CN108503726A - A kind of phthalocyanine-chitosan oligosaccharide conjugate and the preparation method and application thereof - Google Patents
A kind of phthalocyanine-chitosan oligosaccharide conjugate and the preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of phthalocyanine chitosan oligosaccharide conjugates and the preparation method and application thereof, belong to pharmaceutical preparation field.The phthalocyanine chitosan oligosaccharide conjugate is monosubstituted carboxyl class ZnPc and the conjugate of chitosan oligosaccharide or the quaternary ammonium derivative of its conjugate, can be applied to light power antibacterial, light power anticancer, light power diagnosis and photodynamic disinfection.Phthalocyanine chitosan oligosaccharide conjugate of the present invention can have the function that synergistic treatment due to the dual-functional group with phthalocyanine and chitosan oligosaccharide or chitooligosaccharidequaternary quaternary ammonium salt in light power antibacterial；Chitosan oligosaccharide has excellent water solubility and biocompatibility simultaneously, can be effectively improved the amphipathic and biocompatibility of phthalocyanine, and reduce the toxicity of phthalocyanine, improve the clinical value of phthalocyanine.
Description
Technical field
The invention belongs to pharmaceutical preparation fields, and in particular to a kind of phthalocyanine-chitosan oligosaccharide conjugate and preparation method thereof with answer
With.
Background technology
Optical dynamic therapy（Or photodynamic therapy）, substantially it is photosensitizer（Or photosensitive class drug）Photosensitive reaction
In the application of medical domain.Its general mechanism is that photosensitizer is first injected into body, after a period of time（Drug is in target body
In opposite enrichment）, shot at the target body position with the illumination of specific wavelength（Target can import light source by optical fiber etc. in body cavity）, make enrichment
Photosensitizer in target body is excited under light illumination, produces a series of optical physics chemical reactions, and generation can destroy target
Body（Such as microbiological contamination position and cancer cell, tissue etc.）Substance, such as：Active oxygen, singlet oxygen etc..The key of optical dynamic therapy exists
In photosensitizer, however the first photosensitizer Photofrin ratified from nineteen ninety-five U.S. FDA is applied to clinical cancer therapy extremely
The present, the photosensitizer for being approved clinically formally to use is seldom, is mainly exposed in clinical application due to photosensitizer very much
Defect, such as：Dark toxicity height, poorly water-soluble, tissue penetration force difference, targeting deficiency and stability deficiency etc..Therefore, exploitation is new
The photosensitizer with good clinical effect of type becomes urgent problem to be solved.
Phthalocyanine（phthalocyanine）, it is the abbreviation of four benzo tetraazatetradecane porphyrins, is attributed to second generation photosensitizer, by
In its stability is high, optical physics chemical property is excellent, is constantly subjected to pay much attention to certain penetrating power.But mesh
There are still shortcomings for preceding reported biologically active phthalocyanine complex, such as：Lack that amphipathic, dark toxicity is high, raw
Object is selectively bad, complex synthetic route etc., and limits its clinical application.People by various load means, as polymer,
Nucleic acid and protein etc., it is intended to solve defect of the phthalocyanine in clinical application.
Chitosan is a kind of linear hydrophilic polysaccharide obtained by the degradation of chitin that nature derives from a wealth of sources, including the Portugals D-
Polidexide and N- acetyl group-D- two kinds of units of dextran amine.Chitosan oligosaccharide is nontoxic, non-immunogenicity, and has good biofacies
Capacitive.Meanwhile containing more active group on chitosan molecule skeleton（The hydroxyl on amino and 6, carbon on 2, carbon）, it is
Further modification provides platform, thus by extensive concern, in particular for as drug carrier material.In addition, chitosan
It since itself shows positive charge, can effectively interact, and show with the negative electrical charge residue of antimicrobial surface
Certain antibacterial activity.Chitosan oligosaccharide is the oligomer that degradation of chitosan obtains, other than having the excellent activity of chitosan, also
It shows the no advantageous property of many chitosans, such as good water-soluble and antibacterial activity etc., but is directed to property at present
More excellent chitosan oligosaccharide is seldom as the research of drug-loading system.
