CN105521496A - A preparing method of injectable hydrogel of a chemically bonded anticancer medicine - Google Patents
A preparing method of injectable hydrogel of a chemically bonded anticancer medicine Download PDFInfo
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Abstract
The invention discloses a preparing method of injectable hydrogel of a chemically bonded anticancer medicine. Hyperbranched polyamide grafted with the anticancer medicine is adopted as a first component, oxidized sodium alginate is adopted as a second component, and the two components adopt formed -C=N- bonds as crosslinking points to obtain the injectable hydrogel capable of sustained release of the anticancer medicine in a body. The traditional Chinese medicine and hydrogel are chemically bonded, thus prolonging the medicine release period. After the hydrogel is degraded, the medicine is still bonded with a macromolecule compound, thus prolonging the circulation time of the medicine in an organism and correspondingly improving treatment effects of the medicine, thereby reducing the medicine taking frequency and relieving toxic and side effects. The injectable hydrogel has a very good application prospect in the field of biological medicines, tissue engineering, and the like.
Description
One, technical field
The present invention relates to a kind of preparation method of injection aquagel, specifically a kind of preparation method of injection aquagel of chemical bonding cancer therapy drug, is injection aquagel technical field.
Two, background technology
Hydrogel is a class soft material with 3D loose structure, and (as hydrogen bond, hydrophobe interacts to be mostly physical crosslinking, ionic interaction etc.) or chemical crosslinking (as acyl swells key, disulfide bond, imine linkage etc.) form, there is high-moisture, high resiliency, the features such as softness.Therefore hydrogel is in biomedicine, transport of drug, and there is important using value the aspects such as organizational project.Recent years mainly concentrates on the injection aquagel of original position formation to the research of hydrogel.The component of injection aquagel is the liquid that can flow, upon mixing can gel in-situ, does not therefore need the operation of invasive just to implant, enables for tissue engineering material.Another feature of injection aquagel medicine, protein, cell etc. to be mixed with component fluids in advance, enables for field of medicine release.Injection aquagel is highly suitable for clinical treatment.
The daiamid with branched structure is (HPAMAM) a kind of dendritic macromole with specific three dimensional structure, molecular dimension.HPAMAM has structure height branching, and the feature that configuration height is controlled.HPAMAM is easy to hold medicine in intramolecule.Because HPAMMA molecular weight is low, good fluidity, makes it in biological medicine, and the aspects such as targeting transport have tempting application prospect.HPAMAM molecule is peripheral can react with other materials with a large amount of active function groups, forms injectable gel.At present, the gel rubber system based on branched polyamide amine has part bibliographical information.
HongbinZhang etc. use dissaving polymer to be combined with cancer therapy drug, obtain the slow-releasing system that can discharge medicine in human body.But the just physical blending of this system Chinese medicine and polymer, does not produce chemical bond with gel component.(J.Mater.Chem.,2011,21,13530)
SiquanZhu etc. select dissaving polymer to be combined with medicine, obtain the aquogel system that can control multi-medicament release.But this system Chinese medicine and polymer be combined into physical bond.(Biomaterials,2010,31,5445-5454.)
RaghavendraS.Navath etc. utilize PEG and HPAMAM to obtain injectable drug release hydrogel, are used for the treatment of genital system infection.But this system Chinese medicine and hydrogel in conjunction with same be also physical blending.(Mol.Pharmaceutics,2011,8,1209-1223)。
Wei-QingLiu etc. utilize ATRP technology to obtain the dissaving polymer hydrogel of the releasable medicaments with pH response.The mode being combined into physical bond of this hydrogel and medicine.(Mater.Sci.Eng.C2012,32,953-960.)
Because above-mentioned report Chinese medicine is combined with branched polyamide amine or the hydrogel based on branched polyamide amine for physically, the adhesion of medicine and branched polyamide amine is not strong, therefore, the rate of release of medicine is relatively very fast, and duration of efficacy is relatively short.The shortcomings such as medicine frequency is high, the toxic and side effects of medicine is larger may be caused thus.
Three, summary of the invention
The present invention aims to provide a kind of preparation method of injection aquagel of chemical bonding cancer therapy drug, fast with the branched polyamide amine injection aquagel system drug release rate solving physical bond medicine, the shortcoming that duration of efficacy is short, reach prolong drug deenergized period, prolong drug circulation time in vivo, reduce medicine frequency, alleviate the object of toxic and side effects.Subject hydrogel can be advantageously applied to biological medicine, the fields such as organizational project.
