CN102643280B - Folic-acid-modified phthalocyanino-silicon, and preparation method and application thereof - Google Patents
Folic-acid-modified phthalocyanino-silicon, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a folic-acid-modified phthalocyanino-silicon, and a preparation method and application thereof, belonging to the field of preparation of photodynamic medicines or photosensitizers. The folic-acid-modified phthalocyanino-silicon comprises symmetrically substituted phthalocyanino-silicon containing folic acid groups in the axial direction, and asymmetrically substituted phthalocyanino-silicon containing folic acid groups in the axial direction. The folic-acid-modified phthalocyanino-silicon can be used for preparing photodynamic medicines or photosensitizers, and has the advantages of high selectivity, high activity and the like; and the preparation method is simple, and has obvious economic and social benefits.
Description
Technical field
The present invention relates to silicon phthalocyanine of a kind of modified with folic acid and preparation method thereof, belong to photo-dynamical medicine or photosensitizers preparation field.The invention still further relates to their application in optical dynamic therapy, light power diagnosis and the sterilization of light power as photosensitizers.
Background technology
Phthalocyanine complex is the important functional materials of a class, wherein, phthalocyanine complex as photosensitizers the application prospect in optical dynamic therapy (Photodynamic Therapy) noticeable.
So-called optical dynamic therapy (or claiming photodynamic therapy) in fact, is the application of the Photosensitive reaction of photosensitizers (or claiming photosensitive drug) at medical field.Its mechanism is, first photosensitizers is injected to body, (this period waiting time be allow medicine enrichment relatively in target body) after a period of time, rayed target body (to endoceliac target, can import light source by interventional techniques such as optical fiber) with specific wavelength, be enriched in photosensitizers in target body under optical excitation, inspire a series of optical physics photochemical reactions, produced active oxygen, and then destroyed target body (for example cancer cells and cancerous tissue).
In some developed countries, optical dynamic therapy has become the 4th kind of ordinary method for the treatment of cancer.With traditional therapy, as surgical operation, chemotherapy, radiotherapy are compared, the advantage of photodynamic therapy maximum is to carry out selective destruction and needn't perform surgical operation cancerous tissue, and side effect is little, thereby gets most of the attention.
Simultaneously, research in recent years also shows, photodynamic therapy also can be treated the non-Cancerous diseases such as bacterium infection, oral disease, macular degeneration illness in eye, arteriosclerosis, wound infection and tetter effectively.Photosensitizers can also be for light power sterilization, most importantly for the sterilization of water body, blood and blood derivatives.Simultaneously, utilizing the photoluminescent property of photosensitizers to carry out light power diagnosis, is also an important use of medical photosensitive agent.
The key of optical dynamic therapy is photosensitizers, and light power curative effect depends on the quality of photosensitizers.Based on optical dynamic therapy in the potentiality aspect treatment tumour and Other diseases, scientific circles generally believe, optical dynamic therapy will become the important therapy of 21 century, so, as the photosensitizers of optical dynamic therapy core, will become an important and tempting new high-tech industry.
So far, get permission the formal photosensitizers used clinically and be mainly hematoporphyrin derivative.In states such as the U.S., Canada, Germany, Japan, use be the Photofrin(U.S. FDA in nineteen ninety-five official approval Photofrin for clinical anticancer), it is the mixture of the haematoporphyrin oligopolymer that extracts from cow blood and carry out chemical modification.Hematoporphyrin derivative has shown certain curative effect, but also exposed critical defect: maximum absorption wavelength (380-420nm) is not to tissue transmitance red light district (650-800nm) preferably, the skin phototoxicity is large, mixture, form unstable etc., thereby clinical application is restricted, so Development of New Generation photo-dynamical medicine (photosensitizers) is international study hotspot.
Owing to having, maximum absorption wavelength is positioned at the easy ruddiness through tissue zone, the photosensitization ability is strong, biocompatibility is high, be difficult for gathering characteristics such as (because having axial substituting group), and silicon phthalocyanine is paid much attention to as the application of novel photosensitive agent.The axial substituted phthalocyanine silicon (Pc4) of U.S. Case Western Reserve university development has significantly high photodynamic activity, has entered the I clinical trial phase.But, the complex synthetic route of Pc4, preparation cost is high, and poor stability be the more important thing is, and Pc4 is not the medicine that China has independent intellectual property right.In addition, the photosensitizers (comprising the phthalocyanines photosensitizers) of clinical trial at present also lacks specificity and the targeting to tumor tissues and cancer cells.Therefore, in the urgent need to screen new photosensitive activity high, prepare silicon phthalocyanine photosensitizers easy or that there is targeting.Due to photosensitizers and the potential tremendous economic social value of optical dynamic therapy, the refinement of range of application and treatment focus greatly, prepare the axial replacement silicon phthalocyanine title complexs with photosensitive activity is very necessary as drug candidate more.