Invention content
The shortcomings that present invention is exposed for existing phthalocyanine clinical application, by with good characteristic（As good water solubility, can
Biodegradation, non-immunogenicity, nontoxic, modifiability and antibiotic property）Chitosan oligosaccharide as pharmaceutical carrier, provide a kind of phthalein
The preparation method and application of cyanines-chitosan oligosaccharide conjugate.Gained phthalocyanine-chitosan oligosaccharide conjugate shows good antibiotic property and high
Photodynamic activity, as photosensitizer apply have significant advantage.
To achieve the above object, the present invention adopts the following technical scheme that：
A kind of phthalocyanine-chitosan oligosaccharide conjugate, structural formula are following formula（I）~（IV）In any one：
,
,
,
。
The preparation method of the phthalocyanine-chitosan oligosaccharide conjugate includes the following steps：
1）With phthalocyanine compound（1）Or（2）It is reaction raw materials with chitosan oligosaccharide, dimethyl sulfoxide is solvent, 1- hydroxyls
The mixture of base benzotriazole, dicyclohexylcarbodiimide and 4-dimethylaminopyridine is condensation reagent, in ice-water bath and nitrogen
It is warming up to room temperature ~ 35 DEG C under protection, reaction 16 ~ for 24 hours, then column chromatography and exclusion chromatography is used to isolate and purify, obtains formula（I）
Or（III）Conjugate；
2）By formula（I）Or（III）Conjugate be dissolved in a small amount of dimethyl sulfoxide, isopropanol is added and is used as reaction dissolvent, in nitrogen guarantor
It is warming up to 65 ~ 80 DEG C under shield, the aqueous isopropanol of 2,3- epoxypropyltrimethylchloride chlorides is dripped in 1h, reaction 6~
10 h, are then isolated and purified using exclusion chromatography, and quaternized formula is obtained（Ⅱ）Or（IV）Conjugate.
The molecular weight of chitosan oligosaccharide used is 0.3 ~ 10kDa.
Step 1）The molar ratio of middle phthalocyanine compound and chitosan oligosaccharide number of repeat unit is 1:10~30；1- hydroxy benzos used
Triazole, dicyclohexylcarbodiimide, 4-dimethylaminopyridine and chitosan oligosaccharide number of repeat unit molar ratio be 0.5 ~
1.5mmol；Step 2）The molar ratio of middle 2,3- epoxypropyltrimethylchloride chlorides and free amine group in conjugate is 1 ~ 2:1.
The phthalocyanine-chitosan oligosaccharide conjugate can be used for preparing photo-dynamical medicine comprising light power anticancer drug, light power
Antibacterials, light power diagnosis agent and photodynamic disinfection agent etc..The optical dynamic therapy can be that the light power of malignant tumour is controlled
The optical dynamic therapy for the treatment of or carcinoid optical dynamic therapy or non-Cancerous disease.The non-Cancerous disease, can be with
It is bacterium infection or mouth disease or macular degeneration eye disease or artery sclerosis or wound infection or skin
Disease, or virus infection.The photodynamic disinfection can be blood or the light power sterilization purification or water of blood derivatives
Light power sterilization or medical or life device photodynamic disinfection.
Its application process is：Use water or water and the mixed solution of other materials as solvent, dissolving phthalocyanine-chitosan oligosaccharide coupling
Object is configured to corresponding medicament（The concentration of phthalocyanine-chitosan oligosaccharide conjugate is not higher than its saturated concentration in medicament）；In manufactured medicament
Antioxidant, buffer and isotonic agent can also be added, to keep the chemical stability and biocompatibility of photosensitive medicament；
The mass fraction of other materials is not higher than 10% in the mixed solution, and the other materials are castor oil derivative, two
First sulfoxide, ethyl alcohol, glycerine, N,N-dimethylformamide, Liquid Macrogol ~ 3000, cyclodextrin, glucose, tween, poly- second two
One or more of alcohol monostearate.
