CN103910872A - Doxorubicin structure-containing star-shaped polymer and preparation method and use thereof - Google Patents
Doxorubicin structure-containing star-shaped polymer and preparation method and use thereof Download PDFInfo
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Abstract
The invention discloses a doxorubicin structure-containing nonlinear star-shaped polymer and a preparation method and use thereof. The doxorubicin coupled star-shaped polymer has a better effect on treatment of age-related macular degeneration compared with drugs or medicaments in other forms.
Description
Technical field
The invention discloses the star polymer that contains Dx structure and preparation method and the purposes of this polymkeric substance.
Background technology
Dx is a kind of antimitotic and has Cytotoxic medicine.Dx can successfully suppress Several Kinds of Malignancy, comprises acute leukemia, lymphoma, soft tissue and osteosarcoma, children malignant tumors and becomes human solid tumor.Its mechanism of action is the penetrable cell that enters of medicine, is combined with karyomit(e).Thereby the planar rings in medicines structure is inserted between base pair and is combined with DNA and forms mixture, severe jamming DNA is synthetic, DNA dependent rna is synthetic and protein synthesis.But the drug level that produces tumor locus in the required Dx concentration ratio clinical treatment of anti-proliferative effect by this mechanism wants high.In addition Dx is also relevant with redoxomorphism, can participate in reaction and obtain cytotoxic compound, as hydroxy and the hydrogen peroxide etc. of superoxide, activity.The site of action of Dx may be at cytolemma, and Dx is not also reached common understanding in scientific circles for the pharmacodynamic action of various diseases at present, all there is no general character for the mechanism of action of every kind of disease, needs further scientific research to be explained.
Dx is widely used at present, but often needs to be become salt at Point of View of Clinical, and Dx common medicinal form is doxorubicin hydrochloride, needs to become hydrochloride, because the solubleness of Dx own is very low, does not transform the form of salify, cannot apply.And become after hydrochloride, the pharmacodynamics function of Dx declines to a great extent, and therefore this brings very large difficulty to clinical application.
Another shortcoming of Dx is due to strong cytotoxicity itself, therefore the toxicity of itself is very large, after using through being everlasting, within about 10 days, there is obvious bone marrow depression, use after one week, can show very significantly gastrointestinal side effect and cardiac toxic, therefore must after accurate calculation, could apply when medication, and the transformation period of this medicine is very short, brings limitation equally to application.
Preparation method of the present invention, can make the new texture that contains Dx of preparation dissolve in water, prolong half-life, and this preparation method has solved application limitation in the lump, and makes it in age-related macular degeneration disease, bring into play extraordinary action effect.
Summary of the invention
Of the present invention theing contents are as follows:
The star polymer that the invention discloses the Dx coupling shown in following formula I, its structure is as follows:
Structure Y is:
Wherein the molecular weight polyethylene glycol in polymkeric substance is 100-200000, the integer between W=1-500, the preferably integer between W=1-300, n=1-300, the preferably integer of 1-200.
It is characterized in that:
1) the sebacic acid reaction of the 6 arm polyoxyethylene glycol A that contain hydroxyl ending and ethanoyl obtains polymer B, the wherein integer of W=1-500, preferably 1-300; N=1-300, preferably 1-200;
2) polymer B is reacted and is obtained end product with Dx C;
P is
Compd A;
Wherein Structure G is:
Polymer B;
Dx C
Wherein Dx and the 6 arm polyoxyethylene glycol with hydroxyl ending are purchased.The required solvent of described chemical step of the final product of the synthetic new compound that contains Dx is selected from: one or more in benzene, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.
The compound of new system can be prepared into the nanometer formulation that is suitable for topical, microball preparation.Purposes is the medicine of preparation treatment age-related macular degeneration.
Preparation method of the present invention is specific as follows:
1) sebacic acid is refluxed in diacetyl oxide, form ethanoyl-sebacic acid;
2) ethanoyl-sebacic acid is mixed to reaction at 100-200 ℃, reaction times 10min to 10h with the 6 arm polyethylene glycol compound A that end up with hydroxyl; After question response mixture is cooling, washing, the dry polymer B that obtains;
3) by Dx C and polymer B as for 1-96 hour in solvent, after ultrasonic reaction 1-30 minute, in baking oven, foster and obtain formula I polymkeric substance, then homogenizer high-speed stirring 1-10 minute in subzero 30 ℃ of 0-, rotation volatilization obtains crude product, and aftertreatment obtains the nanometer formulation of end product formula I polymkeric substance.
