CN104856952B - A kind of preparation of poly- (L glutamic acid) b polyethylene glycol medicament-carried nano micelles - Google Patents
A kind of preparation of poly- (L glutamic acid) b polyethylene glycol medicament-carried nano micelles Download PDFInfo
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Abstract
L glutamic acid gamma benzyl ester N carboxylic acid anhydrides (BLG NCA) ring-opening polymerisation is triggered to prepare poly- (the L glutamic acid gammas benzyl ester) polymer of end sulfydryl using mercaptoethylmaine first, as Macromolecular chain transfer agent and activated monomer polyethylene glycol methacrylate-styrene polymer (MAPEG, Mn=475g/mol) carry out it is free-radical polymerized, obtain amphiphatic poly- (L glutamic acid gammas benzyl ester)-b polyethylene glycol；Recycle cystamine to be crosslinked poly- (L glutamic acid gammas benzyl ester) therein, while remaining γ benzyl esters group is converted into hydroxy-acid group, and electrostatic load adriamycin, nano-micelle is self-assembly of in aqueous.
Description
Technical field
A kind of preparation of PLGA-b- polyethylene glycol medicament-carried nano micelles, belongs to biomaterial and slow release method
Field.
Background technology
The special nucleocapsid structure of polymer micelle can as antineoplastic microstorage, be a kind of preferable medicine
Delivery systme.But traditional polymer micelle is due to a lack of the identification to tumour cell and response function, thus in tumor locus
Medicine can not be quickly discharged in time, therapeutic effect is not good, the example being applicable to clinically is considerably less.Also there is example in itself
The problems such as such as homeostasis can not be maintained when tackling temperature, the change of pH factors of surrounding environment；Simultaneously the micella by oral administration or
Injection enters after body fluid dilution for many times, is there are the phenomenons such as micellar nanoparticles disintegration in vivo, so as to cause the leakage of medicine.With
The quick emergence of the cross disciplines such as clinical medicine, biochemistry and nano material, a kind of stimulation with cross-linked structure rings
The birth of answering property polymer micelle system is so that above mentioned problem is readily solved, and it is poly- that this new micelle volume not only covers tradition
The advantage of compound micella, strengthens the stability of micellar nanoparticles, while can also be according to all between tumour cell and normal structure
Such as environmental difference of temperature, pH and oxidation-reduction quality reaches positioning, timing, the effect for quantitatively discharging medicine to its Intelligent Recognition,
Realize to medicine transport safely and Targeting delivery purpose.It polymerize at present for this stimulating responsive with cross-linked structure
Thing micella is used for the parcel of antineoplastic and the research of triggering release is still in initial stage, but it will be the diseases such as tumour
Diagnosis and treatment bring new breakthrough.
To ensure micellar nanoparticles safety non-toxic, the poly- second of usual people's selection good biocompatibility and degradability
Glycol and polyglutamic acid are used as the raw material for preparing micella.Polyethylene glycol is because of its stronger hydrophily and low immunogenicity, therefore
It is used as the report of micella hydrophily shell and studies of common occurrence；L-glutamic acid is used as the one of polyaminoacid cyclopean family
Member, it is degradable in vivo easily to be absorbed for Pidolidone monomer and small peptide by organism；In addition, its suspended side chain is abundant to have work
Property carboxylic group, can by chemical means carry out functional modification, strengthen medicine load capacity targeting, medicine,
Daily-use chemical industry, water process and medicament slow release field get most of the attention.
Therefore the present invention selects polyethylene glycol and Pidolidone to be primary raw material, and designing and preparing one kind has pH and reduction
Stimuli-responsive is crosslinked micella, for the Targeting delivery in the high-efficient carrier and tumour cell of adriamycin.Using cystamine as friendship
Join agent and γ-benzyl ester radical reaction, while remaining γ-benzyl ester group is switched into hydroxy-acid group in HBr/HAOc systems, utilize
The mode of electrostatical binding loads adriamycin.Carrier micelle prepared by this method has stronger stability, and medicine is difficult leakage, tool
There is higher bioavilability；The Targeting delivery of medicine can be quickly triggered under simulation faintly acid reducing condition, is shown substantially
PH and reduction dual responsiveness, there is potential application prospect in biological medicine and medicament slow release field.