Beneficial effects of the present invention and outstanding advantage are：
（1）The preparation process of phthalocyanine provided by the invention-chitosan oligosaccharide conjugate is easy, easy to operate, reproducibility is high.
（2）It is the raw materials used in the present invention chitosan oligosaccharide abundance, cheap.
（3）Phthalocyanine-chitosan oligosaccharide conjugate prepared by the present invention can reduce the dark toxicity of phthalocyanine, can be obviously improved simple carboxylic
The water solubility of Assembling Behavior of the base phthalocyanine in water phase, especially quaternary ammonium derivative is more excellent.
（4）Phthalocyanine-chitosan oligosaccharide conjugate prepared by the present invention not only remains the photolytic activity of simple carboxyl zinc phthalocyanine,
Chitosan oligosaccharide or the excellent natural activity of its quaternary ammonium salt are saved, such as is combined to change with electronegative residue on bacterium cell envelope
Become wall permeability of the membrane and plays antibacterial effect.
（5）The antibacterial effect of phthalocyanine-chitosan oligosaccharide conjugate prepared by the present invention is notable, to Candida albicansCandida albicansIC90It can be far below the respective value of simple carboxyl zinc phthalocyanine down to 5 μM（IC90>50 μM）.
（6）Quaternized phthalocyanine-chitosan oligosaccharide conjugate prepared by the present invention can effective position in the line grain of fungal cell
Body has certain targeting, and simple phthalocyanine does not have notable orientation effect.
Specific implementation mode
A kind of phthalocyanine-chitosan oligosaccharide conjugate, preparation method includes the following steps：
1）With phthalocyanine compound（1）Or
（2）It is reaction raw materials with chitosan oligosaccharide（The molar ratio of phthalocyanine compound and chitosan oligosaccharide number of repeat unit is 1:10~30）, dimethyl sulfoxide
Mixture for solvent, I-hydroxybenzotriazole, dicyclohexylcarbodiimide and 4-dimethylaminopyridine is condensation reagent（1- hydroxyls
Base benzotriazole, dicyclohexylcarbodiimide, 4-dimethylaminopyridine and chitosan oligosaccharide number of repeat unit molar ratio be 0.5 ~
1.5mmol）, it is warming up to room temperature ~ 35 DEG C under ice-water bath and nitrogen protection, reaction 16 ~ for 24 hours, then use column chromatography and exclusion
Chromatography isolates and purifies, and obtains
Or；
2）By formula（I）Or（III）Conjugate be dissolved in a small amount of dimethyl sulfoxide, isopropanol is added and is used as reaction dissolvent, in nitrogen guarantor
It is warming up to 65 ~ 80 DEG C under shield, the aqueous isopropanol of 2,3- epoxypropyltrimethylchloride chlorides is dripped in 1h（2,3- epoxies
The molar ratio of hydroxypropyltrimonium chloride and free amine group in conjugate is 1 ~ 2:1）, 6~10 h are reacted, exclusion color is then used
Spectrometry isolates and purifies, and obtains
Or。
The phthalocyanine-chitosan oligosaccharide conjugate can be used for preparing photo-dynamical medicine comprising light power anticancer drug, light power
Antibacterials, light power diagnosis agent and photodynamic disinfection agent etc..The optical dynamic therapy can be that the light power of malignant tumour is controlled
The optical dynamic therapy for the treatment of or carcinoid optical dynamic therapy or non-Cancerous disease.The non-Cancerous disease, can be with
It is bacterium infection or mouth disease or macular degeneration eye disease or artery sclerosis or wound infection or skin
Disease, or virus infection.The photodynamic disinfection can be blood or the light power sterilization purification or water of blood derivatives
Light power sterilization or medical or life device photodynamic disinfection.