Its reaction equation is as follows:
P is
Wherein Structure G is:
Then,
Wherein Structure G is:
Structure Y is:
The polymkeric substance that what the present invention obtained contain Dx structure, is easy to dissolve in water, and its transformation period extend much than Dx, such new compound effect in the time of the model for the treatment of age-related macular degeneration is splendid.
The nanometer formulation that the end product of preparing at this patent is made treatment eye disease relatively in, the medication effect of this patent new compound is very good, surmount the nanometer formulation that is directly wrapped up Dx (not with Dx coupling) by star polymer completely, also surmount the result for the treatment of of the nanometer formulation of being prepared by non-star polymer coupling Dx (polymkeric substance and Dx generation linked reaction, but polymkeric substance is non-star) completely.
Accompanying drawing explanation:
The nuclear magnetic resonance map of the end product of Fig. 1 embodiment 1.
The nanoparticle that Fig. 2 embodiment 1 makes; This reacts synthetic sebacic acid-ethylene glycol star polymer B and directly wraps up nanoparticle-associated doxorubicin; The nanoparticle (Dx with poly-sebacic acid-ethylene glycol polymer (non-star polymer), chemical coupling occurs and reacts the nanoparticle that the polymkeric substance of the non-star of containing Dx structure of gained is made) that Dx-poly-sebacic acid-single armed polyethylene glycol polymer is made after connecting; And medicine accumulative releasing degree and the time chart of Dx ordinary preparation.
Embodiment
Specific embodiment is described in further detail the present invention below, but the present invention not only limits to following examples.
Preparation Example is as follows:
Embodiment 1
1) mixture of sebacic acid 80g in 800ml diacetyl oxide refluxes, to form ethanoyl-sebacic acid;
2) by the 1st) step and put into flask with 6 arm polyoxyethylene glycol 14g Product mixes of hydroxyl ending, at 180 ℃, decompression contains intermingle with reaction 1 hour; Treat that polymkeric substance is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;
3) the 800mg polymkeric substance of 120mg Dx and step 2 is put into the dichloromethane solution 48 hours of 8ml dimethyl sulfoxide (DMSO) and 12ml; Ultrasonic 3 minutes; Then insert in baking oven 1 hour; In subzero 10-20 degree, homogenizer ultra-high speed stirs 3 minutes, then puts into 1% polyvinyl alcohol solution 600 and turns and stir 2 hours; Freeze-drying after centrifugal collection, obtains the nanoparticle of end product.
Embodiment 2
1) mixture of sebacic acid 100g in 900ml diacetyl oxide refluxes, to form ethanoyl-sebacic acid;
2) by the 1st) step and put into flask with 6 arm polyoxyethylene glycol 19g Product mixes of hydroxyl ending, at 180 ℃, decompression contains intermingle with reaction 1 hour; Treat that polymkeric substance is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;
3) the 1000mg polymkeric substance of 200mg Dx and step 2 is put into the dichloromethane solution 24 hours of 6ml dimethyl sulfoxide (DMSO) and 14ml; Ultrasonic 2 minutes; Then insert in baking oven 2 hours; In subzero 10 degree, homogenizer ultra-high speed stirs 2 minutes, then puts into 10% cholic acid solution 600 and turns and stir 3 hours; Freeze-drying after centrifugal collection, obtains the nanoparticle of end product.
Effect experiment is as follows:
Sample prepared by embodiment 1-2, the nanometer formulation (Dx with poly-sebacic acid-ethylene glycol polymer (non-star polymer), chemical coupling occurs and reacts nanoparticle prepared by the polymkeric substance of the non-star of containing Dx structure of gained) that Dx-poly-sebacic acid-single armed polyethylene glycol polymer is made after connecting, (there is not chemical coupling reaction in the star polymer B directly nanoparticle medicine group of the Dx of parcel, Dx does not have structural changes), Dx ordinary preparation (powder injection) carries out respectively stability test, the drug action test of drug release in vitro test and age-related macular degeneration.Stability test:
Star polymer B prepared by 1 group of sample of preparing of embodiment and this patent is the nanoparticle medicine group (not reacting with Dx) of the Dx of parcel directly, and Dx ordinary preparation is got with amount (in Dx) and measured respectively absorbance.Then put into 20 degree incubator 3 months for three groups, take out subsequently and measure 480 nanometer absorbances, the absorbance front and back of the Dx of the visible embodiment 1-2 group of result and ordinary preparation group are without changing, and the nanoparticle group absorbancy of parcel decline 21%.
