CN102643280A - 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 them as the application of photosensitizers in optical dynamic therapy, light power diagnosis and the sterilization of light power.
Background technology
Phthalocyanine complex is one type of important functional material, and wherein, phthalocyanine complex is noticeable as the application prospect of photosensitizers in optical dynamic therapy (Photodynamic Therapy).
So-called optical dynamic therapy (or claim PDT) in fact, is the application that the photosensitization of photosensitizers (or claiming photosensitive drug) is reflected at medical field.Its mechanism is; Earlier photosensitizers is injected body, (this section waiting time be let medicine enrichment relatively in target body) after a period of time is with the rayed target body of specific wavelength (can be by interventional techniques such as optical fiber importing light source to endoceliac target); Be enriched in photosensitizers in the 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 of treatment cancer.With traditional therapy, to compare like surgical operation, chemotherapy, radiotherapy, the photodynamic therapy biggest advantage is to carry out selective destruction and needn't perform surgical operation cancerous tissue, and spinoff is little, thereby gets most of the attention.
Simultaneously, research in recent years shows that also PDT also can be treated non-Cancerous diseases such as infectation of bacteria, oral disease, degeneration of macula illness in eye, arteriosclerosis, wound infection and tetter effectively.Photosensitizers can also be used for the sterilization of light power, most importantly is used for the sterilization of water body, blood and blood derivatives.Simultaneously, utilizing the photoluminescent property of photosensitizers to carry out light power diagnosis, also is 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 disease; Scientific circles generally believe; Optical dynamic therapy will become the important therapy of 21 century, so, will become an important and tempting new high-tech industry as the photosensitizers of optical dynamic therapy core.
So far, get permission the formal clinically photosensitizers that uses and be mainly hematoporphyrin derivative.In states such as the U.S., Canada, Germany, Japan; What use is Photofrin (U.S. FDA is used for clinical anticancer in nineteen ninety-five official approval Photofrin), and it is the mixture of the porporino oligopolymer that from cow blood, extracts and carry out chemical modification.Hematoporphyrin derivative has shown certain curative effect; But also exposed critical defect: maximum absorption wavelength (380-420nm) is not at the red light district preferable to the tissue transmitance (650-800nm); The skin phototoxicity is big; Be mixture, form instability etc., thereby clinical application is restricted, so Development of New Generation photo-dynamical medicine (photosensitizers) is international research focus.
Maximum absorption wavelength is positioned at easy ruddiness zone through tissue, the photosensitization ability is strong, biocompatibility is high, the difficult characteristics such as (because of having axial substituting group) of assembling owing to have, 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 got into the I clinical trial phase.But, the complex synthetic route of Pc4, preparation cost is high, and poor stability 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 target property to tumor tissues and cancer cells.Therefore, press for the silicon phthalocyanine photosensitizers that the new photosensitive activity of screening is high, preparation is easy or have target property.Because the refinement of photosensitizers and optical dynamic therapy potential tremendous economic social value, great range of application and treatment focus, prepare more axial replacement silicon phthalocyanine title complexs with photosensitive activity is very necessary as drug candidate more.
What is worth mentioning is; States such as America and Europe, Japan strengthen the input of novel photosensitive agent and the infiltration dynamics of intellecture property one after another; In this case; Have only and pay much attention to have the exploitation of independent intellectual property right medicine and accelerate the patent protection paces, could guarantee autonomy and the commanding elevation of China at 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 defective of existing photosensitizers, and the silicon phthalocyanine of the modified with folic acid with target property and high photosensitive activity is provided.
For realizing above-mentioned purpose, 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 suc as formula shown in (1):
Formula (1)
What following formula was represented is axial substituted silicon phthalocyanine title complex, and silicon phthalocyanine or title silicon phthalocyanine are that central ion is the phthalocyanine complex of silicon.Phthalocyanine, English name phthalocyanine is the abbreviation of four benzo tetraazatetradecane porphyrins.Axially substituting group connects through siliconoxygen bond, wherein axial substituent R
1Be selected from group shown in the formula (2):
Formula (2)
The structure of the asymmetric substituted phthalocyanine silicon that axially contains the folic acid group provided by the present invention is suc as formula shown in (3):
Formula (3)
In the formula (3), R
1, R
2Be substituting group, structure is suc as formula shown in (4):
Formula (4)
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 may further comprise the steps: (1) is under the protection of rare gas element; Folic acid and NSC 57182 are dissolved in the mixing solutions of DMSO 99.8MIN. and triethylamine; 10 ~ 40 ℃ were reacted 12 ~ 24 hours down; The molar ratio of NSC 57182 and folic acid is 1:1.0 ~ 1.2, and solvent load is that every mmol reactant folic acid needs DMSO 99.8MIN. 20 ~ 25ml and triethylamine 8 ~ 10ml;
(2) in the reaction solution of step (1); Add 2-[4-(2-amino-ethyl) phenoxy] silicon phthalocyanine (structure is suc as formula shown in 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) through dialysis method or/and solvent method, removes excessive raw material and other impurity, through the chromatography release shaft to the symmetrical substituted phthalocyanine silicon that contains the folic acid group with axially contain the asymmetric substituted phthalocyanine silicon of folic acid group, the acquisition target compound.