The content of the invention
It is an object of the present invention to provide a kind of preparation method of PLGA-b- polyethylene glycol medicament-carried nano micelles, with
Pidolidone is that primary raw material prepares activated monomer Pidolidone-γ-benzyl ester-N- carboxylic acid anhydrides (BLG-NCA)；Using mercaptoethylmaine as
It is poly- (Pidolidone-γ-benzyl ester) that initiator triggers BLG-NCA ring-opening polymerisations to obtain end sulfydryl；As Macromolecular chain transfer agent
With activated monomer polyethylene glycol methacrylate-styrene polymer (MAPEG, Mn=475g/mol) reaction, obtain amphiphatic poly- (L- paddy ammonia
Acid-γ-benzyl ester)-b- polyethylene glycol；Cystamine is recycled to be crosslinked poly- (Pidolidone-γ-benzyl ester) therein, while in HBr/
Remaining γ-benzyl ester group is converted into hydroxy-acid group, and electrostatic load adriamycin in HAOc systems, nanometer is formed in aqueous
Micella.
The useful achievement of the present invention：
1), this method, which prepares to carry during medicine is crosslinked micella, introduces disulfide bond, while being born by the way of electrostatical binding
Medicine is carried, with significant pH and reduction response, medicine can be quickly triggered under faintly acid and reducing condition in tumour cell
Targeting delivery.
2), prepared by crosslinking agent of cystamine and carry medicine crosslinking micella, not only assign the characteristic of micellar nanoparticles reduction response,
There is stronger salt tolerance and dilution-resistant after micella is crosslinked through cystamine simultaneously, effectively extension medicine circulation time in vivo and
Drug effect is maintained, targeting moiety is safely and effectively conducted drugs to.
3), the present invention uses polyethylene glycol and Pidolidone for primary raw material, micella degradation in vivo prepared by this method
Afterwards, product safety non-toxic, is easily absorbed by the body, environment-friendly.
4), the present invention loads adriamycin by the way of electrostatical binding, and medicine participates in the composition of micella, improves micelle nano
The stability of particle, the probability of reduction medicine leakage, strengthens curative effect of medication.
Brief description of the drawings
Fig. 1 PLGA-b- polyethylene glycol medicament-carried nano micelles prepare schematic diagram
The infrared spectrogram of each materials of Fig. 2
Fig. 3 medicament-carried nano micelles PLS-1, PLS-2 and PLS-3 particle diameter distribution
The scanning electron microscope (SEM) photograph of Fig. 4 medicament-carried nano micelles：Wherein a, b, c, represent PLS-1, PLS-2 and PLS-3 respectively
Change of size of Fig. 5 medicament-carried nano micelles PLS-2 in 10mM glutathione solution under different time
The drug release patterns of Fig. 6 medicament-carried nano micelles at different conditions
Embodiment
It is described with reference to the drawings and the embodiment of the present invention is described in detail with embodiment, the following example is intended to
The description present invention, but be not intended to limit it and use scope.
Embodiment 1：Hold the preparation of sulfydryl poly- (Pidolidone-γ-benzyl ester)
It is 1 that molar feed ratio is sequentially added in the three-necked flask crossed in advance with nitrogen displacement:40 mercaptoethylmaine (AET)
And BLG-NCA, the two is dissolved in dichloromethane solvent, and it is 10w%, the magnetic under normal temperature in nitrogen atmosphere to make reactant total concentration
Power stirs 72h, concentration of reaction solution, and is added dropwise in excessive acetic acid butyl ester, and ice bath half an hour obtains flocculent deposit, centrifuges
Obtaining to be dried in vacuo at pale yellow precipitate, 35 DEG C must hold sulfydryl poly- (Pidolidone-γ-benzyl ester), abbreviation PLT.