What is particularly worth mentioning is that; the state such as American-European, Japanese strengthens one after another to the input of novel photosensitive agent and the infiltration dynamics of intellecture property; in this case; only have and pay much attention to have the exploitation of independent intellectual property right medicine and accelerate the patent protection paces, guarantee China is in autonomy and the commanding elevation of this important medical field of optical dynamic therapy.
Summary of the invention
Primary and foremost purpose of the present invention is to overcome the existing defect of existing photosensitizers, and the silicon phthalocyanine of the modified with folic acid with targeting and high photosensitive activity is provided.
For achieving the above object, the present invention adopts following technical scheme:
The structure of the symmetrical substituted phthalocyanine silicon that axially contains the folic acid group provided by the present invention is as the formula (1):
Formula (1)
What above formula represented is the silicon phthalocyanine title complex axially replaced, and silicon phthalocyanine or title silicon phthalocyanine, be the phthalocyanine complex that central ion is silicon.Phthalocyanine, English name phthalocyanine, be the abbreviation of four benzo tetraazatetradecane porphyrins.Axially substituting group connects by siloxane bond, wherein axial substituent R
1be selected from group shown in formula (2):
Formula (2)
The structure of the asymmetrically substituted phthalocyanines silicon that axially contains the folic acid group provided by the present invention is as the formula (3):
Formula (3)
In formula (3), R
1, R
2for substituting group, structure as the formula (4):
Formula (4)
The second purpose of the present invention is to provide the preparation method of above-mentioned silicon phthalocyanine compound.The preparation method of silicon phthalocyanine compound of the present invention comprises the following steps: (1) is under the protection of rare gas element, folic acid and dicyclohexylcarbodiimide are dissolved in the mixing solutions of dimethyl sulfoxide (DMSO) and triethylamine, under 10 ~ 40 ℃, react 12 ~ 24 hours, the molar ratio of dicyclohexylcarbodiimide and folic acid is 1:1.0 ~ 1.2, and solvent load is that every mmol reactant folic acid needs dimethyl sulfoxide (DMSO) 20 ~ 25ml and triethylamine 8 ~ 10ml;
(2) in the reaction solution of step (1), add 2-[4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (structure is as shown in Equation 5), its charging capacity is that every mole of folic acid needs 0.1 ~ 0.2 mole, under the protection of rare gas element, 10 ~ 40 ℃ are continued reaction 12 ~ 48h, obtain crude product;
Formula (5)
(3) by dialysis method or/and solvent method, remove excessive raw material and other impurity, by the chromatography release shaft to the symmetrical substituted phthalocyanine silicon that contains the folic acid group with axially contain the asymmetrically substituted phthalocyanines silicon of folic acid group, the acquisition target compound.
The 3rd purpose of the present invention is to provide above-mentioned silicon phthalocyanine compound for the preparation of photo-dynamical medicine or photosensitive medicament.Described photosensitive medicament, or be called for short photosensitizers, or claim the photosensitive drug preparation, be called again light power medicament.Prepared photo-dynamical medicine or photosensitive medicament, can be used for optical dynamic therapy, light power diagnosis or the sterilization of light power.Described optical dynamic therapy can be the optical dynamic therapy of malignant tumour, or carcinoid optical dynamic therapy, or the external smooth power purification treatment of leukemic marrow, or the optical dynamic therapy of non-Cancerous disease.Described non-Cancerous disease, can be that bacterium infects, or oral disease, or macular degeneration illness in eye, or arteriosclerosis, or wound infection, or tetter, or virus infection.Described smooth power sterilization can be the light power sterilization purification of blood or blood derivatives, or the light power sterilization of water, or light power sterilization medical or that live and use device.