Phthalocyanine of the present invention-chitosan oligosaccharide conjugate is in optical dynamic therapy, light power antibacterial, light power diagnosis and photodynamic disinfection
In application, need mating suitable light source, the suitable light source that can connect suitable optical filter by ordinary light source to provide
Or provided by the laser of specific wavelength, the wave-length coverage of light source is 600~800nm, preferably 600-690nm.
Its concrete application method is：It uses water or water and the mixed solution of other materials as solvent, dissolves phthalocyanine-chitosan oligosaccharide
Conjugate is configured to corresponding medicament（The concentration of phthalocyanine-chitosan oligosaccharide conjugate is not higher than its saturated concentration in medicament）；The mixing
In solution the mass fraction of other materials be not higher than 10%, the other materials be castor oil derivative, dimethyl sulfoxide, ethyl alcohol,
Glycerine, N,N-dimethylformamide, Liquid Macrogol ~ 3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate
One or more of.Antioxidant, buffer and isotonic agent can also be added in manufactured medicament, to keep the change of photosensitive medicament
Learn stability and biocompatibility.
For the preparation of local administration, phthalocyanine of the present invention-chitosan oligosaccharide conjugate can be dissolved in penetrating solvents,
Or it is injected into ointment, washing lotion or gel.The dimethyl sulfoxide aqueous solution of the preferred 0.5-35wt% of penetrating solvents.
Using non-limiting embodiment below, the invention will be further described.
Embodiment 1
By 14.5 mg 1- [4- (2- carboxy ethyls) phenoxy group] phthalocyanine（1,0.02 mmol）And 54 mg 1- hydroxy benzos three
Azoles（0.4 mmol）With 41.2mg dicyclohexylcarbodiimides（DCC, 0.4 mmol）It is placed in 25 mL two mouth flasks, is added 2
ML dimethyl sulfoxides lead to N under condition of ice bath2It is protected from light stirring, 49mg 4-dimethylaminopyridine is added after 10 min（0.4 mmol）,
And the 60 mg chitosan oligosaccharides that 1 mL DMSO will be dissolved in（MW=2kDa, 0.4 mmol number of repeat unit）It is slowly dropped in reaction solution,
10 min are reacted under condition of ice bath, are then transferred into and are protected from light 16 h under room temperature.100 ~ 200 mesh silicagel columns are crossed, are first used
DMF：EA=1:5 as eluant, eluent washout impurity, then uses DMF instead：CH3COOH=50：1 eluant, eluent is eluted, and is collected corresponding
Efflux and be spin-dried for, with a small amount of water dissolution, cross glucan G-100 gels, collect first blue ribbon, concentrate, freeze-drying obtains 38
Mg blue meshes, as phthalocyanine（1）With the conjugate for the chitosan oligosaccharide that average molecular weight is 2 kDa（Ι）.According to ultraviolet-visible
The content that absorption spectrometry measures phthalocyanine in the conjugate is 2.47wt%.
The characterize data of product：1H NMR（400 MHz, DMSO）：δ 9.40（M, Pc-H α）, 8.97（S, Pc-H α）,
8.36-7.92（M, Pc-Hβ）, 7.80（S, Pc-Hβ）, 7.43（M, Ar-H）, 7.10（Bra ,-NH-）, 6.58（S, H1）, 5.48-
4.13（M, H3-H6, H6`）, 3.65 (s ,-NH2）, 2.70（T ,-CH2-）, 1.91（S ,-COCH3）.FT-IR（KBr, cm-1）：
3644-3136（-OH and -NH2or -NH-）；3068（- CH-, Pc）；2928,2852（-CH- and -CH2-）；1686
（Amide I, C=O）；1559（Amide II, NH）；1446（C=C）, 808 (Ar-H, para-position）；751（Zn-N）；
996（C-N, heterocyclic nitrogen）；1213,1073（C-O-C）.
