CN108676156A - A kind of reduction response type ABC type block polymers and its preparation method and application - Google Patents
A kind of reduction response type ABC type block polymers and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of reduction response type ABC type block polymers and its preparation method and application, belong to reduction response type pharmaceutical carrier technical field.The present invention has been selected with hydrophilic monomethyl ether polyethylene glycol (mPEG), hydrophobic lactide (LA) and allyl glycidyl ether (AGE) are raw material, then Mercapto-olefin light click-reaction is combined with ring-opening polymerisation, has synthesized the polymer mPEG b PAGE that side chain contains mercapto groupsSHThen b PLLA are self-assembly of micella, and mercapto groups are oxidized to disulfide bond in the presence of hydrogen peroxide, finally synthesize the reduction response type crosslinking micella of high stability.The crosslinking micella of cystine linkage, which not only helps, reduces drug leakage and initial quick release, and also there is reproducibility response in diseased region, i.e. in the presence of reducing agent DTT and glutathione, the drug release behavior for being crosslinked micella is obviously accelerated, to improve therapeutic effect.
Description
Technical field
The invention belongs to restore response type pharmaceutical carrier technical field, and in particular to a kind of reduction response type ABC type blocks
Polymer and its preparation method and application.
Background technology
Polymer micelle is as drug conveying carrier because it has the dissolubility for improving dewatering medicament and reduces protein
The features such as absorption, is increasingly paid close attention to by everybody.However, the structure of polymer micelle can be sent out with the variation of ambient enviroment
Changing, it is difficult to keep stable, this application range for allowing for micella is subject to certain restrictions.Therefore, for reinfored glue binding
The stability and integrality of structure, it is necessary to which we modify polymer segment, introduce difunctional so that polymer micelle
It is crosslinked, to immobilize the structure of polymer micelle.
Stimuli responsive polymers crosslinking micella is primarily referred to as energy Drug controlled release rate, changes simultaneously drug and enters body
A kind of pharmaceutical carrier of interior mode and distribution and realization targeting conveying purpose.With reduce toxic side effect, it is biodegradable,
It improves the releasing effect of drug and extends the characteristic of circulation time in vivo.Have much in relation to this kind of report, such as：Temperature is rung
Answer type crosslinking micella, photoresponse type crosslinking micella etc..So far, the research for micella being crosslinked in relation to reduction response type polymer is got over
Come more, and has prodigious development space in terms of transporting antitumor drug, be especially self-assembly of the amphipathic of micella
Disulfide bond is introduced in polymer.Disulfide bond in human body under normal environment (such as：Temperature, oxidizing condition etc.) be it is stable, so
And in the presence of reducing agent dithiothreitol or glutathione, disulfide bond, which is easy to disconnect, forms mercapto groups, this is one reversible
Process.In addition, the concentration of the glutathione in cancer cell is bigger than the concentration of normal cell, this is easier that disulfide bond is made to disconnect,
Quick release goes out drug.
Based on this, the present invention has selected hydrophilic monomethyl ether polyethylene glycol (mPEG), hydrophobic lactide (LA) with
And allyl glycidyl ether (AGE) these three monomers are raw material, and different average moleculars have been synthesized in a manner of ring-opening polymerisation
Then the triblock polymer of quality introduces thiol group in polymer lateral chain using mercapto-olefin light click-reaction, obtains
Polymer mPEG-b-PAGESHThen-b-PLLA is self-assembly of micella, and mercapto groups quilt in the presence of hydrogen peroxide
It is oxidized to disulfide bond, finally synthesizes the reduction response type crosslinking micella of high stability.It is had studied simultaneously by a series of means
The release in vitro of the chemical constitution of polymer, self assembly behavior in aqueous solution and drug.
Invention content
The technical problem to be solved by the present invention is to provide a kind of reduction response type ABC type block polymers and preparation method thereof and
Using.To achieve the above object, the technical solution adopted by the present invention is a kind of reduction response type ABC type block polymers, special
Sign is that the structural formula of the reduction response type ABC type block polymers is as follows：
M in formula, n, what y was represented is the degree of polymerization of polymer.