The method that silicon phthalocyanine of the present invention prepares photosensitive medicament is: water, or the mixed solution of water and other material, wherein the massfraction of other material is not higher than 10%, as solvent, dissolve the modified with folic acid silicon phthalocyanine, be mixed with containing certain density photosensitive medicament, the concentration of modified with folic acid silicon phthalocyanine is not higher than its saturation concentration; In the solution of making, add antioxidant, buffer reagent and isotonic agent as additive chemical stability and the biocompatibility to keep photosensitive medicament; Described other material is one or more the miscellany in castor oil polyoxyethylene 35 ethers, methyl-sulphoxide, ethanol, glycerine, DMF, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
Beneficial effect of the present invention and outstanding advantage:
(1) silicon phthalocyanine provided by the invention has the height targeting.Contain folic acid in the axial modification group of silicon phthalocyanine provided by the invention, folacin receptor is specific expressed at many epithelial cancer cells (as ovarian cancer, carcinoma of endometrium, renal cancer, cancer of the stomach, lung cancer, mammary cancer, colorectal carcinoma) surface elevation, therefore, silicon phthalocyanine provided by the invention can be by the folate-mediated particular cancer of target in specific manner cell.In silicon phthalocyanine provided by the invention, between folic acid group and silicon phthalocyanine ring, by the bridging of amino-ethyl phenoxy group, this bridged group has following three advantages simultaneously: can effectively the folic acid group be connected on silicon phthalocyanine; Do not affect the specific recognition between folic acid and folacin receptor; Can avoid the impact of folic acid on the silicon phthalocyanine photosensitive activity.This bridged group just determines by a large amount of creative experiments, though some and the similar group of this bridged group, for example, amino-benzene oxygen, or ethyl phenoxy group, or amino-ethyl etc., also be found to have above three advantages simultaneously.
(2) maximum absorption wavelength of silicon phthalocyanine provided by the invention in the aqueous solution is positioned at the 690nm place, and molar absorption coefficient (reaches 10 greatly
5the order of magnitude), its spectral quality not only is better than first-generation photosensitizers greatly, and is better than carrying out other phthalocyanine complexes of clinical experiment.For example, the maximum absorption wavelength of silicon phthalocyanine compound provided by the invention with respect to the Pc4 red shift of the U.S. 14nm, treating spectrum can red shift 14nm, and the tissue penetration ability for the treatment of light is further enhanced, and this is very favourable for optical dynamic therapy and light power diagnosis.
(3), due to axial substituent existence, silicon phthalocyanine provided by the invention substantially forms and exists with monomer in the aqueous solution, has guaranteed the performance of its photodynamic activity.
(4) phthalocyanine complex structure provided by the invention clearly, location isomer not.
(5) the present invention selects the central ion of silicon as phthalocyanine complex, and the biological safety of silicon and biocompatibility are wanted the good ion common in other (zinc, aluminium, magnesium and gallium), and the quantum yield of silicon phthalocyanine generation active oxygen is high.
(6) prepare the required raw material of silicon phthalocyanine provided by the invention and be easy to get, preparation cost is low.
(7) modified with folic acid silicon phthalocyanine provided by the invention shows high photodynamic activity to the s with homofolic acid expression of receptor, kills the required drug level of 50% cancer cells and is low to moderate 29nM and 71nM.
Embodiment
The preparation method of modified with folic acid silicon phthalocyanine compound of the present invention; it is characterized in that: (1) under the protection of rare gas element; folic acid and dicyclohexylcarbodiimide are dissolved in dimethyl sulfoxide (DMSO) and triethylamine mixing solutions; under room temperature ~ 40 ℃, react 12 ~ 24 hours; the molar ratio of dicyclohexylcarbodiimide and folic acid is 1:0 ~ 1.2, and solvent load is that every mmol reactant folic acid needs methyl-sulphoxide 20 ~ 25ml, triethylamine 8 ~ 10ml.(2) in (1) gained reaction soln; add 2-[4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (structure is as shown in Equation 5) (charging capacity is that every mole of folic acid needs 0.1 ~ 0.2 mole); under the protection of rare gas element, reaction 12 ~ 48h is continued in room temperature ~ 40 ℃, obtains crude product.By dialysis method or/and solvent method, remove excessive raw material and other impurity, by the chromatography release shaft to the symmetrical substituted phthalocyanine silicon that contains the folic acid group with axially contain the asymmetrically substituted phthalocyanines silicon of folic acid group, the acquisition target compound.
