.Detect cell inhibitory rate with mtt assay then.The dark toxicity inspection group of cell singly adds ZnPcF is not had irradiation, detects the cell inhibiting rate with mtt assay and sees the following form 2:
Table 2. different concns ZnPcF is to HL-60, SW-1116, MCF-17 and the dark toxic action of HepG2 cell
Under the natural light condition, as ZnPcF concentration＜90 μ gml
-1The time, to breast cancer cell MCF-17, liver cancer cell HepG2, HL60 cell and the dark toxicity of SW-1116 cell are all less, see Table 2.Cell survival is normal, meets the most important condition that the photosensitizers as the PDT therapy must satisfy.It is little to get its light absorption value in 400～600nm wavelength region from the UV-Vis absorption spectra data of ZnPcF in addition, promptly illustrate a little less than the absorption very of ZnPcF to natural light, therefore the photosensitization reaction that causes by natural light than a little less than the blood porphyrin photosensitizers many, so might overcome caused skin phototoxic reactions such as clinical application HPD, this is also confirmed from cytotoxicity experiment.And the ZnPcF maximum absorption wavelength is positioned at near-infrared region (λ
Max=660nm), just in time promptly to be called as " treatment window " wave band consistent with the best band of tissue transmission for this wavelength.Photodynamic effect helps clinical photochemical treatment to tumour by force.
ZnPcF has pair people's acute myeloid leukaemia clone HL-60 cell, colon cancer cell SW-1116 to have tangible phototoxicity and effect to be concentration dependence effect.ZnPcF is to these 2 kinds of tumour cell IC
50Be respectively 42.4 and 33.8 μ M.The dark toxicity of the dark toxicity inspection group of cell proof ZnPcF pair cell is little, meets the most important condition that the photosensitizers as the PDT therapy must satisfy.ZnPcF has potential advantages as anticancer photosensitizer, further to the ZnPcF Study on mechanism, will help fully to excavate the potentiality of its photodynamic therapy.
Below only being preferred embodiment of the present invention, is not to be used to limit the present invention, all personnel that are familiar with this type of technology, and variation of being done or modification within the scope of the invention all is included in the claimed interest field of the present invention.
(3) optical dynamic therapy test in vivo
The preparation of four-(Halothane oxygen base) Phthalocyanine Zinc (ZnPcF) emulsions: external optical dynamic therapy test same as above.
The foundation of solid tumor models: animal: 50 of Kunming mouses, female, fasting was weighed after 10 hours, and body weight 18-19g is provided by Medical University Of Fujian's Experimental Animal Center.The strain of U14 knurl: mouse cervical cancer is to protect to plant to go down to posterity by Medical University Of Fujian's pharmacology.Under aseptic condition, be taken at well-grown U14 knurl piece in the kunming mice body, add physiological saline after shredding 1: 6 (W/W), use glass homogenizer homogenate, 300 mesh filter screens filter, and every mouse is in right fore oxter inoculation 0.2ml, 1 * 10
6Individual/ml cell filtrate.Treat behind 4～5d that tumour grows to about diameter 0.5cm, divide five groups at random.
Experiment grouping and treatment plan: experimental group is through the ZnPcF of abdominal injection different concns, and negative control group is injected the equal-volume solvent.Move to the darkroom after the administration and continue to raise, use 670nm laser illumination tumor locus behind the 48h.The irradiates light power density is 280mW/cm
2, irradiation time is 8min, irradiation dose is 80J/cm
2Illumination finishes and promptly puts back to the darkroom raising, puts to death mouse behind the 5d, strips the knurl piece, calculates tumour inhibiting rate.Inhibiting rate sees the following form 3:
Tumour inhibiting rate %=(the average knurl of the average knurl weight/control animals of 1-experimental group animal is heavy)=(1-T/C)
Statistical procedures: experimental result adopts the t testing procedures in SPSS 10.0 softwares to handle, and data are represented with mean ± standard deviation.
Table 3 F68 (10mg/kg)+ZnPcF is to the optical dynamic therapy effect of mouse U14 transplanted tumor
P＜0.05，P＜0.01.
Various dose ZnPcF is to the effect (seeing Table 3) of the PDT of mouse U14 transplanted tumor.In the experiment, administration ZnPcF, the 670nm red light irradiation is to the U14 tumor inhibition effect, and have dose-dependence, 5～8h after the ZnPcF 2mg/kg illumination, knurl piece surface skin occur obviously red and swollen, the knurl piece is lavender hyperemia, redness disappears in the 15h, and the tumor surface incrustation that continues is sunk, and part mouse tumour behind 3～4d is tear-away.F68 is in the unrestraint effect of 670nm rayed to the U14 solid tumor.During dosage 2mg/kg, it reaches 79.1% to U14 transplanted tumor inhibiting rate.
Claims (10)
1. medical photosensitive agent is characterized in that: be the phthalocyanine derivates of following formula (I):
In the formula: four F are arranged on the phthalocyanine ring
3CH
2The substituting group of CO-, and lay respectively at 2 or 3 positions on the phthalocyanine ring, 9 or 10 positions, 16 or 17 positions, 23 or 24 positions.