The preparation method of the reduction response type ABC type block polymers, includes the following steps：
(1) synthesis of amphipathic nature block polymer mPEG-b-PAGE：
Sodium hydride is added under nitrogen atmosphere in Shrek bottle, and anhydrous THF is added in bottle, stirs 20min
More than, stop stirring and siphoning away the supernatant in bottle, then mPEG is added in Shrek bottle, and this bottle is put into 100
It is stirred in DEG C oil bath pan, after in the mPEG that the NaH in bottle is dissolved in melting, reinjects AGE, bottleneck is sealed, in 100 DEG C of oil baths
It is reacted for 24 hours in pot；After reaction, glacial acetic acid is added to terminate polymerisation, after product is cooled to room temperature, dichloromethane is added
Alkane is dissolved, and silica gel column chromatography method separation product is then used, and first uses isopropanol as eluant, eluent by PAGE and other miscellaneous
Matter rinses out, then uses isopropanol/chloroform instead and rinse and collect, rotate, then by the dissolving of concentrate dichloromethane, suction filtration to remove
Silica white is removed, finally, concentrated by rotary evaporation, vacuum drying are to get mPEG-b-PAGE again；
(2) synthesis of triblock polymer mPEG-b-PAGE-b-PLLA：
A Shrek bottle is put into heating mantle first and vacuumizes, lead to nitrogen, after bottle is cooled to room temperature, thereto
L-LA (L- lactides) is added, then bottle is placed in 40 DEG C of oil bath pans and is vacuumized, later, initiator mPEG-b- is added
PAGE, and oil bath pot temperature is transferred to 120 DEG C, after solid stirring melting in bottle, octoate catalyst stannous is added dropwise with syringe,
It is stirred to react for 24 hours；
After reaction, reaction product is cooled to room temperature, then uses dichloromethane stirring and dissolving, and sink in cold ether
It forms sediment, collected by suction filter cake is finally dried in vacuo to get triblock polymer mPEG-b-PAGE-b-PLLA；
(3) triblock polymer mPEG-b-PAGE of the side chain containing mercapto groupsSHThe synthesis of-b-PLLA：
Triblock polymer mPEG-b-PAGE-b-PLLA is put into Shrek bottle, is then newly steamed with syringe extraction
DMF inject bottle in, after solid whole stirring and dissolving in bottle, add 1,3- dimercaptopropanes and photosensitizer phenyl it is bis- (2,
4,6- trimethylphenyl acyl groups) phosphine oxide, it is protected from light with chest covering, bottle is put into light later and consolidated by drum nitrogen bubble 30min or more
Change in case, Hg lamp irradiation reacts 2h；
After the completion of reaction, reaction solution ice ether is precipitated, then the filter cake CH of collected by suction2Cl2Dissolving, it is so anti-
Again several times, finally filter cake is dried in vacuo.
The reduction response type ABC types block polymer is in the application as anti-cancer medicament carrier.
The present invention has the advantages that compared with prior art：
1, in the presence of hydrogen peroxide, the triblock polymer mPEG-b-PAGE of synthesisSHMercapto groups are by oxygen in-b-PLLA
It is melted into disulfide bond, finally synthesizes the reduction response type core crosslinking micella of high stability；
2, on the one hand the crosslinking micella with cystine linkage contributes to reduce drug leakage and initial outburst release；Another party
Face also has reproducibility response in diseased region, rate of releasing drug can be improved, to improve therapeutic effect.
Description of the drawings
The gel permeation chromatography figure of Fig. 1 polymer, a:mPEG；b:mPEG-b-PAGE；c:mPEG-b-PAGE-b-PLLA1K；
The gel permeation chromatography figure of Fig. 2 polymer, a:mPEG；b:mPEG-b-PAGE；c:mPEG-b-PAGE-b-PLLA4K；
Fig. 3 transmission electron microscope pictures, A mPEG-b-PAGESH-b-PLLA1KMicellar solution；B is mPEG-b-PAGESH-b-
PLLA1KIt is crosslinked micellar solution；C is mPEG-b-PAGESH-b-PLLA4KMicellar solution；D is mPEG-b-PAGESH-b-PLLA4KIt hands over
Join micellar solution；
Release profiles (PBS=7.4,37 DEG C) A of Fig. 4 adriamycins:mPEG-b-PAGESH-b-PLLA4KIt is crosslinked micella, C:
mPEG-b-PAGESH-b-PLLA1KIt is crosslinked micella；(PBS-DTT, 37 DEG C) B:mPEG-b-PAGESH-b-PLLA4KIt is crosslinked micella, D:
mPEG-b-PAGESH-b-PLLA1KIt is crosslinked micella.
Specific implementation mode
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on the above of the present invention belong to this hair
Bright range.