Silicon phthalocyanine compound provided by the invention can be used for preparing photo-dynamical medicine or photosensitive medicament, and prepared photo-dynamical medicine can be applicable in optical dynamic therapy or light power diagnosis.Optical dynamic therapy of the present invention can be the optical dynamic therapy of malignant tumour, or carcinoid optical dynamic therapy, or the external smooth power purification treatment of leukemic marrow, or the optical dynamic therapy of non-Cancerous disease.Non-Cancerous disease of the present invention, can be that bacterium infects, or oral disease, or macular degeneration illness in eye, or arteriosclerosis, or wound infection, or tetter, or virus infection.
Silicon phthalocyanine compound provided by the invention can be used for preparing photo-dynamical medicine or photosensitive medicament, for the sterilization of light power, described smooth power sterilization can be the light power sterilization purification of blood or blood derivatives, or the light power sterilization of water, or light power sterilization medical or that live and use device.
The application of silicon phthalocyanine compound of the present invention in optical dynamic therapy, light power diagnosis and the sterilization of light power, need supporting suitable light source, described suitable light source can be connected that suitable spectral filter provides or be provided by the laser of specific wavelength by ordinary light source, the wavelength region of light source is 600～800nm, preferably 690nm.
The basic skills of utilizing silicon phthalocyanine of the present invention to prepare photo-dynamical medicine (being photosensitive medicament) is: make water, or the mixed solution (content of other material is not higher than 10%(wt%) of water and other material) as solvent, dissolve silicon phthalocyanine of the present invention, be mixed with containing certain density photosensitive medicament, the concentration of silicon phthalocyanine is not higher than its saturation concentration.Described other material can be following one or more mixed: castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N, dinethylformamide, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.In the solution of making, can add antioxidant, buffer reagent and isotonic agent as additive chemical stability and the biocompatibility to keep photosensitive medicament.
The preparation of using for topical, can be dissolved in silicon phthalocyanine of the present invention in the perviousness solvent, maybe will be injected in ointment, washing lotion or gel.The preferred 5-35%(wt% of described perviousness solvent) aqueous solution of methyl-sulphoxide.
The invention will be further described below to adopt non-limiting example.
Embodiment 1
Synthetic and the physico-chemical property of two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine (IV) (structure is shown below):
Under nitrogen protection; by phthalocyanine silicon dichloride (244.7mg; 0.4mmol); the 4-(2-amino-ethyl) phenol 1.2 ~ 2 mmol (preferably 1.6mmol) and NaH join toluene or dimethylbenzene or dioxane 27.2 ~ 32ml (preferred toluene; 30ml), reflux 18 ~ 24 hours (preferably 18 hours).Rotary evaporation in vacuo, except desolventizing, is used the 100ml methylene dichloride to dissolve, the centrifugal insolubles of removing, and dichloromethane solution water extraction (3 * 100ml), collected organic layer, then use dilute hydrochloric acid (0.1 ~ 0.5 mmol) extraction, collects water layer.With in 1M sodium hydroxide and water layer, separate out blue precipitation, centrifugal, washing, vacuum-drying, obtain blue product, productive rate 45%.The maximum absorption band of product in DMSO is positioned at 684 nm places, and the maximum absorption wavelength in the aqueous solution is positioned at the 689nm place.
The structural characterization data of product are as follows: MS(ESI) m/z:813.0 [M]
-;
1h NMR (DMSO-d6, ppm): δ 9.68 (m, 8H, Pc-H α), (8.54 m, 8H, Pc-H β), 5.40 (d, J=8.4 Hz, 4H, CHAr), 2.21 (d, J=8.3 Hz, 4H, CHAr), 1.97 (t, J=7.0 Hz, 4H, CH2), 1.70 (t, J=6.8 Hz, 4H, CH; IR(KBr, cm-1): 1607.9,1524,1429.3,1335.8,1290.8,1166.1,1122.9,1080.9,912.2,760.5,735.6,3054,3020,1504,2922.8,2851.5,1472,3434,3358.6,1252.3.
