CN104856952A - Preparation of poly(L-glutamic acid)-b-polyethylene glycol medicine carrying nano micelle - Google Patents
Preparation of poly(L-glutamic acid)-b-polyethylene glycol medicine carrying nano micelle Download PDFInfo
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- CN104856952A CN104856952A CN201510244130.4A CN201510244130A CN104856952A CN 104856952 A CN104856952 A CN 104856952A CN 201510244130 A CN201510244130 A CN 201510244130A CN 104856952 A CN104856952 A CN 104856952A
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Abstract
The invention firstly adopts mercaptoethylamine to trigger ring opening polymerization of L-glutamic acid-gamma-benzyl ester-N-carboxylic acid anhydride (BLG-NCA) to prepare mercaptyl-terminated (L-glutamic acid-gamma-benzyl ester) polymer, the mercaptyl-terminated (L-glutamic acid-gamma-benzyl ester) polymer is used as a macromolecular chain transfer agent to perform free radical polymerization with activated monomer polyethylene glycol metacrylic acid ester (MAPEG, Mn is equal to 475g/mol), and thereby amphiphilic poly(L-glutamic acid)-b-polyethylene glycol is obtained; cystamine is used for crosslinking L-glutamic acid-gamma-benzyl ester therein, meanwhile the residual gamma-benzyl ester groups are converted into carboxylic acid groups and adriamycin amycin is statically loaded, and thereby the nano micelle is formed by self-assembling in aqueous solution.
Description
Technical field
A preparation for PLGA-b-Polyethylene Glycol medicament-carried nano micelle, belongs to biomaterial and slow release method field.
Background technology
The special nucleocapsid structure of polymer micelle can be used as the microstorage of antitumor drug, is a kind of desirable drug delivery system.But traditional polymer micelle is for want of to identification and the response function of tumor cell, thus can not discharge medicine in time fast at tumor locus, therapeutic effect is not good, and the example that can be applied to clinically is considerably less.Itself also exist and such as can not maintain the problems such as homeostasis when tackling temperature, the pH factors vary of surrounding; It is interior by after body fluid dilution for many times that this micelle oral administration or injection simultaneously enters body, occurs the phenomenons such as micellar nanoparticles disintegration, thus cause the leakage of medicine.Along with clinical medicine, the quick emergence of the cross discipline such as biochemistry and nano material, a kind of birth with the stimulating responsive polymer micelle volume of cross-linked structure makes the problems referred to above be readily solved, this novel micelle volume not only contains the advantage of traditional polymer micelle, strengthen the stability of micellar nanoparticles, simultaneously can also according to such as temperature between tumor cell and normal structure, the environmental difference of pH and oxidation-reduction quality is to its Intelligent Recognition, reach location, regularly, the effect of quantitative release medicine, realize transporting safely and the object of Targeting delivery medicine.At present still initial stage is in for the parcel of antitumor drug and the research of triggering release for this stimulating responsive polymer micelle with cross-linked structure, but it will bring new breakthrough for Diagnosis and Treat of the diseases such as tumor.
For ensureing micellar nanoparticles safety non-toxic, usual people select the Polyethylene Glycol of good biocompatibility and degradability and polyglutamic acid as the raw material preparing micelle.Polyethylene Glycol, because of its stronger hydrophilic and reduced immunogenicity, is therefore used as the report of micelle hydrophilic shell and studies of common occurrence; L-glutamic acid, as a member of polyamino acid cyclopean family, is easily degraded to Pidolidone monomer and small peptide in vivo and is easily absorbed by organism; In addition, its suspended side chain enriches the activated carboxylic group of tool, carries out functional modification by chemical means, strengthens the targeting of the load capacity of medicine, gets most of the attention in medicine, daily-use chemical industry, water treatment and medicament slow release field.
Therefore the present invention selects Polyethylene Glycol and Pidolidone to be primary raw material, designs and prepare one to have pH and reduction stimuli-responsive is cross-linked micelle, for the Targeting delivery in the high-efficient carrier of amycin and tumor cell.Be that cross-linking agent and γ-carbobenzoxy group are rolled into a ball and reacted with cystamine, in HBr/HAOc system, transfer residue γ-carbobenzoxy group group to hydroxy-acid group simultaneously, utilize the mode load amycin of electrostatical binding.Carrier micelle prepared by the method has stronger stability, and medicine is not easily revealed, and has higher bioavailability; The Targeting delivery of energy rapid triggering medicine under simulation faintly acid reducing condition, shows obvious pH and reduction dual responsiveness, has potential application prospect in biological medicine and medicament slow release field.
