CN103865056B - Non-linear polymer and preparation method and purposes containing Doxorubicin structure - Google Patents
Non-linear polymer and preparation method and purposes containing Doxorubicin structure Download PDFInfo
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- CN103865056B CN103865056B CN201210562399.3A CN201210562399A CN103865056B CN 103865056 B CN103865056 B CN 103865056B CN 201210562399 A CN201210562399 A CN 201210562399A CN 103865056 B CN103865056 B CN 103865056B
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Abstract
The invention discloses the non-linear polymer and preparation method and purposes containing Doxorubicin structure.The Doxorubicin is coupled medicine or medicament of the non-linear polymer than other forms in the better for the treatment of AMD.
Description
Technical field
The invention discloses the preparation method and use of the non-linear polymer containing Doxorubicin structure and the polymer
On the way.
Background technology
Doxorubicin is the medicine of a kind of antimitotic and great cytotoxicity.Doxorubicin can successfully suppress a variety of
Malignant tumour, including acute leukemia, lymthoma, soft tissue and osteosarcoma, children malignant tumors and adult solid's knurl.It is acted on
Mechanism is that medicine can penetrate into cell, is combined with chromosome.In medicines structure planar rings insertion base-pair between so as to
DNA combines to form compound, severe jamming DNA synthesis, DNA dependent rna synthesis and protein synthesis.But produced by the mechanism
The drug concentration of tumor locus will height in Doxorubicin concentration ratio clinical treatment needed for raw anti-proliferative effect.In addition Doxorubicin
It is also relevant with redox, it may participate in reaction and obtain cytotoxic compound, such as peroxide, the hydroxy and peroxide of activity
Change hydrogen etc..The site of action of Doxorubicin may be directed to the pharmacodynamic action of various diseases also in cell membrane, current Doxorubicin
Do not reach common understanding in scientific circles, for all no general character of mechanism of action of every kind of disease, need further scientific research and obtain
To explain.
Doxorubicin is widely used at present, but generally requires to be become salt in Point of View of Clinical, such as Doxorubicin, often
It is doxorubicin hydrochloride to see medicinal forms, i.e., need to become hydrochloride, because Doxorubicin solubility itself is very low, does not translate into salt
Form, it is impossible to apply.And become after hydrochloride, the pharmacodynamics function of Doxorubicin declines to a great extent, therefore this gives clinical practice band
Carry out very big difficulty.
Another of Doxorubicin has the disadvantage due to strong CDCC itself, therefore the toxicity of itself is very big, often
There is obvious bone marrow suppression within 10 days or so after use, after one week, you can obviously intestines and stomach are bad anti-for performance
Should and cardiac toxic, therefore must could be applied after accurate calculation during medication, and the half-life period of this medicine is very short, it is same to being applied band
To limit to.
The preparation method of the present invention, can be such that the new construction containing Doxorubicin of preparation is dissolved in water, and extension partly declines
Phase, this preparation method solves application limitation in the lump, and it is very good it is played in AMD disease
Action effect.
The content of the invention
Present disclosure is as follows：
The invention discloses the multi-block polymer of the coupling of the Doxorubicin shown in following formula I, its structure is as follows：
Molecular weight polyethylene glycol wherein in polymer is the integer between 100-200000, n=1-500, preferably n=1-
Integer between 300, m=1-300, preferably 1-200 integer.
The preparation method of 1 polymer：
1) the 8 arm polyethylene glycol A containing hydroxyl end and acetylating decanedioic acid reaction obtain polymer B, wherein n=
1-500 integer, preferably 1-300；M=1-300, preferably 1-200
2) polymer B obtains final product with Doxorubicin C reactions；
Compound A；
Polymer B；
Doxorubicin C
Wherein Doxorubicin and with 8 arm polyethylene glycol of hydroxyl end commercially available from.The new chemical combination containing Doxorubicin of synthesis
Solvent needed for the chemical step of the final product of thing is selected from：Benzene, toluene, pyridine, tetrahydrofuran, chloroform, carbon tetrachloride, two
One or more in chloromethanes, methanol, ethanol, dichloromethane, dimethyl sulfoxide (DMSO), DMF.
The compound of brand-new can be prepared into the nanometer formulation suitable for local administration, microball preparation.Purposes is treated to prepare
The medicine of AMD.
The preparation method of the present invention is specific as follows：
1) decanedioic acid is flowed back in acetic anhydride, forms acetyl group-decanedioic acid；
2) acetyl group-decanedioic acid is mixed with the 8 arm polyethylene glycol compound A with hydroxyl end, at 100-200 DEG C
Reaction, reaction time 10min to 10h；After the cooling of question response mixture, washing is dried to obtain polymer B；
3) by Doxorubicin C and polymer B as 1-96 hours in solvent, ultrasonic reaction is after 1-30 minutes, in an oven
Foster and obtain Formulas I polymer, then homogenizer high-speed stirred 1-10 minutes in subzero 30 DEG C of 0-, rotation volatilization is slightly produced
Thing, post processing obtains the nanometer formulation of end-product Formulas I polymer.