Drug release in vitro test:
By 1 group of embodiment, the nanometer formulation of the polymkeric substance (Dx reacts the polymkeric substance of the non-star of containing Dx structure of gained with poly-sebacic acid-ethylene glycol polymer (non-star polymer) generation chemical coupling) that Dx-poly-sebacic acid-single armed polyoxyethylene glycol is made after connecting, (there is not chemical coupling reaction in the star polymer B directly nanoparticle medicine group of the Dx of parcel, Dx does not have structural changes), and Dx ordinary preparation component have another name called get equivalent medicine (in Dx, every group containing 10mg Dx), then by each group of medicine as in test tube, after soaking with PBS damping fluid, 37 degrees Celsius of lower joltings in shaking table, after timing sampling, under ultraviolet spectrophotometer, measure the content of medicine, and the medicament contg per-cent that after record, calculating discharges, do releasing curve diagram, X-coordinate be the time (my god), ordinate zou is the per-cent discharging.See Fig. 2, the medicine that visible embodiment discharges is more permanent, makes drug half-life longer.
Solubility test in water:
By embodiment 1-2 group, the nanometer formulation of the polymkeric substance (Dx reacts the polymkeric substance of the non-star of containing Dx structure of gained with poly-sebacic acid-ethylene glycol polymer (non-star polymer) generation chemical coupling) that Dx-poly-sebacic acid-ethylene glycol is made after connecting, (there is not chemical coupling reaction in the star polymer B directly nanoparticle medicine group of the Dx of parcel, Dx does not have structural changes), and Dx ordinary preparation component have another name called get equivalent medicine (in Dx, every group containing 100mg Dx), put into respectively test tube, with the dissolving of 10m1PBS damping fluid jolting, situation is dissolved in static rear observation.The dissolved state that records 3 minutes and 20 minutes, result is as follows.
The comparison of table 1 solubleness
The restraining effect of medicine to tela chorioidea's hyperplasia:
Get 120 of male rats, be divided at random 6 groups, be the polymkeric substance that control group, Dx-poly-sebacic acid-ethylene glycol is made after connecting (there is chemical coupling and react the polymkeric substance of the non-star of containing Dx structure of gained in Dx and poly-sebacic acid-ethylene glycol polymer (non-star polymer)) nanometer formulation group, (chemical coupling does not occur reacts the nanoparticle medicine group of Dx that star polymer B directly wraps up, Dx does not have structural changes), embodiment 1-2 group, Dx general formulation group.Each treated animal number is 20.Every rat is chosen a glance at random for experimental eye, and another eye is contrast eye.The equal intraocular injection 10 μ g medicines of each group or the medicine carrying prolonged action preparation containing 10 μ g medicines except control group, control group is given isopyknic PBS solution.
Use laser radiation rat eye, after light is solidifying, has Bubble formation or break up Bruch film with hyporrhea (sometimes with light sound) mark, be designated as available point.After laser photocoagulation, inject each group of medicine to rat right eye eyeball.14d after light is solidifying, tissues observed hyperplasia area also carries out histological examination.Result is as follows:
Table 2 retina and hyperplasia Area comparison (unit: mm of tela chorioidea
2)
With relatively * p < 0.05 of control group group, * * p < 0.01, with the comparison of ordinary preparation group
#p < 0.05,
##p < 0.01
The result of upper table shows, control group retina and choroid generation hyperplasia area are larger, each treatment group respectively different limits dwindled hyperplasia area.Experiment to rat part tissue of eye hyperplasia area shows, each embodiment group can reduce pathology retina and choroidal hamartoplasia area simultaneously, but effect difference to some extent, and the embodiment 1-2 group effect that coupling wherein occurs is better.
The result of histological examination is that under light microscopic, control group light coagulates the visible outer retina in spot place and choroid structure disturbance, retinal pigment epithelium, choroid cambium hyperplasia, free companion's inflammatory cell infiltration.Medicine group compared with control group, the rarely found and less companion's limitation of cambium serous detachment of retina; Embodiment group compares that superpolymer simply wraps up Dx and that the nanoparticle medicine group effect of linked reaction does not occur is more remarkable, and the compound after coupling can significantly reduce tela chorioidea's hyperplasia.Histological examination shows, embodiment group is more thorough to the treatment of age related maculopathy than the nanoparticle medicine group of ordinary preparation group, and retina and choroid to pathology play a role simultaneously.