Summary of the invention
The object of the invention is to provide a kind of preparation method of PLGA-b-Polyethylene Glycol medicament-carried nano micelle, is that primary raw material prepares activated monomer Pidolidone-γ-benzyl ester-N-carboxylic acid anhydrides (BLG-NCA) with Pidolidone; Be that initiator inducing B LG-NCA ring-opening polymerisation obtains end sulfydryl poly-(Pidolidone-γ-benzyl ester) with mercaptoethylmaine; As Macromolecular chain transfer agent and activated monomer polyethylene glycol methacrylate-styrene polymer (MAPEG, M
n=475g/mol) reaction, obtain amphiphatic poly-(Pidolidone-γ-benzyl ester) – b-Polyethylene Glycol; Poly-(Pidolidone-γ-benzyl ester) is wherein cross-linked by recycling cystamine, in HBr/HAOc system, residue γ-carbobenzoxy group group is converted into hydroxy-acid group simultaneously, and electrostatic load amycin, form nano-micelle in aqueous.
Useful achievement of the present invention:
1), the method is prepared medicine carrying and is cross-linked in the process of micelle and introduces disulfide bond, adopt the mode carrying medicament of electrostatical binding simultaneously, there is significant pH and reduction response, can in tumor cell the Targeting delivery of rapid triggering medicine under faintly acid and reducing condition.
2) be, that cross-linking agent is prepared medicine carrying and is cross-linked micelle with cystamine, not only give the characteristic of micellar nanoparticles reduction response, micelle has stronger salt tolerance and dilution-resistant after cystamine is cross-linked simultaneously, effective prolong drug circulation time in vivo and maintenance drug effect, conduct drugs to targeting moiety safely and effectively.
3), the present invention adopts Polyethylene Glycol and Pidolidone to be primary raw material, and after micelle degradation in vivo prepared by the method, product safety non-toxic, is easily absorbed by the body, environmental friendliness.
4), the present invention adopts the mode load amycin of electrostatical binding, and medicine participates in the composition of micelle, improves the stability of micellar nanoparticles, reduces the probability that medicine is revealed, medicament curative effect enhancement.
Accompanying drawing explanation
Fig. 1 PLGA-b-Polyethylene Glycol medicament-carried nano micelle prepare schematic diagram
The infrared spectrogram of each material of Fig. 2
Fig. 3 medicament-carried nano micelle PLS-1, the particle size distribution of PLS-2 and PLS-3
The scanning electron microscope (SEM) photograph of Fig. 4 medicament-carried nano micelle: wherein a, b, c, represents PLS-1 respectively, PLS-2 and PLS-3
The change of size of Fig. 5 medicament-carried nano micelle PLS-2 in the glutathione solution of 10mM under different time
Fig. 6 medicament-carried nano micelle drug release patterns at different conditions
Detailed description of the invention
Accompanying drawings and embodiment are described in detail to the specific embodiment of the present invention, and the following example is intended to describe the present invention, but is not used for limiting its scope of application.
Embodiment 1: the preparation of end sulfydryl poly-(Pidolidone-γ-benzyl ester)
Mercaptoethylmaine (AET) and BLG-NCA that molar feed ratio is 1:40 is added successively in there-necked flask transposed with nitrogen in advance, the two is dissolved in dichloromethane solvent, reactant total concentration is made to be 10w%, in nitrogen atmosphere, room temperature lower magnetic force stirs 72h, concentration of reaction solution, and be added dropwise in excessive acetic acid butyl ester, ice bath obtains flocculent deposit half an hour, centrifugalize obtains pale yellow precipitate, at 35 DEG C, vacuum drying must hold sulfydryl to gather (Pidolidone-γ-benzyl ester), is called for short PLT.
Embodiment 2: the poly-(preparation of Pidolidone-γ-benzyl ester) – b-Polyethylene Glycol
Be dissolved in DMF solution by PLT altogether together with polyethylene glycol methacrylate-styrene polymer (MAPEG), the molecular weight of polyethylene glycol methacrylate-styrene polymer used is M
n=475g/mol, the molar ratio of PLT and polyethylene glycol methacrylate-styrene polymer is 1:1 ~ 1:1.5, the two is dissolved in DMF solvent, reactant total concentration is 15w%, with the AIBN of reactant gross weight 1% for initiator, radical polymerization is carried out under 60 DEG C of conditions, after 24h, reactant liquor is dropwise joined in ultra-pure water and obtain milky turbidity liquid, transferred to molecular cut off be 3500 bag filter in dialyse 72h, 12h changes a water, finally product lyophilization is obtained the poly-(Pidolidone-γ-benzyl ester) – b-Polyethylene Glycol of faint yellow solid, be called for short: PLE,
Embodiment 3: being cross-linked of micelle
By embodiment 2 gained PLE with cystamine is mixed to join in DMF solvent, 1:1,2:1,4:1 feed intake in molar ratio respectively for cystamine and PLE, the two total concentration be dissolved in DMF solvent is 12w%, room temperature is cooled to after 30 DEG C of temperature lower magnetic forces stir 5h, extract reaction solution, dropwise adding wherein in ultra-pure water and stir until there is obvious Tyndall effect, is the bag filter dialysis 72h postlyophilization of 3500 with molecular cut off, then to be made into concentration be that 0.8w% micellar solution is for subsequent use; Prepare the crosslinked micelle of a series of different crosslinking degree according to the above ratio.Synthetic route is shown in Fig. 1.