Embodiment 2：The preparation of poly- (Pidolidone-γ-benzyl ester)-b- polyethylene glycol
PLT is codissolved in DMF solution together with polyethylene glycol methacrylate-styrene polymer (MAPEG), polyethylene glycol first used
The molecular weight of base acrylate is MnThe molar ratio of=475g/mol, PLT and polyethylene glycol methacrylate-styrene polymer is 1:1~
1:1.5, the two is dissolved in DMF solvent, and reactant total concentration is 15w%, using the AIBN of reactant gross weight 1% as initiation
Agent, carries out after radical polymerization, 24h reaction solution being added dropwise in ultra-pure water to obtain milky turbidity liquid under the conditions of 60 DEG C
Body, is transferred into dialysis 72h in the bag filter that molecular cut off is 3500, and 12h changes a water, is finally freeze-dried product
Poly- (Pidolidone-γ-the benzyl ester)-b- polyethylene glycol of faint yellow solid is obtained, referred to as：PLE；
Embodiment 3：The crosslinking of micella
The gained PLE of embodiment 2 and cystamine will be mixed to join in DMF solvent, cystamine and PLE respectively in molar ratio 1:1、
2:1、4:1 feeds intake, and the two total concentration being dissolved in DMF solvent is 12w%, is cooled to after magnetic agitation 5h at a temperature of 30 DEG C
Room temperature, is extracted reaction solution, and is added dropwise in ultra-pure water and is stirred untill having obvious Tyndall effect thereto, uses molecular cut off
To be freeze-dried after 3500 bag filter dialysis 72h, then it is that 0.8w% micellar solutions are standby to be made into concentration；Prepare according to the above ratio
A series of crosslinking micella of different crosslinking degrees.Synthetic route is shown in Fig. 1.
Embodiment 4：Carry the preparation that medicine is crosslinked micella
10 grams of 3 gained micellar solution of Example, is added to the mixed of 0.7 gram of trifluoroacetic acid (TFA) and 4.8 grams of HBr/HOAc
Close in solution (HBr accounts for HOAc 5wt%), at 0 DEG C after magnetic agitation 1h, take 2 grams of reaction solutions, hydrochloric acid Ah mould is added thereto
Distilled water is added dropwise thereto again after element (DOXHCl) powder 10mg, stirring 1h, until solution is in pale red and has substantially
Untill Tyndall effect, lucifuge magnetic agitation 12h transfers the solution into lucifuge in bag filter (molecular cut off 3500) and dialysed
After 24h, it is transferred to constant volume in volumetric flask and is kept in dark place.
Embodiment 5：Infrared spectrum analysis
Using Fourier infrared spectrograph in 4000~500cm-1In the range of above-mentioned product is measured, obtain infrared
3330cm in spectrogram such as Fig. 2, curve PLT-1、1750cm-1、770cm-1And 691cm-1Place corresponds to segment in polymer P LT respectively
The monosubstituted absworption peak of the amino absworption peak of repeat unit, the benzyl ester carbonyl absorption peak of its suspended side chain and phenyl ring；Binding curve
PLT has found that curve PLE not only remains curve PLT characteristic peak with PLE curve comparisons, and in 2950cm-1、1190cm-1
The absworption peak at place is remarkably reinforced, and it corresponds to the ethyoxyl of C-H absworption peaks on PEG main chain backbones and side chain repeat unit respectively
Absworption peak, illustrates that polyethylene glycol (Pidolidone-γ-benzyl ester) polymer P LE is successfully synthesized.Correlation curve PLS and curve
PLE find the two without significant difference, this is probably the reason of its proportion very little after PLE is crosslinked through cystamine, with curve PLE and
PLS compares, it can be seen that is located at amino absworption peak at 3330cm-1 etc. in curve PLS-DOX and has retained, and 1750cm-1、770cm-1And 691cm-1Absworption peak disappear, and positioned at 3500cm-1There is circle and wide absworption peak in place, illustrates benzyl ester in PLE
Group has been converted into hydroxy-acid group and combined with adriamycin.