The present invention utilizes the reactivity of branched polyamide amine functional end-group, makes it to react with medicine, forms chemical bond mould assembly macromolecule medicament carrier; Again chemical bond mould assembly macromolecule medicament carrier is coordinated with the sodium alginate of oxidation subsequently and form injection aquagel system.Because medicine and hydrogel are by chemical bonds, the release of medicine needs the hydrolysis through chemical bond, and correspondingly, drug release period extends.In addition, because medicine is combined on macromole, before macromole is degradable by organism, medicine can stop in vivo all the time, extends its circulation time in vivo.Thus can dosage be reduced, reduce the toxic and side effects of medicine.
The preparation method of the injection aquagel of chemical bonding cancer therapy drug of the present invention, be the over-branched polyamidoamine of with grafting cancer therapy drug (as camptothecine, amycin, 5-fluorouracil, paclitaxel etc.) be the first component, using the sodium alginate of oxidation as second component, two kinds of components are by forming-C=N-key as crosslink sites, obtaining can the injection aquagel of sustained release cancer therapy drug in vivo, comprises the steps:
(1) cancer therapy drug of equimolar amounts and methyl bromoacetate are dissolved in methanol, in the presence of a catalyst room temperature reaction 2-4h, obtain intermediate product---the cancer therapy drug of grafting methyl bromoacetate; Intermediate product and over-branched polyamidoamine are dissolved in methanol simultaneously, are heated to reflux temperature, reaction 4-6h, after reaction terminates, reactant liquor is steamed except desolventizing at 45 DEG C of backspins, precipitate 1-2 time in ice acetone subsequently, ambient temperature in vacuum is dry, obtains the over-branched polyamidoamine of cancer therapy drug grafting;
Described cancer therapy drug is camptothecine, amycin, 5-fluorouracil or paclitaxel etc.;
Described catalyst is triethylamine or Feldalat NM; The addition of catalyst is the 5-15% of cancer therapy drug quality.
The mass ratio of over-branched polyamidoamine and intermediate product is 30:1;
Described over-branched polyamidoamine be prepared as conventional method, specifically with 6.146g methylene-bisacrylamide and 2.584gN-aminoethyl piperazine for monomer is at the methanol/water mixed solvent (V of 60mL
methanol: V
water=1:2) in by Michael addition reaction in 50 DEG C of reactions after five days (Chem.Commun., 2007,2587 – 2589) that obtain.
(2) over-branched polyamidoamine of cancer therapy drug grafting is dissolved in deionized water, be designated as solution A; The sodium alginate of oxidation is dissolved in deionized water, is designated as solution B; Solution A and solution B are injected to after in organism simultaneously, just original position can obtain injection aquagel.
In solution A, the concentration of the over-branched polyamidoamine of cancer therapy drug grafting is 50-350mg/mL;
The concentration of the sodium alginate be oxidized in solution B is 50-250mg/mL;
When being injected in organism, the volume ratio of solution A and solution B is 3:1 to 1:3.
The sodium alginate of described oxidation be with the sodium metaperiodate of the 0.173g/mL sodium alginate that is oxidant and 0.2g/mL with volume ratio 1:1, react that 6h obtains at ambient temperature.
The present invention has following features:
1, compare other branched polyamide amine aquogel systems, hydrogel provided by the present invention and medicine are with chemical bonds, and the release of medicine depends on the hydrolysis of chemical bond, therefore, extends drug release period.
2, compare other branched polyamide amine aquogel systems, in hydrogel provided by the present invention, medicine and over-branched polyamidoamine are with chemical bonds.Before over-branched polyamidoamine is completely degradable by organism, medicine can stop in vivo all the time, extends medicine circulation time in vivo.
3, compare other branched polyamide amine aquogel systems, technology provided by the present invention can reduce medicine frequency, thus reduces the toxic and side effects of medicine.
4, this injection aquagel with long period drug release ability is expected to be applied to biological medicine, the fields such as organizational project.
Four, accompanying drawing explanation
Fig. 1 take 5-fluorouracil as model cancer therapy drug, the course of reaction schematic diagram of the over-branched polyamidoamine of synthesis cancer therapy drug grafting.
Fig. 2 is the forming process of injection aquagel and the photo in kind of hydrogel.Wherein left figure forms gel after sodium alginate soln is injected into ultrabranching polyamide solution fast; Right figure is the bulk gels formed after sodium alginate soln mixes with over-branched polyamidoamine dissolution homogeneity.
Fig. 3 is the degradation process of medicine carrying hydrogel.Wherein abscissa be time/sky, vertical coordinate is the mass ratio of hydrogel and initial condition gel after degraded.
Fig. 4 is the drug release patterns of sodium alginate injection aquagel after the over-branched polyamidoamine/oxidation of grafting cancer therapy drug in embodiment.(abscissa be time/hour; Vertical coordinate is accumulative release rate/%).
