CN102504603B - Conjugate of polymer and biological stain and preparation method and application thereof - Google Patents
Conjugate of polymer and biological stain and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a conjugate of a polymer and a biological stain and a preparation method and application of the conjugate. The conjugate has the formula G-X-B, wherein the polymer G is selected from the group consisting of glucans, fructosans, polymannuronic acid, polyguluronic acid, heteropolysaccharides, mono- or hetero-polysaccharides, mono- or hetero-polyuronic acid polysaccharides, mono- or hetero-polyuronic acid sulfate esters, hydrophilic alcohol high polymers, polylysine, polyglutamic acid and polyaspartic acid; the linking group X is a C1-C10 organic group; and the biological stain or a derivative B thereof may be toluidine blue, methylene blue, Evans blue, neutral red, Janus green or bright cresol purple. The conjugate can stain bilateral neck and submaxillary or submental lymphatic vessels and lymph nodes in New Zealand white rabbits by indirect lymph staining method, without diffusion in tongue body. No obvious toxic and adverse effects appear in all experimental animals in each group, and no obvious pathological changes appear in histological examination of internal organs.
Description
Technical field
The present invention relates to medical field, relate in particular to conjugates of a kind of polymer and biological stain and its production and use.
Background technology
Tumor therapeuticing method is mainly radiotherapy, chemotherapy, targeted therapy and surgical operation.The object of oncotherapy is mainly to obtain higher survival rate, reach this result and not only will excise thoroughly primary tumor in operation, and more important point is to prevent metastases.Wherein tumour cell can be shifted and be obtained numerous experimental results show that [Steven et al:Carcinogenesis 2006 by lymphsystem; 27 (9): 1729].If sentinel lymph node does not shift, the possibility that transfer occurs other lymphoglandula is very little, even if there is jumping characteristic to shift, its probability is also less than 1%[Shoaib et al:Cancer 2001; 91 (10): 2077].For preventing the transfer of tumour, in operation, often find outpost's lymph and excise selectively and clean [Wang Yongsheng: Chinese mastopathy magazine 2007; 1 (1): 5; Li Guojie etc.: medical information (operation credit volume) 2007; 20 (6): 535].Before operation, make the correct judgement of status of lymph node metastasis, the tram of determining lymphatic vessel and lymphoglandula in art is to carry out the key that lymph serum removes.Therefore the lymph traveling that solves each position is extremely important.Utilizing Imaging Technology observation and acquisition outpost's lymphatic vessel and lymphoglandula to distribute is the important method overcoming the above problems.
Lymphography is a kind of simpler, safe and reliable diagnostic method that checks lymph node pathological change, likely differentiates optimum reactive lymphadenectasis and lymphoglandula tumour.The conventional contrast medium of current clinical use is mainly small molecules contrast medium, can clearly observe blood vessel and pathological tissues, as CT contrast medium iopamidol, Schering AG), iopromide, Iomeprol, iopentol, ioversol etc., mri contrast agent gadodiamide and gadopentetic acid.Classical vital dye is observed as Patent indigo plant, methylenum coeruleum and Evant indigo plant are also widely used in lymphoglandula in addition.Although utilize small molecules contrast medium directly and indirect lymphography can make it be enriched in lymphoglandula and be detected [cold new etc.: practical clinical medical magazine 2008; 12 (4): 110; Ye Chuan etc.: modern Obstetric and Gynecologic Department progress 2006; 15 (5): 372-374], but still can not specific observations lymphatic vessel.
Lymphatic vessel cinclides footpath is obviously greater than vessel wall aperture.Therefore must prepare macromolecular contrast agent and staining agent can detect specifically lymphatic vessel and lymphoglandula.Development in recent years macromolecular contrast agent as dextran-DTPA-Gd[Desser et al:J Magn Reson Imaging 1994; 4:467], but only minority report is used for vasculolymphatic detection [Yan et al:Pharm Res 2010; 27:1884], the dye reagent detecting for the auxiliary lymph of performing the operation is not reported especially.