Embodiment 6：
Particle diameter and the distribution of PLS crosslinking micellas (0.5g/L) are determined at 25 DEG C using dynamic laser light scattering instrument (DLS)
The particle diameter of situation such as Fig. 3, it can be seen that with the increase of cystamine crosslinking agent, PLS crosslinking micellar nanoparticles subtracts (PLS- therewith
1,143.7nm；PLS-2,132.9nm；PLS-3,112.8nm), after PLS hydrophobic segment is crosslinked by cystamine, it is to the poly- and thing
Hydrophobic segment produce constraint effect, gather and the intermolecular distance of thing reduce, inner core becomes closer, and the process will necessarily
The particle diameter of micellar nanoparticles is caused to reduce.As cystamine rate of charge increases, this constraint acts on also stronger, the micella of formation
The particle diameter of nano-particle becomes smaller, and this trend is also confirmed in scanning electron microscope (SEM) photograph.
Embodiment 7：
PLS crosslinking micellas in embodiment 4 are dropped on clean copper mesh, dried naturally, metal spraying 5min before test, scanning
The pattern of micellar nanoparticles is observed under voltage modulated 2kV high vacuum environments.It can be seen that in Fig. 4 with the increase of cystamine amount, PLS
The particle diameter for being crosslinked micellar nanoparticles is gradually smaller, and the variation tendency is consistent with the result that DLS is measured.Also it can be observed simultaneously
PLE polymer still keeps preferable spherical morphology after being crosslinked through cystamine, particle is full to be uniformly dispersed.
Embodiment 8：
PLS crosslinking micellas in embodiment 4 are diluted to 0.01mg/mL, taken out in some addition three-necked flasks；Thereto
It is passed through N2After 20min, adding a certain amount of GSH makes its ultimate density in the solution be 10mM；Place it in 37 DEG C of constant temperature
It is incubated in water-bath, compartment time utilization dynamic laser light scattering (DLS) tracking crosslinking micella solution is crosslinked the influence to its particle diameter.
Find that micella particle diameter in reducing environment there occurs great changes after crosslinking in Fig. 5,4h particle diameters slightly have increase after GSH is added；
Micelle inner core is swelled after 10h, and particle diameter increased dramatically under even greater than high concentration the particle diameter of (0.5mg/mL), and particle diameter distribution broadens；
Illustrate that be crosslinked the disulfide bond contained in micella is broken under reducing condition stimulation, hard-packed kernel distortion loosely causes
Micelle inner core is swelled generation the above results under stabilization removal, low concentration.Test shows：Micella is crosslinked in non reducing conditions
Extracellular environment has higher stability, and can occur quickly solution crosslinking in the intracellular environment of reducing condition.
Embodiment 9：
Load medicine in embodiment 4 is crosslinked micella concentration dilution to 1mg/mL, takes 5mL to be put in bag filter (molecular cut off
3500) in, the release experiment of adriamycin is carried out in temperature is 37 DEG C of isothermal vibration shaking table (200rap).Simulate respectively following
Four kinds of release conditions, every group of experiment sets three groups of Duplicate Samples (1) PLS-DOX load medicine crosslinking micellas and discharged under the conditions of PBS 7.4；
(2) PLS-DOX carries medicine crosslinking micella and discharged under the conditions of PBS 5.0；(3) PLS-DOX carries medicine crosslinking micella and deposited in 10mM GSH
Discharged in the case of under the conditions of PBS 7.4；(4) PLS-DOX carries medicine and is crosslinked micella under 10mM GSH existence conditions in PBS
Discharged under the conditions of 5.0.The PBS solution of 50mL correspondence release conditions is added in each beaker.Certain interval of time takes slow outside 4mL bags
Solution is rushed with determining its absorbance A at 483nm483, draw medicine Cumulative release profile.