Fig. 5 is the drug release patterns in the 12h of sodium alginate injection aquagel after the over-branched polyamidoamine/oxidation of grafting cancer therapy drug in embodiment.(abscissa be time/hour; Vertical coordinate is accumulative release rate/%).
Five, detailed description of the invention
Specific description is done below in conjunction with the injection aquagel of embodiment to chemical bonding cancer therapy drug of the present invention.
Embodiment 1:
1, get 5-fluorouracil and each 5mmol of methyl bromoacetate, be dissolved in 5mL methanol, add 0.1g Feldalat NM, room temperature reaction 2h, obtain the 5-fluorouracil of grafting methyl bromoacetate; The 5-fluorouracil getting 3g over-branched polyamidoamine and the modification of 0.1g acrylic acid methyl ester. adds in the methanol solution of 10mL, stir post-heating to 75 DEG C back flow reaction 4h, reactant liquor is steamed at 45 DEG C of backspins, subsequently with 10 times of volume ice acetone precipitations 2 times, precipitate is positioned over drying at room temperature 12h in vacuum drying oven, obtains the over-branched polyamidoamine of 5-fluorouracil grafting.
2, the over-branched polyamidoamine of 0.15g5-fluorouracil grafting is dissolved in 1mL deionized water, is designated as solution A; The sodium alginate that 0.10g is oxidized is dissolved in 1mL deionized water, is designated as solution B; The ratio of solution A and solution B 1:3 by volume mixed, vibrate mix homogeneously under room temperature, can obtain injection aquagel in 1min.
3, the outer drug release test of water gel
Injection aquagel step 2 prepared is placed in the semipermeable membrane of dialysis molecular weight 6000 (MWCO6KD), and being immersed in 6mLpH value is in the PBS buffer solution of 7.4, cultivates at 37 DEG C.Add the fresh PBS buffer solution that equivalent is identical after getting 4mL culture fluid, sample time is 1h, 2h, 4h, 8h, 12h, 24h, 48h, 72h at every turn, then every 24h sampling once.Not have the hydrogel of medicine carrying to make blank reference, same time samples.With ultraviolet light spectrophotometric measurement absorbance.Medicine release concentration is determined by standard curve.As Fig. 3 can see that the burst effect of medicine is little, slow-release time is long, and In vitro metabolism is slow.
Embodiment 2:
1, get camptothecine and each 5mmol of methyl bromoacetate, be dissolved in 5mL methanol, add 0.1g triethylamine, room temperature reaction 3h, obtain the camptothecine of grafting methyl bromoacetate; Get 3g over-branched polyamidoamine subsequently and 0.1g is with the camptothecine of methyl bromoacetate to add in the methanol solution of 10mL, after stirring, be positioned over heating reflux reaction 5h in the oil bath pan of 70 DEG C, reactant liquor is steamed at 45 DEG C of backspins, subsequently with 10 times of volume ice acetone precipitations 2 times, and precipitate is positioned over drying at room temperature 12h in vacuum drying oven, obtain the over-branched polyamidoamine of camptothecine grafting.
2, the over-branched polyamidoamine of 0.15g camptothecine grafting is dissolved in 1mL deionized water, is designated as solution A; The sodium alginate that 0.20g is oxidized is dissolved in 1mL deionized water, is designated as solution B; The ratio of solution A and solution B 2:3 by volume mixed, vibrate mix homogeneously under room temperature, can obtain injection aquagel in 1min.
Embodiment 3:
1, get paclitaxel and each 4mmol of methyl bromoacetate, be dissolved in 10mL methanol, add 0.1g triethylamine, room temperature reaction 2h, obtain the paclitaxel of grafting methyl bromoacetate; Get 3g over-branched polyamidoamine subsequently and 0.1g is with the paclitaxel of methyl bromoacetate to add in the methanol solution of 10mL, after stirring, be positioned over heating reflux reaction 4.5h in the oil bath pan of 80 DEG C, reactant liquor is steamed at 45 DEG C of backspins, subsequently with 10 times of volume ice acetone precipitations 1 time, and precipitate is positioned over drying at room temperature 12h in vacuum drying oven, obtain the over-branched polyamidoamine of paclitaxel grafting.
2, the over-branched polyamidoamine of 0.20g paclitaxel grafting is dissolved in 1mL deionized water, is designated as solution A; The sodium alginate that 0.10g is oxidized is dissolved in 1mL deionized water, is designated as solution B; The ratio of solution A and solution B 1:1 by volume mixed, vibrate mix homogeneously under room temperature, can obtain injection aquagel in 1min.
