CN105859912A - Chondroitin sulfate derivative of nano-methotrexate and preparation method and application of chondroitin sulfate derivative - Google Patents
Chondroitin sulfate derivative of nano-methotrexate and preparation method and application of chondroitin sulfate derivative Download PDFInfo
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- CN105859912A CN105859912A CN201610288963.5A CN201610288963A CN105859912A CN 105859912 A CN105859912 A CN 105859912A CN 201610288963 A CN201610288963 A CN 201610288963A CN 105859912 A CN105859912 A CN 105859912A
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- chondroitin sulfate
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
Abstract
The invention discloses a chondroitin sulfate derivative of nano-methotrexate and a preparation method and application of the chondroitin sulfate derivative and relates to the technical field of synthesis methods and application of methotrexate derivatives. According to the method, 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride is dissolved in a chondroitin sulfate water solution to obtain an activated solution, an acidic methotrexate water solution and the activated solution are mixed to obtain a reactivated mixed solution, and lastly the reactivated mixed solution is put in ultrapure water for dialysis and freeze-drying to obtain the chondroitin sulfate derivative of nano-methotrexate. The preparation method is simple, cost is low, the product can be used for preparing an injection for preventing, treating and stopping osteolytic bone lesions caused by malignant tumors, treating hypercalcemia and reducing bone resorption.
Description
Technical field
The present invention relates to methotrexate derivatives, particularly to chondroitin sulfate derivatives and the preparation method and use thereof of a kind of methotrexate.
Background technology
Malignant tumor has become as the disease of a class serious harm human physical and mental health, brings heavy financial burden to society.Nearly 20 annual morbidities of China rise 69%, annual newly-increased pathogenesis of cancer example 2,200,000, just have one to die from cancer in every five the dead.Along with China living standard improve bring diet, life style, working method, the problem such as aged tendency of population, the sickness rate of cancer raises year by year.Study new cancer therapy drug and reduce the focus that existing toxicity of anticancer agents is Medical research.
The duplication of DNA and RNA and reparation need to utilize tetrahydrofolic acid as substrate to complete these important biochemical reaction.Tetrahydrofolic acid is carried out biosynthesis by folic acid reductase reduction folic acid in vivo.Methotrexate (MTX) is folacin, is a class anti-metabolism antitumor drug.MTX can be combined with folic acid reductase, is blocked the formation of tetrahydrofolic acid by competitive inhibition, thus suppresses the synthesis of DNA, RNA, albumen and thymidylic acid.Methotrexate is widely used in chorionic epithelioma, malignant mole, all kinds of acute leukemia, various soft tissue sarcoma, psoriasis etc..Can also be as immunosuppressant treatment rheumatoid disease.Heavy dose of venoclysis methotrexate is one of critical treatment scheme of chemotherapy of patients, but the bone marrow depression that the methotrexate of heavy dose brings, liver function injury, renal function injury and mucosa lesions still bring problem to clinic.
Following formula is structure of methotrexate formula:
Following formula is folic acid structure formula:
Chondroitin sulfate be (CS) be a Sulfated glycosaminoglycans of class, be distributed widely in extracellular matrix and the cell surface of animal tissue, be distributed mainly in cartilage, bone, blood vessel wall, tendon and sarolemma.By D-Glucose aldehydic acid and N-acetyl-D-galactose with 1,3 glycosidic bonds form disaccharide unit, and relative molecular mass is generally 25000～30000.With regard to degree, sulfate and two species diversity for the distribution in isomerized sugar aldehydic acid chain again, present the inhomogeneity of height.Chondroitin sulfate and the interaction of multiple proteins molecule.Chondroitin sulfate is used for treating osteoarthritis, chronic cystitis, enhancing immunologic function, treatment silver snow disease, anticoagulation antithrombotic, atherosclerosis, protection and repair of neuron, treatment chronic god essence inflammation, and more and more research proves that the absorption of external source CS can play the effect for the treatment of cancer.
Following formula is the structural formula of chondroitin sulfate:
The patent documentation of Publication No. CN 104371009 A provides a kind of GnRH polypeptide-methotrexate conjugate, Preparation Method And The Use, and this invention provides a kind of pharmaceutical composition containing methotrexate, increases the targeting of medicine.The patent documentation of Publication No. CN 104667279 A reduces the toxicity of methotrexate by adjuvant administering drug combinations.
But, it is high to there is cost of material in these prior aries, and technique makes complexity, and operation requires the problems such as loaded down with trivial details, thus cannot large-scale production.