As can be seen that under the conditions of same time and pH, bar is reduced in analog cell glutathion inside (GSH) in Fig. 6
The medicine Cumulative release amount that PLS-DOX under part carries medicine crosslinking micella is all higher than burst size under non reducing conditions, and tracing it to its cause is
Disulfide bond is broken under the stimulation of GSH reducing environments, and micelle inner core distortion is destroyed, loosely organized promotion medicine quick release,
It also found in figure, under non reducing conditions in 48h, crosslinking micella medicine Cumulative release amount under the conditions of acid (pH 5.0) is much larger than
PH 7.4 is crosslinked the burst size of micella, shows good pH and reduction response.The paddy in analog cell is also found in figure
Under the sweet peptide of Guang (GSH) reducing condition, pH 7.4 medicine Cumulative release amount is greater than pH 5.0 burst size, is primarily due in acid
Property under the conditions of GSH reducing powers it is weak compared with neutrallty condition end, in kernel disulfide bond reduction-sensitive response in terms of reduce, hinder
DOX release, causes it under identical reducing condition, pH 5.0 discharges slower result.The glue that in summary prepared by this method
Beam has good pH and reduction response, is expected to be applied in antitumor cell.
Claims (5)
1. a kind of preparation method of PLGA-b- polyethylene glycol medicament-carried nano micelles, comprises the following steps：
1) mercaptoethylmaine and Pidolidone-γ-benzyl ester-N- carboxylic acid anhydrides, are sequentially added in three-necked flask, using dichloromethane to be molten
Agent, in N2Magnetic agitation 72h under normal temperature, concentration of reaction solution in atmosphere, and be added dropwise in excessive butyl acetate, ice bath is cold
But, flocculent deposit is obtained after half an hour, pale yellow precipitate is centrifuged to obtain, poly- (the L- paddy ammonia of sulfydryl must be held by being dried in vacuo at 35 DEG C
Acid-γ-benzyl ester), referred to as：PLT；
2), by step 1) in prepare PLT be codissolved in together with polyethylene glycol methacrylate-styrene polymer in DMF solution, with reactant
The AIBN of gross weight 1% is initiator, carries out after radical polymerization, 24h reaction solution being added dropwise under the conditions of 60 DEG C super
Milky turbidity liquid is obtained in pure water, dialysis 72h in the bag filter that molecular cut off is 3500 is transferred into, 12h is changed once
Water, is finally freeze-dried to obtain poly- (Pidolidone-γ-the benzyl ester)-b- polyethylene glycol of faint yellow solid by product, referred to as：PLE；
3), by step 2) gained PLE and cystamine be mixed to join in DMF solvent, the cooling after magnetic agitation 5h at a temperature of 30 DEG C
To room temperature, extract reaction solution, ultra-pure water is added dropwise thereto, stir untill having obvious Tyndall effect, with retention molecule
It is freeze-dried after measuring the bag filter dialysis 72h for 3500, then it is that 0.8w% micellar solutions are standby to be made into concentration；
4) step 3, is taken) 10 grams of micellar solution of gained, it is added to 0.7 gram of trifluoroacetic acid and 4.8 grams of HBr/HOAc mixed solution
In, HBr accounts for HOAc 5wt%, at 0 DEG C after magnetic agitation 1h, takes 2 grams of reaction solutions, doxorubicin hydrochloride powder is added thereto
Distilled water is added dropwise thereto again after 10mg, stirring 1h, until solution is in pale red and untill having obvious Tyndall effect, keeps away
Light magnetic agitation 12h, is transferred the solution into the bag filter that molecular cut off is 3500, after lucifuge dialysis 24h, is transferred to capacity
Constant volume is kept in dark place in bottle.