2. the preparation method of the described phthalocyanine derivates of claim 1 comprises the following steps:
(i) with 4-nitro phthalic nitrile (II) and trifluoroethanol (III) synthetic intermediate 4-Halothane oxygen base phthalic nitrile (IV);
(ii) in the presence of strong organic bases, use intermediate (IV) and ZnCl
2Reaction obtains four-(Halothane oxygen base) Phthalocyanine Zinc (I);
In the formula: MX=ZnCl
2
3. preparation method according to claim 2 is characterized in that: described step (i) is in the presence of lithium hydroxide LiOH, synthetic intermediate 4-Halothane oxygen base phthalic nitrile (IV) in exsiccant DMSO solvent; The temperature of reaction of described step (i) is 20-30 ℃, and the reaction times is 48-72h, finishes reaction.
4. according to claim 2 or 3 described preparation methods, it is characterized in that: described step (i) is to divide 3-4 time in 2 hours that react after beginning to add lithium hydroxide.
5. according to claim 3 or 4 described preparation methods, it is characterized in that: described step (i) is after reaction is finished, and the reaction solution after lentamente reaction being finished splashes in the deionized water, obtains turbid liquid, and take out freezing back; After turbid liquid after freezing leaves standstill, filter, be washed till neutrality with deionized water, suction filtration gets solid, uses recrystallizing methanol, obtains the intermediate of purifying.
6. according to claim 2 or 3 or 5 described preparation methods, it is characterized in that: described step (ii) is that the intermediate of step (i) is at strong organic bases 1,8-diazabicylo [5,4,0] under the existence of 7-hendecene, synthetic in exsiccant amylalcohol solvent with Zinc Chloride Anhydrous; Described intermediate, strong organic bases 1, the reaction mixture of 8-diazabicylo [5,4,0] 7-hendecene and Zinc Chloride Anhydrous reacts under 60-80 ℃ temperature, feeds nitrogen simultaneously, and condensing reflux 24-48h finishes reaction.
7. preparation method according to claim 6 is characterized in that: described step (ii) after reaction is finished, is chilled to 60 ℃ with reaction mixture, slowly splashes into deionized water, obtains turbid liquid, filter blackish green solid; Place vacuum freeze drier dry blackish green solid, the dry crude product that gets.
8. preparation method according to claim 7 is characterized in that: described crude product neutral alumina chromatography column, with methyl alcohol: chloroform=1: 100 is that moving phase is further purified, four-(Halothane oxygen base) the pure product of Phthalocyanine Zinc.
9. the application of the phthalocyanine derivates of the described formula of claim 1 (I) in the photosensitizer drug that preparation is used as the optical dynamic therapy of tumour.
10. application according to claim 9 is characterized in that: described tumour behaviour acute myeloid leukaemia clone HL-60 cell, colon cancer cell SW-1116, breast cancer cell MCF-17, liver cancer cell HepG2 or cervical cancer U14.
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| CN103435624A (en) * | 2013-09-17 | 2013-12-11 | 福州大学 | Fluorinated coumarin-phthalocyanine conjugate and preparation method and application thereof |
| CN104306971A (en) * | 2014-10-29 | 2015-01-28 | 张树超 | Medicine composition for resisting cervical cancer with matching of photodynamic therapy |
| CN105367579A (en) * | 2015-11-30 | 2016-03-02 | 中国石油大学(华东) | Tetra(trifluoroethoxyl) free phthalocyanine and cobalt complex and preparation method therefor and application thereof |
| CN105384744A (en) * | 2015-11-30 | 2016-03-09 | 中国石油大学(华东) | Tetra(trifluoro ethyoxyl) phthalocyanin europium complex and preparing method and application thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435624A (en) * | 2013-09-17 | 2013-12-11 | 福州大学 | Fluorinated coumarin-phthalocyanine conjugate and preparation method and application thereof |
| CN103435624B (en) * | 2013-09-17 | 2015-07-22 | 福州大学 | Fluorinated coumarin-phthalocyanine conjugate and preparation method and application thereof |
| CN104306971A (en) * | 2014-10-29 | 2015-01-28 | 张树超 | Medicine composition for resisting cervical cancer with matching of photodynamic therapy |
| CN104306971B (en) * | 2014-10-29 | 2017-02-15 | 青岛大学附属医院 | Medicine composition for resisting cervical cancer with matching of photodynamic therapy |
| CN105367579A (en) * | 2015-11-30 | 2016-03-02 | 中国石油大学(华东) | Tetra(trifluoroethoxyl) free phthalocyanine and cobalt complex and preparation method therefor and application thereof |
| CN105384744A (en) * | 2015-11-30 | 2016-03-09 | 中国石油大学(华东) | Tetra(trifluoro ethyoxyl) phthalocyanin europium complex and preparing method and application thereof |
| CN105384744B (en) * | 2015-11-30 | 2018-03-20 | 中国石油大学(华东) | Four (trifluoro ethoxy) phthalocyanine europium complexes and its preparation method and application |
| CN105367579B (en) * | 2015-11-30 | 2018-03-20 | 中国石油大学(华东) | Four (trifluoro ethoxy) free base phthalocyanines and cobalt complex with and its preparation method and application |
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