Summary of the invention
It is an object of the invention to overcome drawbacks described above, develop a kind of chondroitin sulfate derivatives.
Chondroitin sulfate derivatives of the present invention is the nanosphere of the chondroitin sulfate modified with methotrexate, and the structural formula of the chondroitin sulfate derivatives of described nanometer methotrexate is:
In above formula, m is the amount of the chondroitin sulfate loop structure not connecting methotrexate, and m is the integer of 20～300；N is the amount of the chondroitin sulfate loop structure connecting methotrexate, and n is the integer of 22～150.
The present invention can be made into injection, and the disease aspects such as preventing and treating, treatment chorionic epithelioma, malignant mole, all kinds of acute leukemia, various soft tissue sarcoma, psoriasis are had curative effect.The present invention can improve methotrexate permeability in vivo, reduces the medicine zest to mucosa, and makes methotrexate slowly discharge, and reduces methotrexate side effect in vivo, improves human rehabilitation treatment level, improves patient medication safe mass.
Heretofore described chondroitin sulfate includes the one in chondroitin sulfate A (CS-A), chondroitin sulfate C (CS-C), chondroitin sulfate D (CS-D) or chondroitin sulfate E (CS-E).These concrete materials are the different substituents group of chondroitin sulfate.
The present invention also proposes the preparation method of the chondroitin sulfate derivatives of above nanometer methotrexate.
Preparation method step of the present invention is:
1) by the aqueous solution of 4-(4,6-dimethoxy-triazine-2-base)-4-methyl morpholine hydrochloride vitriolization chrondroitin, activated solution is obtained；
2) aqueous solution of acid methotrexate is mixed with activated solution, through magnetic agitation, obtain re-activation mixed liquor；
3) re-activation mixed liquor is placed in ultra-pure water dialysis, lyophilizing, obtains the chondroitin sulfate derivatives of nanometer methotrexate.
The present invention is with 4-(4,6-dimethoxy-triazine-2-base)-4-methyl morpholine hydrochloride is couplant, with the amino in methotrexate, the carboxylic acid sodium after activation in chondroitin sulfate is coupled into amido link the two combined, so that methotrexate is modified on chondroitin sulfate, form nanosphere.
The present invention directly modifies methotrexate by chemical method, and this methotrexate modified model medicine not only preparation method is simple, and low cost, raw material is simple and easy to get, low to technological requirement, can be with large-scale production.
In order to connect more methotrexate on chondroitin sulfate, the nanoparticle of formation can wrap up more medicine, and the mixing mol ratio of described chondroitin sulfate and methotrexate is 1: 1～20.
In order to activate carboxylic group as much as possible, being conducive to connecting more methotrexate, molten and methotrexate the mixing mol ratio of described 4-(4,6-dimethoxy-triazine-2-base)-4-methyl morpholine hydrochloride is 1.2: 1.
In order to the fastest gives unwanted impurity, changing water at first three every 2h of dialysis, every 4h changes a water afterwards.
In order to activate carboxyl as much as possible, in described step 1), described 4-(4,6-dimethoxy-triazine-2-base)-4-methyl morpholine hydrochloride is 1.2: 1 with the mixing mol ratio of chondroitin sulfate in the aqueous solution of chondroitin sulfate.
Third object of the present invention is: propose the application of the chondroitin sulfate derivatives of nanometer methotrexate, for preparing preventing and treating, the osteolytic lesion stoping malignant tumor to cause, treatment hypercalcemia, the injection of minimizing bone resorption.
This injection can significantly reduce the vigor of tumor cell, the propagation of suppression tumor cell.
Accompanying drawing explanation
Fig. 1 is that the atom that the nanoparticle that embodiment 1 obtains is dispersed in water is tried hard to.
Fig. 2 is that the atom that the nanoparticle that embodiment 2 obtains is dispersed in water is tried hard to.
Fig. 3 is methotrexate, the concentration of methotrexate-chondroitin sulfate and the graph of a relation of tumor cell activity.
Detailed description of the invention
For the more complete feature introducing the present invention, it is further described by the methotrexate containing amino and the chondroitin sulfate newtype drug reacting generation and preparation method thereof and the application in terms of chorionic epithelioma, malignant mole, all kinds of acute leukemia, various soft tissue sarcoma, psoriasis of this medicine below in conjunction with being embodied as case.
One, the preparation of the chondroitin sulfate derivatives of methotrexate:
Embodiment 1:
1,1.0g chondroitin sulfate is dissolved in 20mL ultra-pure water.