Embodiment 2
Axially contain the symmetrical substituted phthalocyanine silicon of folic acid group and axially contain the synthetic and physico-chemical property of the asymmetrically substituted phthalocyanines silicon (IV) of folic acid group:
The structure that axially contains the symmetrical substituted phthalocyanine silicon of folic acid group is shown below:
The structural formula of asymmetrically substituted phthalocyanines silicon that axially contains the folic acid group is as follows:
Under nitrogen protection; by folic acid (100mg; 0.23mmol) and dicyclohexylcarbodiimide 0.23-0.28mmol (preferably 0.23mmol) be dissolved in dimethyl sulfoxide (DMSO) 4-6ml (preferably 5ml) and the preferred 2ml of triethylamine 1.8-2.3ml() in mixing solutions, room temperature reaction 12-24 hour (preferably 16 hours).Remove by filter white insolubles, in filtrate, add 2-[4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine 0.023-0.046mmol (preferably 0.04mmol), under nitrogen protection, room temperature reaction 12-48 hour (preferably 24 hours).After reaction finishes, the centrifugal insolubles of removing, add reaction soln in 0 ℃ of ether (100ml) of vigorous stirring, filters, with ether (2 * 20ml) and methylene dichloride (2 * 20ml) filter wash cake.Filter cake is dissolved in methyl-sulphoxide (6ml), water is separated out, the precipitation obtained is dissolved with DMF, and take DMF as silicagel column collection second component and the 3rd component for eluent, after concentrating under reduced pressure, with the further separation and purification of gel column (Bio-Beads S-X3), obtain the symmetrical substituted phthalocyanine silicon (productive rate 10%) that axially contains the asymmetrically substituted phthalocyanines silicon of folic acid group and axially contain the folic acid group respectively.
The maximum absorption band of symmetrical substituted phthalocyanine silicon in DMSO that axially contains the folic acid group is positioned at 684 nm places, and the maximum absorption wavelength in the aqueous solution is positioned at the 690nm place.Its structural characterization data are as follows: MS(ESI) m/z:1659.2 [M]
-;
1h NMR (DMSO-d6, ppm): δ 11.46 (brs, 2H, NH), 9.70 – 9.60 (m, 8H, Pc-H α), 8.62 (s, 2H, CH, pteridine), 8.52 (dd, J=5.7,2.9 Hz, 8H, Pc-H
β), 7.49 (d, J=8.7 Hz, 4H, folate CH
ar), 6.56 (d, J=8.8 Hz, 4H, folate CH
ar), 5.39 (d, J=8.4 Hz, 4H, Pc CH
ar), 4.49 (d, J=6.2 Hz, 4H, CH
2nHPh), 4.10 – 4.00 (m, 2H, CH), 2.39 – 2.29 (m, 4H, folate CH
2), 2.19 (d, J=8.4 Hz, 4H, Pc CH
ar), 2.10 – 1.94 (m, 8H, Pc CH
2and folate CH
2), 1.73 (d, J=6.9 Hz, 4H, Pc CH
2).
The maximum absorption band of asymmetrically substituted phthalocyanines silicon in DMSO that axially contains the folic acid group is positioned at 684 nm places, and the maximum absorption wavelength in the aqueous solution is positioned at the 690nm place.The structural characterization data are as follows: MS(ESI): m/z 1237.2 [M+H]
+,
1h NMR (DMSO-d6, ppm): δ 9.70 – 9.63 (m, 8H, Pc-H α), 8.62 (s, 1H, CH, pteridine), 8.56 – 8.47 (m, 8H, Pc-H β), 7.56 (d, J=8.3 Hz, 2H, folate CHAr), 6.96 (d, J=8.4 Hz, 1H, NH), 6.57 (d, J=8.7 Hz, 2H, folate CHAr), 5.38 (d, J=8.5 Hz, 4H, Pc CHAr), 4.49 (d, J=5.6 Hz, 2H, CH2NHPh), 4.10 – 4.00 (m, H, CH), 2.38 (m, 2H, folate CH2), 2.25 – 2.14 (m, 6H, Pc CH2 and folate CH2), 1.89 (t, J=7.2 Hz, 4H, Pc CH2), 1.71 (t, J=6.9 Hz, 4H, Pc CH2).
In above-mentioned preparation process, utilize dialysis tubing (Spectra/Por tubing, MD 45, MW cutoff 1000) to carry out purifying to crude product, then by gel column, further separate, also can obtain target compound.