The 3rd purpose of the present invention is to provide above-mentioned silicon phthalocyanine compound to be used to prepare photo-dynamical medicine or photosensitive medicament.Said photosensitive medicament, or be called for short photosensitizers, or claim the photosensitive drug preparation, be called light power medicament again.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 an infectation of bacteria, or oral disease, or degeneration of macula 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 medical or life is sterilized with the light power of 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, and dissolving modified with folic acid silicon phthalocyanine; Be mixed with and contain certain density photosensitive medicament, the concentration of modified with folic acid silicon phthalocyanine is not higher than its saturation concentration; In the solution of processing, add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament; Described other material is castor oil polyoxyethylene 35 ethers, methyl-sulphoxide, ethanol, glycerine, N, the miscellany of one or more in dinethylformamide, Liquid Macrogol-3000, Schardinger dextrins, glucose, tween, the YMS 2.
Beneficial effect of the present invention and outstanding advantage:
(1) silicon phthalocyanine provided by the invention has height target property.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 (like 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 through folate-mediated specificity ground target particular cancer cell.In silicon phthalocyanine provided by the invention, between folic acid group and the silicon phthalocyanine ring, through the bridging of amino-ethyl phenoxy, this bridged group has following three advantages simultaneously: can effectively the folic acid group be connected on the silicon phthalocyanine; Do not influence the specific recognition between folic acid and the folacin receptor; Can avoid the influence of folic acid to the silicon phthalocyanine photosensitive activity.This bridged group is just definite through a large amount of creative experiments, though some and the similar group of this bridged group, for example, amino-benzene oxygen, or ethyl phenoxy, or amino-ethyl etc., also coming to light 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 superior to first-generation photosensitizers greatly, and is superior to 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; Promptly treating spectrum can red shift 14nm, and the tissue penetration ability of treatment light is further enhanced, and this is that ten minutes is favourable for optical dynamic therapy and light power diagnosis.
(3) owing to axial substituent existence, silicon phthalocyanine provided by the invention forms with monomer basically in the aqueous solution and exists, and 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 it is good for other common ion (zinc, aluminium, magnesium and gallium) that the biological safety of silicon and biocompatibility are wanted, and silicon phthalocyanine produces the quantum yield height of active oxygen.
(6) the required raw material of preparation silicon phthalocyanine provided by the invention is easy to get, and 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: ⑴ is under the protection of rare gas element; Folic acid and NSC 57182 are dissolved in DMSO 99.8MIN. and the triethylamine mixing solutions; Room temperature ~ 40 ℃ following reaction 12 ~ 24 hours, the molar ratio of NSC 57182 and folic acid is 1:0 ~ 1.2, solvent load is that every mmol reactant folic acid needs methyl-sulphoxide 20 ~ 25ml, triethylamine 8 ~ 10ml.⑵ in (1) gained reaction soln; Add 2-[4-(2-amino-ethyl) phenoxy] silicon phthalocyanine (structure is suc as formula shown in 5) (charging capacity is that every mole of folic acid needs 0.1 ~ 0.2 mole); Under the protection of rare gas element, room temperature ~ 40 ℃ continuation reaction 12 ~ 48h obtains crude product.⑶ or/and solvent method, removes excessive raw material and other impurity through dialysis method, through the chromatography release shaft to the symmetrical substituted phthalocyanine silicon that contains the folic acid group with axially contain the asymmetric substituted phthalocyanine 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 the 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 an infectation of bacteria, or oral disease, or degeneration of macula 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; Be used 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 medical or life is sterilized with the light power of 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 provided by the laser of specific wavelength by ordinary light source; The wavelength region of light source is 600～800nm, preferred 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 is as solvent; Dissolve silicon phthalocyanine according to the invention; Be mixed with and contain 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, Schardinger dextrins, glucose, tween, YMS 2.In the solution of processing, can add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament.