Summary of the invention
For the defect and the deficiency that exist being applied to contrast medium that lymphography used and staining agent in prior art, the invention provides the conjugates of a kind of polymer and biological stain, preparation method and the purposes in lymphatic vessel and lymphoglandula development thereof of described conjugates is also provided.Conjugates good water solubility provided by the invention, can permeate in vivo, energy specific detection lymphatic vessel and lymphoglandula; And development time is long, can provide sufficient clinical operation and observing time; And described conjugates does not have obvious Toxicity of Kidney and hepatotoxicity.
For achieving the above object, the present invention adopts following technical proposals to be achieved:
A conjugates for polymer and biological stain, it has the structure shown in following general formula (I):
G-X-B
(I)
Wherein: G is polymer, X is linking group, and B is biological stain and derivative thereof;
Described polymer is glucan, Polylevulosan class, polymannuronic acid class, guluronic acid class, assorted poly-polyose, list or assorted poly-Sulfate of polysaccharide class, list or heteroglycan aldehydic acid polyose, list or heteroglycan aldehydic acid sulfuric acid ester, wetting ability alcohols superpolymer, polylysine, polyglutamic acid or poly aspartic acid;
Described biological stain and derivative thereof are toluidine blue, methylenum coeruleum, AZO-blue, toluylene red, strong that green or bright cresyl viollet;
Described linking group is the organic group containing 1-10 carbon atom.
Further improvement to technical scheme: described glucan polymer is dextran, polymannuronic acid class is polymannuronic acid propyl ester sulfuric ester sodium salt, guluronic acid class is guluronic acid propyl ester sulfuric ester sodium salt, and heteroglycan aldehydic acid sulfuric acid ester is propylene glycol alginate sodium sulfate.
Further improvement to technical scheme: described linking group is carbonyl, malonyl, succinyl, maleoyl, fumaroyl base, glutaryl-, adipyl or diethylenetriamine penta-acetyl.
Further improvement to technical scheme: described polymer molecular weight ranges is 4,000-2000,000.
Further improvement to technical scheme: described biological stain and derivative thereof are preferably toluidine blue and/or AZO-blue.
Further improvement to technical scheme: described linking group is preferably succinyl.
Further improvement to technical scheme: the osmotic pressure in the described conjugates aqueous solution is 20-100mmol/L, particle diameter is 100-1000nm.
Saccharan described in the present invention also provides and the preparation method of biological stain conjugates, described method is: with dimethyl formamide, N,N-DIMETHYLACETAMIDE, HMPA, methyl-sulphoxide or methyl-2-pyrrolidone are solvent, under 0-30 ℃ of condition, triethylamine in 1-5 mol ratio, pyridine, diisopropyl ethyl amine, N-methylmorpholine, sodium bicarbonate, sodium hydroxide or 4-N, under the catalysis of N-dimethyl aminopyridine, the carbonyl dimidazoles of the biological stain of 1 mol ratio and 1-5 mol ratio, malonyl chloride, succinic chloride, maleoyl-chlorine, MALEIC ANHYDRIDE, fumaryl chloride, succinic acid list acyl chlorides, Succinic anhydried, glutaryl chlorine, glutaryl chlorine, Adipoyl Chloride, hexanodioic acid list acyl chlorides or diethylene triamine pentacetic acid (DTPA) anhydride reactant, prepare biological stain acylate,
By biological stain acylate dimethyl formamide, N,N-DIMETHYLACETAMIDE, HMPA, methyl-sulphoxide or methyl-2-pyrrolidone dissolve, N in 0.1-1 mol ratio, N-dicyclohexylcarbodiimide, N, N-DIC, benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate, two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride, carbonyl dimidazoles, 3-(diethoxy phosphoryl oxy)-1, 2, 3-phentriazine-4-ketone, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 2-(7-azo benzotriazole)-N, N, N, N-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N, under the catalysis of N-tetramethyl-urea hexafluorophosphate, the biological stain acylate of 0.1-1 mol ratio with by the polymer of sugar unit 1 mol ratio, react the conjugates of preparing polymer and biological stain.