4-(4,6-dimethoxy-triazine-2-the base)-4-methyl morpholine hydrochloride of 0.769g is dissolved in the solution that step (1) obtains, activates 30min.
2, the methotrexate of 1.2g is dissolved in the ultra-pure water of 10mL, and regulation pH is that acidity is to being completely dissolved.
3, solution step (3) obtained adds in the solution after step (2) activation, is placed in magnetic stirrer reaction 5h.
4, pouring in bag filter by reactant liquor after 5h, dialyse in ultra-pure water 48h, every 4h change a water.
5, after 48h, solution lyophilizing in the bag filter of step (5) gained is obtained wanted target product.
6, to target product analysis, its structural formula is as follows:
In above formula, m is: the integer of 20～300；N is: the integer of 22～150.
Embodiment 2:
1,53.2mg chondroitin sulfate is dissolved in 5mL ultra-pure water.
2,4-(4,6-dimethoxy-triazine-2-the base)-4-methyl morpholine hydrochloride of 40.91mg is dissolved in the solution that step (1) obtains, activates 30min.
3, the methotrexate of 63.84mg is dissolved in the ultra-pure water of 5mL, and regulation pH is that acidity is to being completely dissolved.
4, solution step (3) obtained adds in the solution after step (2) activation, is placed in magnetic stirrer reaction 6h.
5, pouring in bag filter by reactant liquor after 6h, dialyse in ultra-pure water 48h, every 4h change a water.
6, after 48h, solution lyophilizing in step (5) gained bag filter is obtained wanted target product.
7, target product is analyzed, analyzes its structural formula as follows:
In above formula, m is: the integer of 20～300；N is: the integer of 22～150.
Two, the product made by atomic force microscope checking both the above embodiment:
As shown in Figure 1, 2, the chondroitin sulfate derivatives nanosphere diameter of the methotrexate that two examples are made is about 200nm, for nanosized product.
Three, application:
1, the chondroitin sulfate derivatives injection of nanometer methotrexate is made:
The chondroitin sulfate of a kind of methotrexate spreads out the injection that thing is prepared as, including the phosphate buffered saline(PBS) of PH 7.4 and be scattered in the chondroitin sulfate derivatives of nanometer methotrexate of phosphate buffered saline(PBS), wherein the concentration of the chondroitin sulfate derivatives of nanometer methotrexate is 1mg/ml.
2, application and the result:
In order to verify the chondroitin sulfate derivatives inhibitory action to tumor cell of nanometer methotrexate.Methotrexate, methotrexate-chondroitin sulfate treatment is given 48 hours with Hela cell, observation of cell vigor, and calculate cell viability situation by MTT experiment well-known in the art, obtain Fig. 3 result.
In Fig. 3, curve " methotrexate " represents: curve represents the growing state of the dosage suppression tumor cell of methotrexate variable concentrations, and cell viability is the lowest, and to represent inhibition the best.
In Fig. 3, curve " methotrexate-chondroitin sulfate " represents: curve represents the growing state of the dosage suppression tumor cell of methotrexate-chondroitin sulfate variable concentrations, and cell viability is the lowest, and to represent inhibition the best.
As seen from Figure 3, the chondroitin sulfate derivatives of nanometer methotrexate prepared by the employing present invention, the chondroitin sulfate derivatives injection making nanometer methotrexate can significantly reduce the vigor of tumor cell, the propagation of suppression tumor cell.
Visible, use osteolytic lesion, treatment hypercalcemia that the injection made of the present invention can be used for preventing and treating, stoping malignant tumor to cause, reduce bone resorption, or be used for preventing and treating, treating the diseases such as chorionic epithelioma, malignant mole, all kinds of acute leukemia, various soft tissue sarcoma, psoriasis.
Claims (9)
1. the chondroitin sulfate derivatives of a nanometer methotrexate, it is characterised in that described chondroitin sulfate derivatives is the nanosphere of the chondroitin sulfate modified with methotrexate, and the structural formula of the chondroitin sulfate derivatives of described nanometer methotrexate is:
In above formula, m is: the integer of 20～300；N is: the integer of 22～150.
The chondroitin sulfate derivatives of nanometer methotrexate the most according to claim 1, it is characterized in that, described chondroitin sulfate includes the one in chondroitin sulfate A (CS-A), chondroitin sulfate C (CS-C), chondroitin sulfate D (CS-D) or chondroitin sulfate E (CS-E).