Embodiment 2
By 30 mg embodiments, 1 gained phthalocyanine-chitosan oligosaccharide conjugate（Ι）(the free amine group of 0.194 mmol）It is dissolved in a small amount of diformazan
It in base sulfoxide, and is added drop-wise in 5 mL isopropanols, is warming up to 65 DEG C under nitrogen protection, be then added and be dissolved in advance in three times
59 mg in 1mL aqueous isopropanols（0.374 mmol）It is half small that interval is added dropwise in 2,3- epoxypropyltrimethylchloride chlorides every time
When, 8 h are reacted, reaction is stopped, G-100 sephadexes are crossed in concentration, collect the first blue ribbon, concentrated freeze-dried, obtain 39.8 mg
Blue reticular structure solid, as phthalocyanine（1）With the conjugate for the chitosan oligosaccharide that average molecular weight is 2 kDa（Ι）Quaternized spread out
Biology（Ⅱ）.The degree of substitution that quaternary ammonium root in the conjugate is measured according to nuclear magnetic resonance spectroscopy is 0.943（I.e. 1 chitosan repeats
0.943 quaternary ammonium root is connected on unit）.
The characterize data of product：1H NMR（400 MHz, DMSO）： δ 8.48-7.52（M, Pc-H）, 7.09（Br ,-
NH-）, 6.49-6.22（M, H1, Hb）, 5.61-3.68（M, H3-H6, H6`）, 3.28-3.18（M, Hc）, 3.15（S, N+（CH3）3）,
1.90（S ,-COCH3）.FT-IR（KBr, cm-1）：3653-3100（-OH and -NH2or -NH-）；3017（- CH-, Pc）；
2921,2852（-CH- and -CH2-）；1657（Amide I, C=O）；1574（Amide II, NH）；1478（-N（CH3）3 +）；
1415(C=C）, 812（Ar-H）；1149,1102,1054（C-O-C）；967（C-N, heterocyclic nitrogen）, 764
（Zn-N）.
Embodiment 3
By phthalocyanine used in embodiment 1（1）Replace with phthalocyanine（2）, remaining step is the same as embodiment 1, obtained phthalocyanine（2）Chitosan oligosaccharide
Conjugate（III）, and the content of phthalocyanine is 2.04wt% in conjugate.
The characterize data of product：1H NMR（400 MHz, DMSO） δ 9.51-9.30（M, Pc-H α）, 8.96（D,J=7.6
Hz, Pc-H α）, 8.22（M, Pc-Hβ）, 7.97（D,J=8.3 Hz, Pc-Hβ）, 7.53-7.33（Dd,J=7.6,7.2 Hz, Ar-
H）, 5.98（S, H1）, 5.52-3.57（M, H3-H6, H6ˊ）, 2.84（Dt,J=27.5,9.5 Hz, CH2-Pc/H2）, 2.36（D,J=
14.0 Hz, CH2-Pc）, 1.84（S ,-COCH3）, 1.54-1.19（M, CH2-Pc）.FT-IR（KBr, cm-1）：3608-3049（-
OH and -NH2or -NH-）；3109（- CH-, Pc）；2936,2871（-CH- and -CH2-）；1672（Amide I, C=
O）；1598（Amide II, NH）；1452（C=C）, 804 (Ar-H, para-position）；754（Zn-N）；939（C-N,
heterocyclic nitrogen）；1237,1091（C-O-C）.
Embodiment 4
By conjugate used in embodiment 2（I）Replace with 3 gained conjugate of embodiment（III）, remaining step is the same as embodiment 2, system
Obtain phthalocyanine（2）The quaternary ammonium derivative of chitosan oligosaccharide conjugate（IV）, it is also 0.943 to eventually detect its quaternized degree of substitution.