Polymer described in the present invention also provides and biological stain conjugates are in the application for the preparation of in lymphographic contrast medium.
Further improvement to technical scheme: described polymer and biological stain conjugates are lyophilized injectable powder or aqueous injection.
Compared with prior art, advantage of the present invention and positively effect are: the good water solubility of the dextran that the present invention makes and toluidine blue conjugates, dextran and AZO-blue conjugates, propylene glycol alginate sodium sulfate and toluidine blue conjugates, propylene glycol alginate sodium sulfate and AZO-blue conjugates, polylysine and toluidine blue conjugates and polylysine and AZO-blue conjugates, can permeate in vivo; Utilize contrast agent molecule amount prepared by conjugates of the present invention to be greater than the small molecules contrast medium of current clinical use, can specific detection lymphatic vessel and lymphoglandula, and also development time is long, and can be provided sufficient clinical operation and observing time; And described conjugates does not have obvious Toxicity of Kidney and hepatotoxicity.
Embodiment
Below in conjunction with embodiment, technical scheme of the present invention is described in further detail.
The preparation of embodiment 1, toluidine blue acylate
Get toluidine blue (2.00g, 6.54mmol), Succinic anhydried (0.65g, 6.54mmol), DMAP (DMAP) (0.80g, 6.54mmol) is in 100ml two-mouth bottle, drying under reduced pressure 1 hour.Under nitrogen protection, add dry dimethyl formamide (DMF) 50ml, stirring at room reaction 10 hours, TLC detection reaction is complete.In reaction solution, add 500ml ethyl acetate, fully stir, filter, vacuum-drying obtains blue solid toluidine blue acylate 2.02g, yield 83.5%.
The preparation of embodiment 2, AZO-blue acylate
Get AZO-blue (2.00g, 2.08mmol), Succinic anhydried (0.42g, 4.19mmol), DMAP be DMAP (0.52g, 4.19mmol) in 100ml two-mouth bottle, drying under reduced pressure 1 hour.Under nitrogen protection, add dry DMF 50ml, stirring at room reaction 10 hours, TLC detection reaction is complete.In reaction solution, add 500ml ethyl acetate, fully stir, filter, vacuum-drying obtains blue solid AZO-blue acylate 1.8g, yield 80.1%.
Except toluidine blue and AZO-blue, described biological stain can also be other dyestuffs for cell or tissue dyeing such as methylenum coeruleum, toluylene red, strong that green or bright cresyl viollet.
The preparation of embodiment 3, dextran and toluidine blue conjugates
Get the described toluidine blue acylate (2.00g making; 4.92mmol); dextran 40 (2.40g, by glucose unit 14.81mmol), EDCHCl (1.42g; 7.39mmol); HOBt (1.00g, 7.39mmol), DMAP (1.20g; 9.86mmol) in 100ml there-necked flask, vacuum-drying 0.5 hour.Under ice bath, add dimethyl sulfoxide (DMSO) (DMSO) 50ml, ultrasonic dissolution, stirring at room reaction 12 hours, TLC detects, and reacts completely.In reaction solution, add 500ml ethyl acetate, stir 0.5 hour, filter, vacuum-drying obtains dextran and toluidine blue conjugates 3.32g productive rate is 75%.
The preparation of embodiment 4, dextran and AZO-blue conjugates
Get carbonyl dimidazoles (CDI) (0.54g, 3.35mmol) and be dissolved in 30ml DMSO, add AZO-blue acylate (1.80g, 1.67mmol), reaction solution at room temperature stirs and spends the night.Then add dextran (1.63g, 10.07mmol), the lower 80 ℃ of reactions of nitrogen protection 24 hours.TLC detects, and reacts completely, and reaction solution is poured in the ethyl acetate of 200ml, fully stirs, and filters.Filter cake is washed three times by ethyl acetate.Vacuum-drying obtains dextran and AZO-blue conjugates 2.12g, and productive rate is 81%.