(1) synthesis of amphipathic nature block polymer mPEG-b-PAGE：
Weigh 0.12g sodium hydride (NaH, contain mineral oil, 60%), be added to a 100mL history Lay under nitrogen atmosphere
In gram bottle, while the anhydrous THF of 10mL are extracted with syringe, be added in bottle, after agitator treating about 20min, stopped stirring and simultaneously will
Supernatant in bottle siphons away, and then weighs 10.00g mPEG (Mn=5000) and is added in Shrek bottle, and this bottle is put into
It is stirred in 100 DEG C of oil bath pans, after in the mPEG that the NaH in bottle is dissolved in melting, reinjects the AGE of 2.40mL, seal bottleneck,
It is reacted for 24 hours in 100 DEG C of oil bath pans.
After reaction, a small amount of glacial acetic acid is added to terminate polymerisation, after product is cooled to room temperature, is added certain
The dichloromethane of amount is dissolved, and silica gel column chromatography method separation product is then used, and first uses isopropanol will as eluant, eluent
PAGE and other impurity rinse out, then use isopropanol/chloroform instead and rinse and collect, rotate, then by concentrate dichloromethane
Dissolving is filtered to remove silica white, finally, concentrated by rotary evaporation, vacuum drying again.
(2) synthesis of triblock polymer mPEG-b-PAGE-b-PLLA：
The Shrek bottle of a 100mL is put into heating mantle first vacuumize, logical nitrogen waits for bottle repeatedly three times
After son is cooled to room temperature, nitrogen is opened greatly, and a certain amount of L-LA is added thereto, then bottle is placed in 40 DEG C of oil bath pans
Vacuumize 20min and then it is secondary open big nitrogen, be added a certain amount of initiator mPEG-b-PAGE, and by oil bath pot temperature tune
To 120 DEG C, after solid stirring melting in bottle, 2-3 drop octoate catalyst stannous is added dropwise with syringe, is stirred to react for 24 hours.
After reaction, reaction product is cooled to room temperature, then with a small amount of dichloromethane stirring and dissolving, and in cold second
It precipitates in ether, then collected by suction filter cake, is finally dried in vacuo.
The generated data of 1 triblock polymer of table
(3) triblock polymer mPEG-b-PAGE of the side chain containing mercapto groupsSHThe synthesis of-b-PLLA：
It weighs a certain amount of triblock polymer mPEG-b-PAGE-b-PLLA to be put into 100mL Shrek bottles, then use
Syringe extracts in the DMF injection bottles that 30mL newly steams, and after solid whole stirring and dissolving in bottle, adds a certain amount of 1,3-
Dimercaptopropane and bis- (the 2,4,6- trimethylphenyls acyl group) phosphine oxides ([C=C] of photosensitizer phenyl:[SH]:[photosensitizer]=1:
20:0.1) it, is protected from light with the covering of black carton, after drum nitrogen bubble 30min, seals bottleneck, and bottle is put into photocuring case,
Hg lamp irradiation reacts 2h.
After the completion of reaction, reaction solution ice ether is precipitated, then the filter cake CH of collected by suction2Cl2Dissolving, so
It is repeated several times, is finally dried in vacuo filter cake.
2 polymer mPEG-b-PAGE of tableSHThe generated data of-b-PLLA
As depicted in figs. 1 and 2, what a was represented is polyethylene glycol (mPEG), polymer mPEG-b-PAGE, the c representative that b is represented
Be triblock polymer mPEG-b-PAGE-b-PLLA.We can observe that, they flow through chromatographic column from a to c from figure
The required time is sequentially reduced, and that is to say that their rate of outflow is getting faster, this is just illustrating their average molecular matter
It measures increasing.In addition, according to standard curve analysis it is found that their narrow molecular weight distribution, this illustrates the polymer point of synthesis
Cloth is uniform.Therefore, this fully shows that we successfully synthesize triblock polymer mPEG-b-PAGE-b-PLLA.
(4) medicine and vitro drug release are carried
1. the preparation of polymer micelle solution
(a) polymer mPEG-b-PAGESH-b-PLLA1KThe preparation of micellar solution:
Weigh the polymer mPEG-b-PAGE of 200mg synthesisSH-b-PLLA1KIn 100mL single-necked flasks, it is added simultaneously
The DMF that 5mL newly steams is added to prevent disulfide bond crosslinking in 10mg dithiothreitol (DTT)s (DTT), after solid dissolving in bottle, drips dropwise
Add the secondary water of 25mL, and it is to be dripped every 35s mono- to control rate of addition, and after being added dropwise, 3500Da is loaded into after stirring 3h
Bag filter in, dialyse 4 days, and in the meantime daily all need be added 10mg DTT.Finally, by mixed solution in bag filter
It pours into the volumetric flask of 200mL, secondary water constant volume is used in combination, at this time a concentration of 1mg/mL of micellar solution.