The characterize data of product：1H NMR（400 MHz, DMSO） δ 9.48-9.30（M, Pc-H α）, 8.90（D, Pc-H
α）, 8.28（M, Pc-Hβ）, 7.80（M, Pc-Hβ）, 7.50-7.31（M, Ar-H）, 6.01（M, H1, Hb）, 5.50-3.55（M, H3-
H6, H6ˊ）, 3.25（D,J=6.0 Hz Hc）, 3.14（S, N+（CH3）3）, 2.34（M, CH2）, 1.86-1.75 (m, CH2/-
COCH3）, 1.24,2.68（M, CH2）.FT-IR（KBr, cm-1）：3647-3106（-OH and -NH2or - NH-）；3019（-
CH-, Pc）；2929,2873（-CH- and -CH2-）；1652（Amide I, C=O）；1573（Amide II, NH）；1474（-N
（CH3）3 +）；1441(C=C）, 821（Ar-H）；1209,1133,1097（C-O-C）；962（C-N, heterocyclic
nitrogen）, 791（Zn-N）.
Embodiment 5
Photo-dynamical medicine is prepared using phthalocyanine-chitosan oligosaccharide conjugate and its quaternary ammonium derivative obtained by the present invention（I.e. photosensitive medicament）
Method be：With the mixed solution of water or water and other materials（The content of other materials is not higher than 10wt% in mixed solution）Make
For solvent, phthalocyanine-chitosan oligosaccharide conjugate and its quaternary ammonium derivative of the present invention are dissolved, the uniform medicament of au bleu is prepared（Medicament
A concentration of 0.1mM of middle phthalocyanine）；The other materials are castor oil derivative, dimethyl sulfoxide, ethyl alcohol, glycerine, N, N- dimethyl
One or more of formamide, Liquid Macrogol ~ 3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.
Antioxidant, buffer and isotonic agent can also be added in manufactured medicament, to keep the chemical stability and biology of photosensitive medicament
Compatibility.
Phthalocyanine-chitosan oligosaccharide conjugate and its quaternary ammonium derivative obtained by the present invention are dissolved in 0.5-35wt% dimethyl sulfoxides
Aqueous solution in, can be used as the preparation of local administration.
Embodiment 6
Photo-dynamical medicine, photosensitive medicament prepared by the present invention or photosensitizer, in light power anticancer, light power antibacterial, light power
In diagnosis and application method and prior art in photodynamic disinfection with described in non-present invention phthalocyanine-chitosan oligosaccharide conjugate and
The application method of photosensitive medicament or photosensitizer prepared by its quaternary ammonium derivative is identical, but needs mating suitable light source, described suitable
Suitable light source can be connected suitable optical filter to provide or be provided by the laser of specific wavelength, the wave of light source by ordinary light source
Long ranging from 600~800nm, preferably 600-690nm.
Embodiment 7
Conjugate prepared by embodiment 1,2（Ι）With quaternized conjugate（II）It is dissolved in DMSO solution, 1mM is made（With phthalocyanine
Meter）Photosensitive medicament, test to Candida albicansCandida albicansDark toxicity and photodynamic activity.
By the photosensitive medicament of above-mentioned preparation respectively with 106 CFU/mL bacteria suspensions mix, and the content of phthalocyanine is diluted to 5 respectively
μM, 10 μM, 20 μM and 50 μM, in 37 DEG C of incubator culture 3h, not plus conjugate and the bacteria suspension of phthalocyanine is added as a contrast
Group.In the feux rouges of >=610 nm（15mW/cm2）30 min of lower irradiation, after illumination, with the 20 μ L mixing of liquid-transfering gun quantitative
Bacteria suspension after diluting certain multiple, is uniformly coated on SDA media surfaces, and 37 DEG C of constant temperature are protected from light inversion culture, and 48 h of interval are seen
Examine counting.
Above-mentioned wavelength is to connect heat-insulated sink by the halogen lamp of 500W to increase in the filter of 610nm more than the feux rouges of 610nm
Mating plate provides.