The conjugates of the dextran that the present invention makes and the conjugates of toluidine blue and dextran and AZO-blue has significantly water-soluble, and the osmotic pressure in the aqueous solution is between 20-100mmol/L, and particle diameter is between 100-1000nm.
The preparation of embodiment 5, propylene glycol alginate sodium sulfate and toluidine blue conjugates
Get CDI (0.79g, 4.91mmol) and be dissolved in 50ml DMSO, add toluidine blue acylate (2.05g, 4.93mmol), reaction solution at room temperature stirs and spends the night.Then add propylene glycol alginate sodium sulfate (12.51g, 14.79mmol).The lower 80 ℃ of reactions of nitrogen protection 24 hours.TLC detects, and reacts completely, and reaction solution is poured into the ethyl acetate of 500ml, fully stirs, and filters.Filter cake is washed three times by ethyl acetate.Vacuum-drying obtains propylene glycol alginate sodium sulfate and toluidine blue conjugates 11.64g, and productive rate is 80%.
The preparation of embodiment 6, propylene glycol alginate sodium sulfate and AZO-blue conjugates
Get CDI (0.54g, 3.36mmol) and be dissolved in 50ml DMSO, add AZO-blue acylate (1.80g, 1.68mmol), reaction solution at room temperature stirs and spends the night.Then add propylene glycol alginate sodium sulfate (12.51g, 14.79mmol).The lower 80 ℃ of reactions of nitrogen protection 24 hours.TLC detects, and reacts completely, and reaction solution is poured into the ethyl acetate of 200ml, fully stirs, and filters, and filter cake is washed three times by ethyl acetate.Vacuum-drying obtains propylene glycol alginate sodium sulfate and AZO-blue conjugates 4.73g, and productive rate is 78%.
Embodiment 7, polylysine and toluidine blue conjugates preparation
Get CDI (0.79g, 4.91mmol) and be dissolved in 20ml DMSO, add toluidine blue acylate (2.05g, 4.93mmol), reaction solution at room temperature stirs and spends the night.Then add polylysine (1.91g, 14.67mmol).The lower 80 ℃ of reactions of nitrogen protection 24 hours.TLC detects, and reacts completely, and reaction solution is poured into the ethyl acetate of 500ml, fully stirs, and filters.Filter cake is washed three times by ethyl acetate.Vacuum-drying obtains polylysine and toluidine blue conjugates 3.09g, and productive rate is 78%.
The preparation of embodiment 8, polylysine and AZO-blue conjugates
Get CDI (0.54g, 3.36mmol) and be dissolved in 10ml DMSO, add AZO-blue acylate (1.80g, 1.68mmol), reaction solution at room temperature stirs and spends the night.Then add polylysine (1.91g, 14.67mmol).The lower 80 ℃ of reactions of nitrogen protection 24 hours.TLC detects, and reacts completely, and reaction solution is poured into the ethyl acetate of 200ml, fully stirs, and filters, and filter cake is washed three times by ethyl acetate.Vacuum-drying obtains polylysine and AZO-blue conjugates 4.73g, and productive rate is 78%.