Embodiment 3
The method of utilizing silicon phthalocyanine of the present invention to prepare photo-dynamical medicine (or claiming photosensitive medicament) is: make water, or the mixed solution (content of other material is not higher than 10%(wt%) of water and other material) as solvent, dissolve silicon phthalocyanine of the present invention, be mixed with blue solution (being photosensitive medicament) uniformly, in photosensitive medicament, the concentration of silicon phthalocyanine is 0.08mM.Described other material can be following one or more mixed: castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N, dinethylformamide, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.Also can be first with hydrochloric acid or sulfuric acid or etc. acidic substance two [4-(2-amino-ethyl) phenoxy group] of the present invention silicon phthalocyanine is converted into to the form of salt, then use above-mentioned dissolution with solvents.In the solution of making, can add antioxidant, buffer reagent and isotonic agent as additive chemical stability and the biocompatibility to keep photosensitive medicament.
Silicon phthalocyanine of the present invention is dissolved in to 5-35%(wt%) aqueous solution of methyl-sulphoxide, can be used as the preparation that topical is used.
Embodiment 4
Photo-dynamical medicine, photosensitive medicament or photosensitizers that the present invention is prepared, at optical dynamic therapy, or light power diagnosis, or the using method in the sterilization of light power is identical with the using method of the photosensitive medicament that uses non-phthalocyanine of the present invention or porphyrin compound to prepare in prior art or photosensitizers, but need supporting suitable light source, described suitable light source can be connected that suitable spectral filter provides or be provided by the laser of specific wavelength by ordinary light source, the wavelength region of light source is 300-800nm, preferably 690nm.
Embodiment 5
The symmetrical substituted phthalocyanine silicon title complex that the present invention is axially contained to the folic acid group is dissolved in 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution, makes the photosensitive medicament of 0.08mM.Test their dark toxicity and photodynamic activities to human liver cancer cell HepG2 and human cervical carcinoma Hela cell.
The photosensitive medicament of 0.08mM is diluted in cell culture fluid, makes the cell culture fluid containing silicon phthalocyanine compound of different concns.Cancer cells is cultivated 2 hours respectively in the nutrient solution of the silicon phthalocyanine compound that contains different concns, abandoned thereafter nutrient solution, after cleaning cell with PBS, add new nutrient solution (not containing silicon phthalocyanine compound).The illumination experiment group, cell is carried out to red light irradiation, and (exciting light sources used is the ruddiness that wavelength is greater than 610nm, irradiates 30 minutes, and the power that irradiates light is 15mw * cm
-2); The irradiation group, be not placed in dark place 20 minutes by cell.After illumination or not illumination, the survival rate of cell adopts mtt assay to investigate.Concrete experimental procedure referring to "
bioorganic & Medicinal Chemistry Letters ", 2006,16,2450-2453.
The ruddiness that above-mentioned wavelength is greater than 610nm is that the halogen lamp by 500W connects heat insulation tank and strengthens in the spectral filter of 610nm and provide.
Result shows, if do not carry out illumination, the symmetrical substituted phthalocyanine silicon that the present invention axially contains the folic acid group does not does not kill and wound and the growth-inhibiting effect human liver cancer cell HepG2 and human cervical carcinoma Hela cell, shows that they do not have dark toxicity; If but carried out red light irradiation, the symmetrical substituted phthalocyanine silicon that the present invention axially contains the folic acid group would show the significantly high tumor cell viability that kills and wounds.By the concentration of investigation silicon phthalocyanine compound and the dose-effect relationship of cell survival rate, can obtain the toxic limit medium dose (IC under illumination condition
50, kill the required drug level of 50% cancer cells).Result shows, the present invention axially contains the IC of the symmetrical substituted phthalocyanine silicon of folic acid group to Hela cell and HepG2 cell
50value is respectively 71nM and 118nM, and its power of light to the Hela cell suppresses activity and is significantly higher than the HepG2 cell.The expression of s surface folacin receptor is abundanter, and there is not folacin receptor basically in the hepatoma Hep G 2 cells surface, illustrates that the symmetrical substituted phthalocyanine silicon that the present invention axially contains the folic acid group has folacin receptor mediated cancer cells targeting.
Change above-mentioned 1% castor oil derivative (Cremophor EL, the wt%) aqueous solution into 1% castor oil derivative (Cremophor EL, wt%) phosphate buffer soln (PBS), also can obtain same experimental result.