(b) polymer mPEG-b-PAGESH-b-PLLA4KThe preparation of micellar solution:
Preparing for micellar solution is as above, weighs the polymer mPEG-b-PAGE of 20mg synthesisSH-b-PLLA4KIt is mono- in 100mL
In mouth flask, a concentration of 0.1mg/mL of final micellar solution.
2. being crosslinked the preparation of micella
(a) polymer mPEG-b-PAGESH-b-PLLA1KIt is crosslinked the preparation of micella:
By the polymer mPEG-b-PAGE of a concentration of 1mg/mL of the 200mL of above-mentioned preparationSH-b-PLLA1KMicellar solution is set
In 500mL single-necked flasks, the H that 2mL mass fractions are 1% is added2O2, 72h is then stirred at room temperature, at this moment solution is at muddy shape
State is still generated without precipitation.Later, dry on freeze drier, it is to be dried completely after, then with secondary water-dispersed on a small quantity, connect
It and is transferred in 3500Da bag filters, dialysis is for 24 hours.Finally it is lyophilized with freeze drier.
(b) polymer mPEG-b-PAGESH-b-PLLA4KIt is crosslinked the preparation of micella
Polymer mPEG-b-PAGESH-b-PLLA4KThe preparation method for being crosslinked micella is as above.
Fig. 3 is the transmission electron microscope picture of uncrosslinked micella and crosslinking micella, it can be seen that the micella particle diameter of gained
Narrowly distributing, good dispersion.Meanwhile the pattern of the micella after crosslinking does not change, and remains spherical micella.
3. the preparation of carrier micelle
(a) polymer mPEG-b-PAGESH-b-PLLA1KIt is crosslinked the load medicine of micella
The DOXHCl for weighing 5mg is put into the single-necked flask of 100mL, and DMF and 3.80 μ L that 2.50mL newly steams is added
Triethylamine after being completely dissolved, adds 30mg mPEG-b-PAGESH-b-PLLA1KIt is crosslinked micella, after 2h is stirred at room temperature, by it
It is transferred in 3500Da bag filters, dialysis is for 24 hours.After the completion of dialysis, the solution in bag filter is lyophilized on freeze drier, it is standby
With whole process need to be protected from light.
(b) polymer mPEG-b-PAGESH-b-PLLA4KIt is crosslinked the load medicine of micella
Polymer mPEG-b-PAGESH-b-PLLA4KThe medicine-carrying method for being crosslinked micella is as above, wherein weighing the DOX of 2mg
HCl, 1.50 μ L triethylamines.
4. vitro drug release is tested
(a) drug release in PBS buffer solution (pH=7.4)
(b) drug release in the PBS-DTT solution of 10mmol/L
After testing, calculating, it is known that the drugloading rate and encapsulation rate of carrier micelle, mPEG-b-PAGESH-b-PLLA1KIt hands over
Join micella：LC (%)=4.15%, encapsulation rate EE (%)=25.90%, mPEG-b-PAGESH-b-PLLA4KIt is crosslinked micella：LC
(%)=5.77%, EE (%)=36.74%.Fig. 4 be the burst size of the DOXHCl (doxorubicin hydrochloride) of carrier micelle at any time
Between the curve that changes.As we can clearly see from the figure, only PBS buffer solutions it is existing under the conditions of, the accumulation for being crosslinked micella is released
About it is seldom high-volume 30% and 55% respectively, while shows slower rate of release.But after reducing agent DTT is added,
The drug release behavior of crosslinking carrier micelle is obviously accelerated, and in the 12h of beginning, cumulative release amount has been more than 50%, even
Reach 85%.This behavior that in the presence of reducing agent DTT, the rate of release of adriamycin improves shows crosslinking carrier micelle tool
There is the drug release behavior of reduction response type.