Embodiment 4:
1, get amycin and each 6mmol of methyl bromoacetate, be dissolved in 5mL methanol, add 0.1g triethylamine, room temperature reaction 4h, obtain the amycin of grafting methyl bromoacetate; Get 3g over-branched polyamidoamine subsequently and 0.1g is with the amycin of methyl bromoacetate to add in the methanol solution of 10mL, after stirring, be positioned over heating reflux reaction 6h in the oil bath pan of 75 DEG C, reactant liquor is steamed at 45 DEG C of backspins, subsequently with 10 times of volume ice acetone precipitations 1 time, and precipitate is positioned over drying at room temperature 12h in vacuum drying oven, obtain the over-branched polyamidoamine of amycin grafting.
2, the over-branched polyamidoamine of 0.20g amycin grafting is dissolved in 1mL deionized water, is designated as solution A; The sodium alginate that 0.15g is oxidized is dissolved in 1mL deionized water, is designated as solution B; The ratio of solution A and solution B 3:2 by volume mixed, vibrate mix homogeneously under room temperature, can obtain injection aquagel in 1min.
Claims (8)
1. the preparation method of the injection aquagel of a chemical bonding cancer therapy drug, it is characterized in that: be the over-branched polyamidoamine of the cancer therapy drug with grafting be the first component, using the sodium alginate of oxidation as second component, two kinds of components are by forming-C=N-key as crosslink sites, and obtaining can the injection aquagel of sustained release cancer therapy drug in vivo;
Described cancer therapy drug comprises camptothecine, amycin, 5-fluorouracil or paclitaxel.
2. preparation method according to claim 1, is characterized in that comprising the steps:
(1) be dissolved in methanol by the cancer therapy drug of equimolar amounts and methyl bromoacetate, room temperature reaction 2-4h, obtains intermediate product in the presence of a catalyst; Intermediate product and over-branched polyamidoamine are dissolved in methanol simultaneously, are heated to reflux temperature, reaction 4-6h, after reaction terminates, reactant liquor is steamed except desolventizing at 45 DEG C of backspins, precipitate 1-2 time in ice acetone subsequently, ambient temperature in vacuum is dry, obtains the over-branched polyamidoamine of cancer therapy drug grafting;
(2) over-branched polyamidoamine of cancer therapy drug grafting is dissolved in deionized water, be designated as solution A; The sodium alginate of oxidation is dissolved in deionized water, is designated as solution B; Solution A and solution B are injected to after in organism simultaneously, just original position can obtain injection aquagel.
3. preparation method according to claim 2, is characterized in that:
Described catalyst is triethylamine or Feldalat NM; The addition of catalyst is the 5-15% of cancer therapy drug quality.
4. preparation method according to claim 2, is characterized in that:
The mass ratio of over-branched polyamidoamine and intermediate product is 30:1.
5. preparation method according to claim 2, is characterized in that:
In solution A, the concentration of the over-branched polyamidoamine of cancer therapy drug grafting is 50-350mg/mL.
6. preparation method according to claim 2, is characterized in that:
The concentration of the sodium alginate be oxidized in solution B is 50-250mg/mL.
7. the preparation method according to claim 2,5 or 6, is characterized in that:
When being injected in organism, the volume ratio of solution A and solution B is 3:1 to 1:3.
8. preparation method according to claim 2, is characterized in that:
The sodium alginate of described oxidation be with the sodium metaperiodate of the 0.173g/mL sodium alginate that is oxidant and 0.2g/mL with volume ratio 1:1, react that 6h obtains at ambient temperature.
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| CN107007550A (en) * | 2017-05-24 | 2017-08-04 | 上海中医药大学 | A kind of amphipathic copolymer of redox response and its preparation method and application |
| WO2019053269A1 (en) * | 2017-09-15 | 2019-03-21 | Université De Strasbourg | Injectable hybrid alginate hydrogels and uses thereof |
| CN115960474A (en) * | 2022-12-23 | 2023-04-14 | 湖南金桥新材料科技有限公司 | Preparation method of high-solid-content liquid brilliant blue |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107007550A (en) * | 2017-05-24 | 2017-08-04 | 上海中医药大学 | A kind of amphipathic copolymer of redox response and its preparation method and application |
| CN107007550B (en) * | 2017-05-24 | 2020-06-26 | 上海中医药大学 | Redox-responsive amphiphilic copolymer and preparation method and application thereof |
| WO2019053269A1 (en) * | 2017-09-15 | 2019-03-21 | Université De Strasbourg | Injectable hybrid alginate hydrogels and uses thereof |
| CN115960474A (en) * | 2022-12-23 | 2023-04-14 | 湖南金桥新材料科技有限公司 | Preparation method of high-solid-content liquid brilliant blue |
| CN115960474B (en) * | 2022-12-23 | 2023-10-31 | 湖南金桥新材料科技有限公司 | Preparation method of high-solid-content liquid brilliant blue |
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