2. a kind of preparation method of PLGA-b- polyethylene glycol medicament-carried nano micelles according to claim 1, it is special
Levy is in step 1) in, the molar ratio of mercaptoethylmaine and Pidolidone-γ-benzyl ester-N- carboxylic acid anhydrides is 1:30~1:50；Two
Person is dissolved in dichloromethane solvent, and reactant total concentration is 10w%.
3. a kind of preparation method of PLGA-b- polyethylene glycol medicament-carried nano micelles according to claim 1, it is special
Levy is in step 2) in, the molecular weight of polyethylene glycol methacrylate-styrene polymer used is Mn=475g/mol, PLT and polyethylene glycol first
The molar ratio of base acrylate is 1:1~1:1.5, the two is dissolved in DMF solvent, and reactant total concentration is 15w%.
4. a kind of preparation method of PLGA-b- polyethylene glycol medicament-carried nano micelles according to claim 1, it is special
Levy is in step 3) in, cystamine and PLE respectively in molar ratio 1:1、2:1、4:1 is fed intake, and the two is dissolved in DMF solvent, reaction
Thing total concentration be 12w%, synthesize by above-mentioned three kinds of ingredient proportions obtain three kinds carry medicines be crosslinked micellas, be respectively designated as PLS-1,
PLS-2、PLS-3。
5. a kind of application of PLGA-b- polyethylene glycol medicament-carried nano micelles in pharmaceutical carrier is prepared, it is characterized in that
Preparation method according to claim 1 obtains PLGA-b- polyethylene glycol medicament-carried nano micelles, by wherein gathering
The electrostatic interaction carrying medicament adriamycin of (Pidolidone) side chain carboxyl group, the paddy Guang that concentration is 10mM is placed in by medicament-carried nano micelle
In sweet peptide solution, insoluble drug release is carried out under the mild acid conditions of pH=5.0~6.0, medicament-carried nano micelle display reduction and pH are double
Weight sensitiveness.
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| CN105395483B (en) * | 2015-12-21 | 2018-09-28 | 江南大学 | One kind can deoxidization, degradation dissaving polymer nano-micelle and preparation method thereof |
| CN107281500A (en) * | 2016-04-08 | 2017-10-24 | 中国科学院化学研究所 | A kind of adriamycin composite and preparation method and application |
| JPWO2018025699A1 (en) | 2016-08-02 | 2019-05-30 | 日本化薬株式会社 | Active targeting type polymer derivative, composition containing the polymer derivative and use thereof |
| CN106750376B (en) * | 2016-12-26 | 2018-09-28 | 江南大学 | A kind of preparation method of the turnover reduction sensitivity reversible crosslink nano-micelle of charge |
| WO2019157714A1 (en) * | 2018-02-14 | 2019-08-22 | Jan Jeng Shiung | Amphiphilic block copolymer, nanoparticle containing the same, medicinal composition thereof and method of inhibiting ribonucleic acid binding to human antigen r using the same |
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| CN111592645B (en) * | 2020-06-04 | 2022-09-06 | 广州医科大学附属肿瘤医院 | Polyethylene glycol-aliphatic saturated polyester block copolymer with aldehyde group on side chain and application thereof |
| CN114409607B (en) * | 2022-01-26 | 2023-08-08 | 长春理工大学 | Thioether group-containing N-carboxyl cyclic anhydride and preparation method and application thereof |
| CN115894905B (en) * | 2022-08-30 | 2023-08-08 | 山东华铂凯盛生物科技有限公司 | Preparation method and application of high-purity narrow-molecular-weight-distribution methoxy polyethylene glycol-poly (L-sodium glutamate) |
| CN115197433B (en) * | 2022-09-13 | 2023-01-24 | 山东华铂凯盛生物科技有限公司 | Preparation method of nano-drug carrier methoxypolyethylene glycol-poly (L-sodium glutamate) |
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