Its reaction equation is as follows：
The polymer containing Doxorubicin structure that the present invention is obtained, it is easy to dissolved in water, and its half-life period is than more
It is soft more many than star extension, such noval chemical compound excellent when treating the model of AMD.
In comparison of the nanometer formulation that end-product prepared by this patent is made in treatment eye disease, the new chemical combination of this patent
The medication effect of thing is very good, surmounts Doxorubicin (not being coupled with Doxorubicin) is directly wrapped up by polymer completely
Nanometer formulation.
Brief description of the drawings：
The nuclear magnetic resonance map of the end-product of Fig. 1 embodiments 1.
Nano-particle that Fig. 2 embodiments 1 are made, this reaction synthesis decanedioic acid-ethylene glycol polymer directly parcel it is how soft
Than star nanoparticle and the medicine accumulative releasing degree and time chart of Doxorubicin ordinary preparation.
Embodiment
Specific embodiment is described in further detail to the present invention below, but the present invention not only limits to following examples.
Prepare embodiment as follows：
Embodiment 1
1) mixture backflows of the decanedioic acid 80g in 800ml acetic anhydrides, to form acetyl group-decanedioic acid；
2) 1) step and is put into flask with 8 arm polyethylene glycol 18g product mixes of hydroxyl end, subtracted at 180 DEG C
The poly- reaction of pressure solution 1 hour；Thing to be polymerized is cooled to room temperature chloroform and dissolved, and with petroleum ether and drying；
3) the 800mg polymer of 120mg Doxorubicins and step 2 is put into 8ml dimethyl sulfoxide (DMSO)s and 12ml dichloromethane
48 hours in alkane solution；Ultrasound 3 minutes；Then insert in baking oven 1 hour；The homogenizer ultrahigh speed stirring 3 in subzero 10-20 degree
Minute, then it is put into 1% poly-vinyl alcohol solution 600 turns and stirs 2 hours；Freezed after being collected by centrifugation, produce receiving for end-product
Rice corpuscles.
Embodiment 2
1) mixture backflows of the decanedioic acid 100g in 900ml acetic anhydrides, to form acetyl group-decanedioic acid；
2) 1) step and is put into flask with 8 arm polyethylene glycol 30g product mixes of hydroxyl end, subtracted at 180 DEG C
The poly- reaction of pressure solution 1 hour；Thing to be polymerized is cooled to room temperature chloroform and dissolved, and with petroleum ether and drying；
3) the 1000mg polymer of 200mg Doxorubicins and step 2 is put into 6ml dimethyl sulfoxide (DMSO)s and 14ml dichloromethane
24 hours in alkane solution；Ultrasound 2 minutes；Then insert in baking oven 2 hours；2 points are stirred in homogenizer ultrahigh speed in subzero 10 degree
Clock, is then put into 10% cholic acid solution 600 turns and stirs 3 hours；Freezed after being collected by centrifugation, produce the nanoparticle of end-product
Son.
Effect experiment is as follows：
The Doxorubicin that is directly wrapped up by the embodiment 1-2 samples prepared and with decanedioic acid-ethylene glycol polymer is received
(chemical coupling reaction does not occur for grain of rice medicine group, Doxorubicin does not have structure change), Doxorubicin ordinary preparation (powder-injection)
Stability test, drug release in vitro experiment and the drug action of AMD experiment are carried out respectively.
Stability test：
It is many that decanedioic acid-ethylene glycol polymer prepared by the sample of 1 group of preparation of embodiment and this patent is directly wrapped up
The soft nanoparticle pharmaceutical group (not reacted with Doxorubicin) than star, Doxorubicin ordinary preparation takes same amount (with Doxorubicin
Meter) absorbance is determined respectively.Then three groups are put into 20 degree of incubators 3 months, then take out and determine 480 nanometers of absorbances,
As a result visible embodiment 1-2 groups and the absorbance of the Doxorubicin of ordinary preparation group are front and rear without change, and the nanoparticle wrapped up
Group absorbance declines 20.5%.
Drug release in vitro is tested：
By 1 group of embodiment, the nanoparticle pharmaceutical group for the Doxorubicin that decanedioic acid-ethylene glycol polymer is directly wrapped up and many
It is soft also known as to take the medicine (in terms of Doxorubicin, every group of Doxorubicin containing 10mg) of equivalent than star ordinary preparation component, then will be respectively
Group medicine after being soaked with PBS, shakes, after timing sampling, at ultraviolet point as in test tube in shaking table under 37 degrees Celsius
The content of medicine is determined under light photometer, and the medicament contg percentage of release is calculated after record, releasing curve diagram, abscissa is done
For the time (my god), ordinate for release percentage.See Fig. 2, it is seen that the medicine of embodiment release is more permanent, makes drug half-life
It is longer.