Embodiment 4: medicine carrying is cross-linked the preparation of micelle
Example 3 gained micellar solution 10 grams, join (HBr accounts for the 5wt% of HOAc) in the mixed solution of 0.7 gram of trifluoroacetic acid (TFA) and 4.8 grams of HBr/HOAc, after 0 DEG C of lower magnetic force stirs 1h, get 2 grams of reactant liquors, add doxorubicin hydrochloride (DOXHCl) powder 10mg wherein, dropwise distilled water is added wherein again after stirring 1h, until solution is pale red and has obvious Tyndall effect, lucifuge magnetic agitation 12h, after solution being transferred to bag filter (molecular cut off 3500) middle lucifuge dialysis 24h, be transferred to standardize solution in volumetric flask to keep in Dark Place.
Embodiment 5: infrared spectrum analysis
Adopt Fourier infrared spectrograph at 4000 ~ 500cm
-1scope in above-mentioned product is measured, obtain infrared spectrogram as Fig. 2,3330cm in curve PLT
-1, 1750cm
-1, 770cm
-1and 691cm
-1the monosubstituted absworption peak of the amino absworption peak of segmental repeat unit, the benzyl ester carbonyl group absworption peak of its suspended side chain and phenyl ring in the corresponding polymer P LT of place's difference; Binding curve PLT and PLE curve comparison find, curve PLE not only remains the characteristic peak of curve PLT, and at 2950cm
-1, 1190cm
-1the absworption peak at place obviously strengthens, and it corresponds to the ethyoxyl absworption peak of C-H absworption peak on PEG main chain backbone and side chain repetitive respectively, illustrates that polyethylene glycol-(Pidolidone-γ-benzyl ester) polymer P LE successfully synthesizes.Without obviously difference both correlation curve PLS and curve PLE finds, this may be PLE its proportion cause very little after cystamine is cross-linked, compare with curve PLE and PLS, can find out that the amino absworption peak etc. being positioned at 3330cm-1 place in curve PLS-DOX retains all to some extent, and 1750cm
-1, 770cm
-1and 691cm
-1absworption peak disappear, and be positioned at 3500cm
-1there is circle and wide absworption peak in place, illustrates that in PLE, carbobenzoxy group group has been converted into hydroxy-acid group and has been combined with amycin.
Embodiment 6:
Adopt dynamic laser light scattering instrument (DLS) at 25 DEG C, measure PLS and be cross-linked the size and distribution situation of micelle (0.5g/L) as Fig. 3, can find out, along with the increase of cystamine cross-linking agent, the particle diameter that PLS is cross-linked micellar nanoparticles subtracts (PLS-1,143.7nm thereupon; PLS-2,132.9nm; PLS-3,112.8nm), after the hydrophobic segment of PLS is cross-linked by cystamine, its hydrophobic segment that is poly-to this and thing produces constraint effect, poly-and the intermolecular distance of thing reduces, and inner core becomes tightr, and this process will inevitably cause the particle diameter of micellar nanoparticles to reduce.Along with cystamine rate of charge increases, this constraint effect is also stronger, and the particle diameter of the micellar nanoparticles of formation becomes less, and this trend is also confirmed in scanning electron microscope (SEM) photograph.
Embodiment 7:
PLS in embodiment 4 is cross-linked micelle drop on clean copper mesh, naturally dries, metal spraying 5min before test, under scanning voltage modulation 2kV high vacuum environment, observe the pattern of micellar nanoparticles.Can find out the increase along with cystamine amount in Fig. 4, the particle diameter that PLS is cross-linked micellar nanoparticles is less gradually, and the result that this variation tendency and DLS record conforms to.Also can be observed PLE polymer simultaneously and still keep good spherical morphology after cystamine is crosslinked, particle is full to be uniformly dispersed.