Embodiment 6
Change the silicon phthalocyanine compound in above-mentioned enforcement 5 into asymmetrically substituted phthalocyanines silicon title complex that the present invention axially contains the folic acid group, other conditions are constant, and result is as follows: the asymmetrically substituted phthalocyanines silicon title complex that the present invention axially contains the folic acid group does not have dark toxicity.But, under red light irradiation, show the significantly high tumor cell viability that kills and wounds, to the IC of Hela cell and HepG2 cell
50value is respectively 29nM and 103nM.The asymmetrically substituted phthalocyanines silicon title complex that the present invention axially contains the folic acid group suppresses activity to the light power of Hela cell and is significantly higher than the HepG2 cell, also illustrates that the asymmetrically substituted phthalocyanines silicon that the present invention axially contains the folic acid group has folacin receptor mediated cancer cells targeting.
Embodiment 7
The symmetrical substituted phthalocyanine silicon title complex that the present invention is axially contained to the folic acid group is dissolved in 1% castor oil derivative (Cremophor EL, wt%) PBS damping fluid, makes the photosensitive medicament of 0.1mM, tests their light power inhibition activity to fungi.Fungi is Candida albicans CMCC (F) C1a(Candida albicans, C. albicans).Under red light irradiation, (exciting light sources used is the ruddiness that wavelength is greater than 610nm, irradiates 30 minutes, and the power that irradiates light is 15mw * cm
-2), the present invention axially contains the symmetrical substituted phthalocyanine silicon title complex of folic acid group can 100% Killing Candida Albicans, and the solvent control group, irradiation group, not administration of an irradiation group all do not affect the growth of Candida albicans in an administration.
The foregoing is only preferred embodiment of the present invention, all equalizations of doing according to the present patent application the scope of the claims change and modify, and all should belong to covering scope of the present invention.
Claims (5)
1. a symmetrical substituted phthalocyanine silicon that axially contains the folic acid group, it is characterized in that: its structural formula is as follows:
Axial substituting group wherein
2. an asymmetrically substituted phthalocyanines silicon that axially contains the folic acid group, it is characterized in that: its structural formula is as follows:
Axial substituting group wherein
，
3. the preparation method of a modified with folic acid silicon phthalocyanine as claimed in claim 1 or 2, it is characterized in that: described preparation method comprises the following steps:
(1) under the protection of rare gas element, folic acid and dicyclohexylcarbodiimide are dissolved in the mixing solutions of dimethyl sulfoxide (DMSO) and triethylamine, under 10 ~ 40 ℃, react 12 ~ 24 hours, the molar ratio of dicyclohexylcarbodiimide and folic acid is 1:1.0 ~ 1.2, and solvent load is that every mmole reactant folic acid needs dimethyl sulfoxide (DMSO) 20 ~ 25ml and triethylamine 8 ~ 10ml;
(2), in the reaction solution of step (1), add 2-[4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, its charging capacity is that every mole of folic acid needs 0.1 ~ 0.2 mole, under the protection of rare gas element, 10 ~ 40 ℃ are continued reaction 12 ~ 48h, obtain crude product;
Described 2-[4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine, its structural formula is as follows:
(3) by dialysis method or/and solvent method, remove excessive raw material and other impurity, by the chromatography release shaft to the symmetrical substituted phthalocyanine silicon that contains the folic acid group with axially contain the asymmetrically substituted phthalocyanines silicon of folic acid group, the acquisition target compound.
4. the application of a modified with folic acid silicon phthalocyanine as claimed in claim 1 or 2 is characterized in that: for the preparation of photo-dynamical medicine or photosensitive medicament.
5. the application of modified with folic acid silicon phthalocyanine according to claim 4, it is characterized in that: the method for preparing photosensitive medicament is: water, or the mixed solution of water and other material, wherein the massfraction of other material is not higher than 10%, as solvent, dissolve the modified with folic acid silicon phthalocyanine, be mixed with containing certain density photosensitive medicament, the concentration of modified with folic acid silicon phthalocyanine is not higher than its saturation concentration; In the solution of making, add antioxidant, buffer reagent and isotonic agent as additive chemical stability and the biocompatibility to keep photosensitive medicament;
Described other material is one or more in castor oil polyoxyethylene 35 ethers, methyl-sulphoxide, ethanol, glycerine, DMF, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
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| CN103254223B (en) * | 2013-05-30 | 2015-04-15 | 福州大学 | Silicon phthalocyanine axially modified by aminoethyl phenoxyl and polyethylene glycol oligomer |
| CN103435639B (en) * | 2013-08-26 | 2016-01-27 | 福州大学 | Silicon phthalocyanine of the asymmetric modification of a kind of axial nucleosides and its preparation method and application |
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