The result shows that working as conjugate（Ι）Solution concentration when being up to 50 μM, if without illumination, to Candida albicans
It does not kill and growth inhibition effect；Likewise, quaternized conjugate（II）Solution concentration be up to 20 μM also almost without antibacterial
Phenomenon shows that they do not have dark toxicity.Under illumination condition, conjugate（Ι）With（II）IC90（Kill 90% Candida albicans
Drug concentration needed for bacterium）It is 9.15 μM and 4.63 μM respectively, and phthalocyanine（1）IC90But it is more than 50 μM, illustrates obtained by the present invention
Phthalocyanine-chitosan oligosaccharide conjugate has higher photodynamic activity.
Embodiment 8
The conjugate by embodiment 7 prepared by embodiment 3,4（III）With quaternized conjugate（IV）Carry out phototoxicity and dark poison
Property experiment.The results show that working as conjugate（III）Solution concentration when being up to 50 μM, if without illumination, to Candida albicans
It does not kill and growth inhibition effect；Likewise, quaternized conjugate（IV）Solution concentration be up to 20 μM also almost without antibacterial
Phenomenon, it was demonstrated that the dark toxicity of gained conjugate is relatively low；Under illumination condition, conjugate（III）With（IV）IC90Respectively
38.52 μM and 4.79 μM, and phthalocyanine（2）IC90But it is more than 50 μM, illustrates phthalocyanine-chitosan oligosaccharide conjugate obtained by the present invention again
With higher photodynamic activity.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification should all belong to the covering scope of the present invention.
Claims (5)
1. a kind of phthalocyanine-chitosan oligosaccharide conjugate, it is characterised in that：Its structural formula is following formula（I）~（IV）In any one：
,
,
,
。
2. a kind of method preparing phthalocyanine as described in claim 1-chitosan oligosaccharide conjugate, it is characterised in that：Including following step
Suddenly：
1）With phthalocyanine compoundOrIt is reaction raw materials with chitosan oligosaccharide, dimethyl sulfoxide is solvent, 1- hydroxyls
The mixture of benzotriazole, dicyclohexylcarbodiimide and 4-dimethylaminopyridine is condensation reagent, is protected in ice-water bath and nitrogen
It is warming up to room temperature ~ 35 DEG C under shield, reaction 16 ~ for 24 hours, then column chromatography and exclusion chromatography is used to isolate and purify, obtains formula（I）Or
（III）Conjugate；
2）With formula（I）Or（III）Conjugate be raw material, isopropanol is solvent, is warming up to 65 ~ 80 DEG C under nitrogen protection, drop
Add the aqueous isopropanol of 2,3- epoxypropyltrimethylchloride chlorides, react 6~10 h, then uses exclusion chromatography to detach pure
Change, obtains quaternized formula（Ⅱ）Or（IV）Conjugate.
3. the preparation method of phthalocyanine according to claim 2-chitosan oligosaccharide conjugate, it is characterised in that：Chitosan oligosaccharide used
Molecular weight is 0.3 ~ 10kDa.
4. the preparation method of phthalocyanine according to claim 3-chitosan oligosaccharide conjugate, it is characterised in that：Step 1）Middle phthalocyanine
The molar ratio of compound and chitosan oligosaccharide number of repeat unit is 1:10~30；I-hydroxybenzotriazole used, dicyclohexyl carbon two are sub-
The molar ratio of amine, 4-dimethylaminopyridine and chitosan oligosaccharide number of repeat unit is 0.5 ~ 1.5mmol；
Step 2）The molar ratio of middle 2,3- epoxypropyltrimethylchloride chlorides and free amine group in conjugate is 1 ~ 2:1.