Preparation for topical is used can be dissolved in silicon phthalocyanine of the present invention in the perviousness solvent, maybe will be injected in ointment, washing lotion or the gel.The aqueous solution of the preferred 5-35% of said perviousness solvent (wt%) methyl-sulphoxide.
Below adopt non-limiting example that the present invention is described further.
Embodiment 1
Synthetic and the physico-chemical property of two [4-(2-amino-ethyl) phenoxy] silicon phthalocyanine (IV) (structure is shown below):
Under nitrogen protection; With phthalocyanine silicon dichloride (244.7mg, 0.4mmol), 4-(2-amino-ethyl) phenol 1.2 ~ 2 mmol (preferred 1.6mmol) and NaH join toluene or YLENE or dioxane 27.2 ~ 32ml (preferred toluene; 30ml), reflux 18 ~ 24 hours (preferred 18 hours).Rotary evaporation in vacuo removes and desolvates, and uses the dissolving of 100ml methylene dichloride, the centrifugal insolubles of removing, and (3 * 100ml), collected organic layer is used Hydrogen chloride (0.1 ~ 0.5 mmol) extraction to the extraction of dichloromethane solution water then, collects water layer.With in the 1M sodium hydroxide and water layer, separate out blue deposition, centrifugal, washing, vacuum-drying, 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 following: 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 asymmetric substituted phthalocyanine 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 asymmetric substituted phthalocyanine silicon that axially contains the folic acid group is following:
Under nitrogen protection; With folic acid (100mg; 0.23mmol) and NSC 57182 0.23-0.28mmol (preferred 0.23mmol) be dissolved in DMSO 99.8MIN. 4-6ml (preferred 5ml) and triethylamine 1.8-2.3ml (preferably 2ml) mixing solutions room temperature reaction 12-24 hour (preferred 16 hours).Remove by filter white insolubles, in filtrating, add 2-[4-(2-amino-ethyl) phenoxy] silicon phthalocyanine 0.023-0.046mmol (preferred 0.04mmol), under the nitrogen protection, room temperature reaction 12-48 hour (preferred 24 hours).After reaction finished, the centrifugal insolubles of removing added reaction soln in 0 ℃ of ether (100ml) of vigorous stirring, filtered, with ether (2 * 20ml) and methylene dichloride (2 * 20ml) filter wash cakes.Filter cake is dissolved in the methyl-sulphoxide (6ml); Water is separated out; The deposition that obtains is dissolved with DMF; And be that eluent is collected second component and the 3rd component with silicagel column with DMF, respectively behind the concentrating under reduced pressure, axially contained the asymmetric substituted phthalocyanine silicon of folic acid group and axially contained the symmetrical substituted phthalocyanine silicon (productive rate 10%) of folic acid group with the further separation and purification of gel column (Bio-Beads S-X3).
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 following: 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), and 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 asymmetric 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.The structural characterization data are following: 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) that crude product is carried out purifying, further separate through gel column then, 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 is as solvent; Dissolve silicon phthalocyanine according to the invention; Be mixed with blue solution (being photosensitive medicament) uniformly, the concentration of silicon phthalocyanine is 0.08mM in the photosensitive medicament.Described other material can be following one or more mixed: castor oil derivative (Cremophor EL), methyl-sulphoxide, ethanol, glycerine, N; Dinethylformamide, Liquid Macrogol-3000, Schardinger dextrins, glucose, tween, YMS 2.Also can be earlier with hydrochloric acid or sulfuric acid or etc. acidic substance two [4-(2-amino-ethyl) phenoxy] of the present invention silicon phthalocyanine is converted into the form of salt, use above-mentioned dissolution with solvents then.In the solution of processing, can add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament.
Silicon phthalocyanine of the present invention is dissolved in the aqueous solution of 5-35% (wt%) 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 method for use of the photosensitive medicament of the non-phthalocyanine of the present invention of utilization or porphyrin compound preparation in the method for use in the light power sterilization and the prior art or photosensitizers is identical, but the supporting suitable light source of need, and described suitable light source can be connected that suitable spectral filter provides or provided by the laser of specific wavelength by ordinary light source; The wavelength region of light source is 300-800nm, preferred 690nm.
Embodiment 5
The symmetrical substituted phthalocyanine silicon title complex that the present invention is axially contained the folic acid group is dissolved in 1% castor oil derivative, and (Cremophor EL wt%) in the aqueous solution, processes 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 the cell culture fluid, processes the cell culture fluid that contains silicon phthalocyanine compound of different concns.Cancer cells was cultivated 2 hours in the nutrient solution of the silicon phthalocyanine compound that contains different concns respectively, abandoned nutrient solution thereafter, behind PBS cleaning cell, add new nutrient solution (not containing silicon phthalocyanine compound).Illumination experimental group, pair cell are carried out red light irradiation, and (used exciting light sources is the ruddiness of wavelength greater than 610nm, shines 30 minutes, and the power of irradiates light is 15mw * cm
-2); The irradiation group did not place the dark place 20 minutes with cell.After illumination or the 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.