The observation of indirectly developing of the conjugates of embodiment 9, dextran and toluidine blue
Get 30 of healthy new zealand white rabbits, body weight is 2.4～3.6kg.Be divided at random three groups, 10 every group.With ketamine (80mg/kg, 1.6ml) and diazepam (5mg/kg, 1ml) intramuscular anesthesia rabbit.Rabbit is fixed on rabbit operating table to row bilateral neck preserved skin ，Shu district 2.5% iodophor disinfection, the lignocaine local subcutaneous injecting anesthetic with 1.0%.In neck center, do stringer otch and be about 10cm, the separated subcutis in superficial layer fascia place, fully manifests under the interior arteriovenous of neck and bilateral neck, jaw and lymphonodi submentales, protects in neck and deep facial of neck in operation.Front two groups of dextran of the nearly lingual margin mucous membrane of row bilateral back hemostasis 1.0% (0.14mmol/L) and each 0.1ml of toluidine blue of toluidine blue conjugates and 1.0% (32.6mmol/L) respectively, injection zone does not all give the massage.The 1st station lymph arriving with dyeing lymphatic vessel is become sentinel lymph node (sentinel lymph node, SLN), observes dyeing time and the fading time of cervical lymphatics and SLN, and measures each dyestuff at the range of scatter of tongue body tissue.Each treated animal, after SLN dyeing, respectively painted 10 minutes (all before dyeing lymphatic vessel fades) and within 1 hour, respectively cut 2 rabbit bilateral neck SLN, and is fixed on row histopathological examination in 10.0% formaldehyde; All the other animals are sewed up the incision, and respectively at 1 day, the dyeing situation of observing afterwards SLN for 2 days, raise afterwards to put to death after 4 weeks and cut bilateral neck lymphoglandula, heart, lungs, liver and kidney and send pathological examination.Each treated animal is before experiment and raise after 4 weeks each venous blood samples detection routine blood test, gpt, glutamic-oxal(o)acetic transaminase, blood urea nitrogen and creatinine.The 3rd group of equal temporary interruption bilateral internal carotid artery, with the capable arteria carotis communis of remaining needle, inject respectively conjugates and each 1ml of toluidine blue solution of dextran and toluidine blue, observe tongue body tissue staining process and bilateral neck lymphoglandula dyeing situation, and respectively cut tongue body, lymphoglandula, muscle tissue, the capable histopathologic examination of submaxillary gland.Two kinds of dyestuffs all can dye lymphatic vessel and lymphoglandula by indirect lymph staining.
After row tongue body mucous membrane hemostasis, it is (21.667 ± 0.193) second that the conjugates group of dextran and toluidine blue arrives the required time of SLN, toluidine blue group is (3.219 ± 0.335) second, record data statistical analysis is known, conjugates group and the toluidine blue group of dextran and toluidine blue relatively have obvious prolongation, difference has statistical significance, P=0.000.The conjugates group lymphatic vessel of dextran and toluidine blue is (19.700 ± 1.337) minute from dyeing to the time of obviously fading, toluidine blue group is (14.300 ± 0.949) minute, known both differences of record data statistical analysis have statistical significance, P=0.000.It is (10.500 ± 1.080) mm that the conjugates group of dextran and toluidine blue is injected the latter 5 minutes scopes in tongue body diffusion, and toluidine blue group is (20.000 ± 1.054) mm, after 5 minutes, both scopes are without obvious expansion, both have statistical significance at difference, F=0.15, P=0.000.After 2 days, toluidine blue group lymphoglandula fades completely, and the still obviously dyeing after 4 weeks of the conjugates group of dextran and toluidine blue.
Embodiment 10, conjugates are to the secondary experiment of the poison of laboratory animal
Viewing duration is respectively organized laboratory animal and all without obvious toxicity, is occurred, data difference not statistically significant before and after every laboratory examination experiment, P > 0.05, the internal organs histological examination of censorship also has no obvious pathological change (table 1).Contrast injection site, toluidine blue group engrain obviously fades after being organized in 4 weeks, and the conjugates group injection site of dextran and toluidine blue is obviously dyeing still, but dyestuff is at the 4 weeks≤2mm of diffusion diameter of telasubmucosa.Difference not statistically significant, P > 0.05, the internal organs histological examination of censorship also has no obvious pathological change.Contrast injection site, toluidine blue group engrain obviously fades after being organized in 4 weeks, and the conjugates group injection site of dextran and toluidine blue is obviously dyeing still, but dyestuff is at the 4 weeks≤2mm of diffusion diameter of telasubmucosa.
Table 1: the main Comparison of experiment results of the conjugates of dextran and toluidine blue
Above embodiment is only in order to technical scheme of the present invention to be described, but not is limited; Although the present invention is had been described in detail with reference to previous embodiment, for the person of ordinary skill of the art, the technical scheme that still can record previous embodiment is modified, or part technical characterictic is wherein equal to replacement; And these modifications or replacement do not make the essence of appropriate technical solution depart from the spirit and scope of the present invention's technical scheme required for protection.