5. a kind of phthalocyanine as described in claim 1-chitosan oligosaccharide conjugate is used to prepare the application in photo-dynamical medicine, feature
It is：The photo-dynamical medicine includes light power anticancer drug, light power antibacterials, light power diagnosis agent and photodynamic disinfection
Agent.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110511299A (en) * | 2019-09-09 | 2019-11-29 | 福州大学 | A kind of phthalocyanine-carboxymethyl chitosan carbohydrate conjugates and the preparation method and application thereof |
| CN111303167A (en) * | 2020-03-30 | 2020-06-19 | Tcl华星光电技术有限公司 | Color development material, optical filter and preparation method thereof |
| CN112618729A (en) * | 2021-01-19 | 2021-04-09 | 河南中医药大学 | Preparation method and application of tripterine-chitosan oligosaccharide coupling drug |
| CN113855844A (en) * | 2021-09-18 | 2021-12-31 | 军事科学院军事医学研究院环境医学与作业医学研究所 | Antibacterial material and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62162083A (en) * | 1986-01-13 | 1987-07-17 | 株式会社興人 | Fixing of phthalocyanine derivative |
| CN1898018A (en) * | 2003-12-22 | 2007-01-17 | 昭和电工株式会社 | Polysaccharide granular polymer formed wtih bonded phthalocyanine frame |
| CN105585571A (en) * | 2016-03-10 | 2016-05-18 | 福州大学 | Peripheral mono-substituted zinc phthalocyanine complex and doxorubicin conjugate thereof |
| CN105622682A (en) * | 2016-03-10 | 2016-06-01 | 福州大学 | Zinc(II) carboxyl phthalocyanine and adriamycin conjugate and preparation and application thereof |
| CN109293738A (en) * | 2016-03-10 | 2019-02-01 | 福州大学 | One kind has the Phthalocyanine Zinc adriamycin conjugate of phototherapy and chemotherapy Synergistic anti-cancer effect |
-
2018
- 2018-04-19 CN CN201810355821.5A patent/CN108503726B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62162083A (en) * | 1986-01-13 | 1987-07-17 | 株式会社興人 | Fixing of phthalocyanine derivative |
| CN1898018A (en) * | 2003-12-22 | 2007-01-17 | 昭和电工株式会社 | Polysaccharide granular polymer formed wtih bonded phthalocyanine frame |
| CN105585571A (en) * | 2016-03-10 | 2016-05-18 | 福州大学 | Peripheral mono-substituted zinc phthalocyanine complex and doxorubicin conjugate thereof |
| CN105622682A (en) * | 2016-03-10 | 2016-06-01 | 福州大学 | Zinc(II) carboxyl phthalocyanine and adriamycin conjugate and preparation and application thereof |
| CN109293738A (en) * | 2016-03-10 | 2019-02-01 | 福州大学 | One kind has the Phthalocyanine Zinc adriamycin conjugate of phototherapy and chemotherapy Synergistic anti-cancer effect |
Non-Patent Citations (2)
| Title |
|---|
| 邵宇飞等: ""壳聚糖与羧基酞菁锌复合物的制备及相关性质研究"", 《海峡药学》 * |
| 邵宇飞等: ""羧基酞菁锌与壳聚糖偶联物的制备"", 《福州大学学报（自然科学版）》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110511299A (en) * | 2019-09-09 | 2019-11-29 | 福州大学 | A kind of phthalocyanine-carboxymethyl chitosan carbohydrate conjugates and the preparation method and application thereof |
| CN110511299B (en) * | 2019-09-09 | 2021-09-28 | 福州大学 | Phthalocyanine-carboxymethyl chitosan conjugate and preparation method and application thereof |
| CN111303167A (en) * | 2020-03-30 | 2020-06-19 | Tcl华星光电技术有限公司 | Color development material, optical filter and preparation method thereof |
| CN112618729A (en) * | 2021-01-19 | 2021-04-09 | 河南中医药大学 | Preparation method and application of tripterine-chitosan oligosaccharide coupling drug |
| CN113855844A (en) * | 2021-09-18 | 2021-12-31 | 军事科学院军事医学研究院环境医学与作业医学研究所 | Antibacterial material and preparation method and application thereof |
| CN113855844B (en) * | 2021-09-18 | 2022-08-12 | 军事科学院军事医学研究院环境医学与作业医学研究所 | Antibacterial material and preparation method and application thereof |
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