3. the preparation method of the chondroitin sulfate derivatives of nanometer methotrexate as claimed in claim 1, it is characterised in that comprise the following steps:
1) by the aqueous solution of 4-(4,6-dimethoxy-triazine-2-base)-4-methyl morpholine hydrochloride vitriolization chrondroitin, activated solution is obtained；
2) aqueous solution of acid methotrexate is mixed with activated solution, through magnetic agitation, obtain re-activation mixed liquor；
3) re-activation mixed liquor is placed in ultra-pure water dialysis, lyophilizing, obtains the chondroitin sulfate derivatives of nanometer methotrexate.
The preparation method of the chondroitin sulfate derivatives of nanometer methotrexate the most according to claim 3, it is characterised in that described chondroitin sulfate includes the one in chondroitin sulfate A (CS-A), chondroitin sulfate C (CS-C), chondroitin sulfate D (CS-D) or chondroitin sulfate E (CS-E).
5. according to the preparation method of the chondroitin sulfate derivatives of nanometer methotrexate described in claim 3 or 4, it is characterised in that the mixing mol ratio of described chondroitin sulfate and methotrexate is 1: 1～20.
6. according to the preparation method of the chondroitin sulfate derivatives of nanometer methotrexate described in claim 3 or 4, it is characterized in that molten and methotrexate the mixing mol ratio of described 4-(4,6-dimethoxy-triazine-2-base)-4-methyl morpholine hydrochloride is 1.2: 1.
The preparation method of the chondroitin sulfate derivatives of nanometer methotrexate the most according to claim 3, it is characterised in that every 2～6h change a water in dialysis procedure.
The preparation method of the chondroitin sulfate derivatives of nanometer methotrexate the most according to claim 3, it is characterized in that in described step 1), described 4-(4,6-dimethoxy-triazine-2-base)-4-methyl morpholine hydrochloride is 1.2: 1 with the mixing mol ratio of chondroitin sulfate in the aqueous solution of chondroitin sulfate.
9. the application of the chondroitin sulfate derivatives of nanometer methotrexate as claimed in claim 1, for preparing preventing and treating, the osteolytic lesion stoping malignant tumor to cause, treatment hypercalcemia, the injection of minimizing bone resorption.
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Citations (5)
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|---|---|---|---|---|
| US4489065A (en) * | 1981-07-02 | 1984-12-18 | Valcor Scientific Ltd. | Chondroitin drug Complexes |
| CN101289482A (en) * | 2007-09-29 | 2008-10-22 | 辽宁利锋科技开发有限公司 | Cambogic acid glycoside derivates and the like, preparation and uses thereof |
| CN102125547A (en) * | 2010-12-22 | 2011-07-20 | 中国药科大学 | Pharmaceutical composition containing gambogic acid medicament and preparation method thereof |
| CN102772823A (en) * | 2012-07-25 | 2012-11-14 | 华南理工大学 | Preparation method of hyaluronic acid/gelatin/chondroitin sulfate bone repair bionic scaffold |
| CN103301472A (en) * | 2013-04-28 | 2013-09-18 | 中国药科大学 | Amphiphilic polysaccharide-anti-tumor medicament conjugate capable of releasing medicines specifically at lesion site of living body, as well as preparation method and application of medicinal composition of amphiphilic polysaccharide-anti-tumor medicament conjugate |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4489065A (en) * | 1981-07-02 | 1984-12-18 | Valcor Scientific Ltd. | Chondroitin drug Complexes |
| CN101289482A (en) * | 2007-09-29 | 2008-10-22 | 辽宁利锋科技开发有限公司 | Cambogic acid glycoside derivates and the like, preparation and uses thereof |
| CN102125547A (en) * | 2010-12-22 | 2011-07-20 | 中国药科大学 | Pharmaceutical composition containing gambogic acid medicament and preparation method thereof |
| CN102772823A (en) * | 2012-07-25 | 2012-11-14 | 华南理工大学 | Preparation method of hyaluronic acid/gelatin/chondroitin sulfate bone repair bionic scaffold |
| CN103301472A (en) * | 2013-04-28 | 2013-09-18 | 中国药科大学 | Amphiphilic polysaccharide-anti-tumor medicament conjugate capable of releasing medicines specifically at lesion site of living body, as well as preparation method and application of medicinal composition of amphiphilic polysaccharide-anti-tumor medicament conjugate |
Non-Patent Citations (2)
| Title |
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| MATTEO D"ESTE ET AL.: "A systematic analysis of DMTMM vs EDC/NHS for ligation of amines to Hyaluronan in water", 《CARBOHYDRATE POLYMERS》 * |
| MUNETAKAKUNISHIMA ET AL.: "Synthesis and characterization of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride", 《TETRAHEDRON LETTERS》 * |
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