Separately get the 5-6 female mice in age in week, mean body weight 25g, mouse is divided into 6 groups at random, it is control group, the nanometer formulation group of the polymkeric substance (Dx reacts the polymkeric substance of the non-star of containing Dx structure of gained with poly-sebacic acid-ethylene glycol polymer (non-star polymer) generation chemical coupling) that Dx-poly-sebacic acid-ethylene glycol is made after connecting, (there is not chemical coupling reaction in the star polymer B directly nanoparticle medicine group of the Dx of parcel, Dx does not have structural changes), embodiment 1-2 group, Dx general formulation group.Except control group, in the equal ball of each group, inject 3 μ g medicines or the preparation containing 3 μ g medicines, control group is given isopyknic PBS solution.
In every group of mouse, get at random 12 eyes and carry out induced with laser CNV disposal, after laser photocoagulation, inject above-mentioned each group of medicine (inject 3ug medicine or the preparation containing 3ug medicine except control group in the equal ball of each group, control group is given isopyknic PBS solution) to eyeball of mouse more subsequently.After 7 days, mouse is carried out to fundus fluorescein angiography (being called for short FFA), the formation of CNV has or not fluorescence leakage as basis for estimation according to FFA.Result is as follows:
The incidence of 7d CNV after table 3 light is solidifying
The capable FFA of 7d after laser photocoagulation, in every eye, the situation of 6 the solidifying spot formation of light CNV, sees the above table respectively.
Claims (10)
1. in the structure being shown below, contain the star polymer of Dx structure, its structure is as follows:
Structure Y is:
2. the polymkeric substance of claim 1, wherein the molecular weight polyethylene glycol in polymkeric substance is 100-200000, the integer between W=1-500, the preferably integer between W=1-300, n=1-300, the preferably integer of 1-200.
3. the preparation method of polymkeric substance as claimed in claim 1, is characterized in that:
1) the sebacic acid reaction of the 6 arm polyoxyethylene glycol A that contain hydroxyl ending and ethanoyl obtains polymer B, the wherein integer of W=1-500, preferably 1-300; N=1-300, preferably 1-200;
2) polymer B is reacted and is obtained final product with Dx C;
P is
Compd A;
Wherein Structure G is:
Polymer B;
Dx C
4. the method for claim 3, wherein said chemical step 1-2 selects solvent to be selected from: one or more in benzene, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, methyl alcohol, ethanol, methylene dichloride, dimethyl sulfoxide (DMSO), DMF.
5. the compound of claim 1 can be prepared into the nanometer formulation that is suitable for topical, microball preparation.
6. described in claim 5, part is intravitreal injection administration or other mode administrations of eye.
7. the purposes of the compound of claim 1, purposes is the medicine of preparation treatment eye disease.
8. the purposes of the compound of claim 1, purposes is the medicine of preparation treatment eye age related disease.
9. the purposes of the compound of claim 8, purposes is the medicine of preparation treatment retina and choroid age related disease.
10. the purposes of the compound of claim 8, purposes is the medicine of preparation treatment age related maculopathy disease.
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| CN201310006772.1A CN103910872A (en) | 2013-01-04 | 2013-01-04 | Doxorubicin structure-containing star-shaped polymer and preparation method and use thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104829828A (en) * | 2013-01-08 | 2015-08-12 | 张雅珍 | Preparation and application of drug-grafted polymer |
| CN105037700A (en) * | 2013-01-08 | 2015-11-11 | 张雅珍 | Preparation and application of polymer being grafted with drug |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101031287A (en) * | 2004-03-02 | 2007-09-05 | 麻省理工学院 | Nanocell drug delivery system |
| CN101624443A (en) * | 2009-08-11 | 2010-01-13 | 中国人民解放军第四军医大学 | Preparation method for amycin pro drug and application thereof |
| CN103910867A (en) * | 2012-12-31 | 2014-07-09 | 张雅珍 | Nonlinear polymer having doxorubicin structure, and preparation method and application thereof |
-
2013
- 2013-01-04 CN CN201310006772.1A patent/CN103910872A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101031287A (en) * | 2004-03-02 | 2007-09-05 | 麻省理工学院 | Nanocell drug delivery system |
| CN101624443A (en) * | 2009-08-11 | 2010-01-13 | 中国人民解放军第四军医大学 | Preparation method for amycin pro drug and application thereof |
| CN103910867A (en) * | 2012-12-31 | 2014-07-09 | 张雅珍 | Nonlinear polymer having doxorubicin structure, and preparation method and application thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104829828A (en) * | 2013-01-08 | 2015-08-12 | 张雅珍 | Preparation and application of drug-grafted polymer |
| CN105037700A (en) * | 2013-01-08 | 2015-11-11 | 张雅珍 | Preparation and application of polymer being grafted with drug |
| CN104829828B (en) * | 2013-01-08 | 2018-08-17 | 张雅珍 | A kind of preparation and use of the polymer of grafting drug |
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