Claims (7)
1. a conjugates for polymer and biological stain, is characterized in that it has the structure shown in following general formula (I):
G-X-B
(I)
Wherein: G is polymer, X is linking group, and B is biological stain and derivative thereof;
Described polymer is glucan, Polylevulosan class, polymannuronic acid class, guluronic acid class, assorted poly-polyose, list or assorted poly-Sulfate of polysaccharide class, list or heteroglycan aldehydic acid polyose, list or heteroglycan aldehydic acid sulfuric acid ester; Described polymer molecular weight ranges is 4,000-2000,000;
Described biological stain and derivative thereof are toluidine blue, methylenum coeruleum, AZO-blue, toluylene red, strong that green or bright cresyl viollet;
Described linking group is carbonyl, malonyl, succinyl, maleoyl, fumaroyl base, glutaryl-, adipyl or diethylenetriamine penta-acetyl;
Osmotic pressure in the described conjugates aqueous solution is 20-100 mmol/L, and particle diameter is 100-1000 nm.
2. the conjugates of a kind of polymer according to claim 1 and biological stain, it is characterized in that described glucan polymer is dextran, polymannuronic acid class is polymannuronic acid propyl ester sulfuric ester sodium salt, guluronic acid class is guluronic acid propyl ester sulfuric ester sodium salt, and heteroglycan aldehydic acid sulfuric acid ester is propylene glycol alginate sodium sulfate.
3. the conjugates of a kind of polymer according to claim 1 and biological stain, is characterized in that described biological stain and derivative thereof are preferably toluidine blue and/or AZO-blue.
4. the conjugates of a kind of polymer according to claim 1 and biological stain, is characterized in that described linking group is preferably succinyl.
5. the preparation method of a saccharan according to claim 1 and biological stain conjugates, it is characterized in that described method is: with dimethyl formamide, N,N-DIMETHYLACETAMIDE, HMPA, methyl-sulphoxide or methyl-2-pyrrolidone are solvent, under 0-30oC condition, triethylamine in 1-5 mol ratio, pyridine, diisopropyl ethyl amine, N-methylmorpholine, sodium bicarbonate, sodium hydroxide or 4-N, under the catalysis of N-dimethyl aminopyridine, the carbonyl dimidazoles of the biological stain of 1 mol ratio and 1-5 mol ratio, malonyl chloride, succinic chloride, maleoyl-chlorine, MALEIC ANHYDRIDE, fumaryl chloride, succinic acid list acyl chlorides, Succinic anhydried, glutaryl chlorine, glutaryl chlorine, Adipoyl Chloride, hexanodioic acid list acyl chlorides or diethylene triamine pentacetic acid (DTPA) anhydride reactant, prepare biological stain acylate,
By biological stain dimethyl formamide, N,N-DIMETHYLACETAMIDE, HMPA, methyl-sulphoxide or methyl-2-pyrrolidone dissolving for acylate; under the carbonyl dimidazoles of 0.1-1 mol ratio or the catalysis of EDCHCl, HOBt and three kinds of couplings of DMAP, the biological stain acylate of 0.1-1 mol ratio with by the polymer of sugar unit 1 mol ratio, react the conjugates of preparing polymer and biological stain.
6. polymer according to claim 1 and biological stain conjugates are in the application for the preparation of in lymphographic contrast medium.
7. polymer according to claim 6 and biological stain conjugates, in the application for the preparation of in lymphographic contrast medium, is characterized in that described polymer and biological stain conjugates are lyophilized injectable powder or aqueous injection.
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| G.. Faulkner, 等.The use of fluorochromes for the identification of β(1→3) glucans.《Canadian Journal of Botany》.1973,第51卷(第8期),第1504页. |
| The use of fluorochromes for the identification of β(1→3) glucans;G.. Faulkner, 等;《Canadian Journal of Botany》;19730831;第51卷(第8期);第1504页 * |
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