Solubility test in water：
By embodiment 1-2 groups, the nanoparticle pharmaceutical group for the Doxorubicin that decanedioic acid-ethylene glycol polymer is directly wrapped up and
Doxorubicin ordinary preparation component also known as takes the medicine (in terms of Doxorubicin, every group of Doxorubicin containing 100mg) of equivalent, puts respectively
Enter in test tube, with 10mlPBS buffer solutions and shake, it is static after observation dissolving situation.The record dissolving of 3 minutes and 20 minutes
State is as a result as follows.
The solubility of table 1 compares
Inhibitory action of the medicine to tela chorioidea's hyperplasia：
Male rat 100 is taken, 5 groups, i.e. control group is randomly divided into, that decanedioic acid-ethylene glycol polymer is directly wrapped up is many
The soft nanoparticle pharmaceutical group (chemical coupling reaction not occurring, Doxorubicin does not have structure change) than star, embodiment 1-2 groups are more
It is soft than star general formulation group.Each group number of animals is 20.It is experimental eye at a glance that every rat, which randomly selects, and another eye is control
Eye.The equal μ g medicines of intraocular injection 10 of each group or the load medicine durative action preparation containing 10 μ g medicines in addition to control group, control group is to isometric
PBS solution.
With laser irradiation in rats eyeball, there is bubble to produce or (ring) mark with light sometimes with hyporrhea after light is solidifying and hit
Broken Bruch films, are designated as available point.After laser photocoagulation, each group medicine is injected to rat right eye eyeball.14d after light is solidifying, tissues observed
Hyperplasia area simultaneously carries out histological examination.As a result it is as follows：
The retina of table 2 and tela chorioidea's hyperplasia Area comparison (unit：mm2)
Compared with control group group*P ＜ 0.05,**P ＜ 0.01, are compared with ordinary preparation group#P ＜ 0.05,##P ＜ 0.01
The result of upper table shows that control group retina and choroid generation hyperplasia area are larger, and each treatment group difference is not
Hyperplasia area is reduced with limit.Experiment to rat part tissue of eye hyperplasia area shows that each embodiment group can subtract simultaneously
Small lesion retina and choroidal hyperblastosis area, but effect difference, wherein the embodiment 1-2 groups being coupled
It is better.
The result of histological examination is that visible outer retina and train of thought membrane structure are disorderly at the solidifying spot of control group light under light microscopic
Disorderly, retinal pigment epithelium, choroid cambium hyperplasia, free companion's inflammatory cell infiltration.Medicine group and control group phase
Than cambium is rarely found and less with serosa circumscripta detachment of retina；Embodiment group is simply wrapped more compared to high polymer
Soft more notable without occurring the effect of the nanoparticle pharmaceutical group of coupling reaction than star, the compound after coupling can substantially reduce train of thought
Membrane tissue hyperplasia.Histological examination shows, embodiment group than ordinary preparation group nanoparticle pharmaceutical group to age-related macular
Lesions treatment more thoroughly, the retina and choroid of lesion are played a role simultaneously.
Claims (10)
1. the polymer containing Doxorubicin in the structure being shown below, its structure is as follows：
2. the molecular weight polyethylene glycol in the polymer of claim 1, wherein polymer is between 100-200000, n=1-500
Integer, m=1-300 integer.
3. the preparation method of polymer as claimed in claim 1, it is characterised in that：
1) the 8 arm polyethylene glycol A containing hydroxyl end and acetylating decanedioic acid reaction obtain polymer B, wherein n=1-
500 integer；M=1-300；2) polymer B obtains final product with Doxorubicin C reactions；
Compound A；
Polymer B；
Doxorubicin C.
4. the method for claim 3, wherein the chemical step 1-2 is selected from from solvent：Benzene, toluene, pyridine, tetrahydrofuran,
One or more in chloroform, carbon tetrachloride, dichloromethane, methanol, ethanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide.
5. the polymer of claim 1, the polymer can be prepared into the nanometer formulation suitable for local administration, microballoon system
Agent.
6. the polymer of claim 5, the part is dosing eyes.
7. the purposes of the polymer of claim 1, purposes treats the medicine of eye disease to prepare.
8. the purposes of the polymer of claim 1, purposes treats the medicine of eye age-related disease to prepare.
9. the purposes of the polymer of claim 8, purposes treats the medicine of retina and choroid age-related disease to prepare
Thing.
10. the purposes of the polymer of claim 8, purposes treats the medicine of age-related maculopathy disease to prepare.
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| CN105037700A (en) * | 2013-01-08 | 2015-11-11 | 张雅珍 | Preparation and application of polymer being grafted with drug |
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| CN102068703A (en) * | 2011-01-05 | 2011-05-25 | 武汉理工大学 | Doxorubicin multi-targeting drug delivery system and preparation method and application thereof |
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