Embodiment above describes the basic principles and main features and advantage of the present invention, and the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe the originals of the present invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (4)
1. a kind of preparation method of reduction response type ABC type block polymers, it is characterised in that include the following steps：(1) amphiphilic
The synthesis of property block copolymer mPEG-b-PAGE：
Sodium hydride is added under nitrogen atmosphere in Shrek bottle, and anhydrous THF is added in bottle, stirs 20min or more,
Stop stirring and siphoning away the supernatant in bottle, then mPEG is added in Shrek bottle, and this bottle is put into 100 DEG C of oil baths
It is stirred in pot, after in the mPEG that the NaH in bottle is dissolved in melting, reinjects AGE, seal bottleneck, it is anti-in 100 DEG C of oil bath pans
It should for 24 hours；After reaction, glacial acetic acid is added and terminates polymerisation, after product is cooled to room temperature, be added dichloromethane by its
Then dissolving uses silica gel column chromatography method separation product, isopropanol is first used to rinse PAGE and other impurity as eluant, eluent
Fall, then use isopropanol/chloroform instead and rinse and collect, rotate, then by the dissolving of concentrate dichloromethane, suction filtration to remove silica gel
Powder, finally, concentrated by rotary evaporation, vacuum drying are to get mPEG-b-PAGE again；
(2) synthesis of triblock polymer mPEG-b-PAGE-b-PLLA：
A Shrek bottle is put into heating mantle first vacuumize, logical nitrogen is added thereto after bottle is cooled to room temperature
Bottle is then placed in 40 DEG C of oil bath pans and vacuumizes by L-LA, later, initiator mPEG-b-PAGE is added, and by oil bath pot temperature
Degree is transferred to 120 DEG C, after solid stirring melting in bottle, octoate catalyst stannous is added dropwise with syringe, is stirred to react for 24 hours；
After reaction, reaction product is cooled to room temperature, then uses dichloromethane stirring and dissolving, and precipitated in cold ether,
Collected by suction filter cake is finally dried in vacuo to get triblock polymer mPEG-b-PAGE-b-PLLA；
(3) triblock polymer mPEG-b-PAGE of the side chain containing mercapto groupsSHThe synthesis of-b-PLLA：
Triblock polymer mPEG-b-PAGE-b-PLLA is put into Shrek bottle, then extracts the DMF newly steamed with syringe
It injects in bottle, after solid whole stirring and dissolving in bottle, adds 1,3- dimercaptopropanes and photosensitizer phenyl bis- (2,4,6-
Trimethylphenyl acyl group) phosphine oxide, it is protected from light with chest covering, bottle is put into photocuring case by drum nitrogen bubble 30min or more later
In, Hg lamp irradiation reacts 2h or more；
After the completion of reaction, reaction solution ice ether is precipitated, then the filter cake CH of collected by suction2Cl2Dissolving, it is several repeatedly
It is secondary, finally filter cake is dried in vacuo.
2. the reduction response type ABC type block polymers that method as claimed in claim 1 is prepared.
3. reduction response type ABC types block polymer is in the application as anti-cancer medicament carrier as claimed in claim 2.
4. application as claimed in claim 3, which is characterized in that the anticancer drug is adriamycin.
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Cited By (2)
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| CN112546237A (en) * | 2020-12-19 | 2021-03-26 | 广东工业大学 | Polyethylene glycol metal nano-composite and preparation method and application thereof |
| CN114410090A (en) * | 2022-01-25 | 2022-04-29 | 高国惠 | Preparation method of packaging film |
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| CN102060991A (en) * | 2010-11-26 | 2011-05-18 | 浙江大学 | Amphiphilic prodrug of 7- ethyl-10-hydroxycamptothecin and preparation method thereof |
| CN102604065A (en) * | 2012-03-27 | 2012-07-25 | 中国科学院长春应用化学研究所 | Cross-linked biologically degradable carrier polymer, micelle and vesicle, and preparation method and application of the cross-linked biologically degradable carrier polymer, micelle and vesicle |
| WO2014130846A1 (en) * | 2013-02-22 | 2014-08-28 | Seungpyo Hong | Transdermal drug delivery using amphiphilic dendron-coil micelles |
| CN104262600A (en) * | 2014-09-09 | 2015-01-07 | 天津大学 | Double-sensitive amphiphilic copolymer containing Schiff base and mercapto group on same side group, as well as preparation method and application of double-sensitive amphiphilic copolymer |
| CN108066770A (en) * | 2016-11-16 | 2018-05-25 | 烟台药物研究所 | Amphipathic nature polyalcohol prodrug of reduction response release active compound and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112546237A (en) * | 2020-12-19 | 2021-03-26 | 广东工业大学 | Polyethylene glycol metal nano-composite and preparation method and application thereof |
| CN114410090A (en) * | 2022-01-25 | 2022-04-29 | 高国惠 | Preparation method of packaging film |
| CN114410090B (en) * | 2022-01-25 | 2023-08-15 | 佛山市顺德区建德包装实业有限公司 | Preparation method of packaging film |
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