Above-mentioned wavelength is that halogen lamp through 500W connects the spectral filter that heat insulation tank adds greater than 610nm and provides greater than the ruddiness of 610nm.
The result shows that 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.Through 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, promptly kill the required drug level of 50% cancer cells).The result shows that 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 light power 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 liver cancer HepG2 cell surface, explains that the symmetrical substituted phthalocyanine silicon that the present invention axially contains the folic acid group has folacin receptor mediated cancer cells target property.
(Cremophor EL, wt%) aqueous solution changes 1% castor oil derivative into (Cremophor EL, wt%) phosphate buffer soln (PBS) also can obtain same experimental result with above-mentioned 1% castor oil derivative.
Embodiment 6
Change the silicon phthalocyanine compound in the above-mentioned enforcement 5 into asymmetric substituted phthalocyanine silicon title complex that the present invention axially contains the folic acid group, other conditions are constant, and the result is following: the asymmetric substituted phthalocyanine 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 asymmetric substituted phthalocyanine 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, explains that also the asymmetric substituted phthalocyanine silicon that the present invention axially contains the folic acid group has folacin receptor mediated cancer cells target property.
Embodiment 7
The symmetrical substituted phthalocyanine silicon title complex that the present invention is axially contained the folic acid group is dissolved in 1% castor oil derivative, and (Cremophor EL wt%) in the PBS damping fluid, processes the photosensitive medicament of 0.1mM, tests their the light power of fungi is suppressed active.Used fungi is Candida albicans CMCC (F) C1a (Candida albicans, C. albicans).(used exciting light sources is the ruddiness of wavelength greater than 610nm, shines 30 minutes, and the power of irradiates light is 15mw * cm under red light irradiation
-2), the symmetrical substituted phthalocyanine silicon title complex that the present invention axially contains the folic acid group can 100% be killed Candida albicans, and solvent control group, an administration irradiation group, not administration of an irradiation group all do not influence the growth of Candida albicans.
The above is merely preferred embodiment of the present invention, and all equalizations of doing according to claim of the present invention change and modify, and all should belong to covering scope of the present invention.
Claims (5)
1. symmetrical substituted phthalocyanine silicon that axially contains the folic acid group, it is characterized in that: its structural formula is as follows:
Wherein axial substituting group
2. asymmetric substituted phthalocyanine silicon that axially contains the folic acid group, it is characterized in that: its structural formula is as follows:
Wherein axial substituting group
3. the preparation method of a modified with folic acid silicon phthalocyanine according to claim 1 or claim 2, it is characterized in that: described preparation method may further comprise the steps:
(1) under the protection of rare gas element; Folic acid and NSC 57182 are dissolved in the mixing solutions of DMSO 99.8MIN. and triethylamine; 10 ~ 40 ℃ were reacted 12 ~ 24 hours down; The molar ratio of NSC 57182 and folic acid is 1:1.0 ~ 1.2, and solvent load is that every mmol reactant folic acid needs DMSO 99.8MIN. 20 ~ 25ml and triethylamine 8 ~ 10ml;
(2) in the reaction solution of step (1), add 2-[4-(2-amino-ethyl) phenoxy] 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] silicon phthalocyanine, its structural formula is as follows:
(3) through dialysis method or/and solvent method, removes excessive raw material and other impurity, through the chromatography release shaft to the symmetrical substituted phthalocyanine silicon that contains the folic acid group with axially contain the asymmetric substituted phthalocyanine silicon of folic acid group, the acquisition target compound.
4. the application of a modified with folic acid silicon phthalocyanine according to claim 1 or claim 2 is characterized in that: be used to prepare 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, and wherein the massfraction of other material is not higher than 10%; As solvent; Dissolving modified with folic acid silicon phthalocyanine is mixed with and contains certain density photosensitive medicament, and the concentration of modified with folic acid silicon phthalocyanine is not higher than its saturation concentration; In the solution of processing, add inhibitor, buffer reagent and isotonic agent as chemicalstability and the biocompatibility of additive to keep photosensitive medicament;
Described other material is castor oil polyoxyethylene 35 ethers, methyl-sulphoxide, ethanol, glycerine, N, the miscellany of one or more in dinethylformamide, Liquid Macrogol-3000, Schardinger dextrins, glucose, tween, the YMS 2.
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