Embodiment 8:
PLS in embodiment 4 is cross-linked micelle and is diluted to 0.01mg/mL, take out and somely add in there-necked flask; Pass into N wherein
2after 20min, add a certain amount of GSH and make its ultimate density in this solution be 10mM; Place it in 37 DEG C of thermostat water baths and hatch, the crosslinked micelle solution of compartment time utilization dynamic laser light scattering (DLS) tracking is cross-linked the impact on its particle diameter.Find in Fig. 5 that crosslinked rear micelle particle diameter in reducing environment there occurs great changes, after adding GSH, 4h particle diameter slightly increases; After 10h, micelle inner core is swelling, particle diameter sharply increase even be greater than high concentration under the particle diameter of (0.5mg/mL), particle size distribution broadens; Illustrate that the intrafascicular disulfide bond contained of cross-linked rubber ruptures under reducing condition stimulates, hard-packed kernel distortion is loose causes stabilization removal, and under low concentration, swelling generation the above results occurs micelle inner core.Test shows: crosslinked micelle has higher stability at the extracellular environment of non reducing conditions, and can occur to separate fast crosslinked at the intracellular environment of reducing condition.
Embodiment 9:
Medicine carrying in embodiment 4 being cross-linked micelle concentration dilution to 1mg/mL, getting 5mL and be put in bag filter (molecular cut off 3500), is the release experiment of carrying out amycin in the isothermal vibration shaking table (200rap) of 37 DEG C in temperature.The following four kinds of release conditions of simulation respectively, often group experiment setting three groups of Duplicate Samples (1) PLS-DOX medicine carryings are cross-linked micelle and discharge under PBS 7.4 condition; (2) PLS-DOX medicine carrying is cross-linked micelle and discharges under PBS 5.0 condition; (3) PLS-DOX medicine carrying is cross-linked micelle and discharges under PBS 7.4 condition under 10mM GSH exists situation; (4) PLS-DOX medicine carrying is cross-linked micelle and discharges under PBS 5.0 condition under 10mM GSH existence condition.The PBS solution of the corresponding release conditions of 50mL is added in each beaker.Certain interval of time gets the outer buffer solution of 4mL bag and 483nm place measures its absorbance A
483, draw medicine Cumulative release profile.
Can find out in Fig. 6, under same time and pH condition, the medicine Cumulative release amount that the PLS-DOX medicine carrying be under analog cell glutathion inside (GSH) reducing condition is cross-linked micelle is all greater than burst size under non reducing conditions, tracing it to its cause is disulfide bond fracture under GSH reducing environment stimulates, micelle inner core distortion is destroyed, loosely organized promotion medicine discharges fast, also find in figure, under non reducing conditions in 48h, crosslinked micelle medicine Cumulative release amount under acid (pH 5.0) condition is cross-linked the burst size of micelle much larger than pH 7.4, demonstrate good pH and reduction response.Also find in figure under analog cell glutathion inside (GSH) reducing condition, the medicine Cumulative release amount of pH 7.4 is greater than the burst size of pH 5.0, it is main because GSH reducing power is weak compared with neutrallty condition end in acid condition, in kernel, the reduction-sensitive response aspect of disulfide bond reduces, hinder the release of DOX, cause it under identical reducing condition, pH 5.0 discharges slower result.The micelle that in summary prepared by the method has good pH and reduction response, is expected to be applied in antitumor cell.
Claims (6)
1. a preparation method for PLGA-b-Polyethylene Glycol medicament-carried nano micelle, comprises the following steps:
1), in there-necked flask, adding mercaptoethylmaine (AET) and Pidolidone-γ-benzyl ester-N-carboxylic acid anhydrides (BLG-NCA) successively, is solvent with dichloromethane, at N
2in atmosphere, room temperature lower magnetic force stirs 72h, concentration of reaction solution, and is added dropwise in excessive butyl acetate, ice bath cools, and obtain flocculent deposit after half an hour, centrifugalize obtains pale yellow precipitate, at 35 DEG C, vacuum drying must hold sulfydryl to gather (Pidolidone-γ-benzyl ester), is called for short: PLT;
2), by step 1) in preparation PLT be dissolved in DMF solution altogether together with polyethylene glycol methacrylate-styrene polymer (MAPEG), with the AIBN of reactant gross weight 1% for initiator, radical polymerization is carried out under 60 DEG C of conditions, after 24h, reactant liquor is dropwise joined in ultra-pure water and obtain milky turbidity liquid, transferred to molecular cut off be 3500 bag filter in dialyse 72h, 12h changes a water, finally product lyophilization is obtained faint yellow solid poly-(Pidolidone-γ-benzyl ester) – b-Polyethylene Glycol, abbreviation: PLE;
3), by step 2) gained PLE and cystamine (Cys) be mixed to join in DMF solvent, room temperature is cooled to after 30 DEG C of temperature lower magnetic forces stir 5h, extract reaction solution, dropwise add ultra-pure water wherein, stir until there is obvious Tyndall effect, with the bag filter dialysis 72h postlyophilization that molecular cut off is 3500, then to be made into concentration be that 0.8w% micellar solution is for subsequent use;
4), get step 3) gained micellar solution 10 grams, join (HBr accounts for the 5wt% of HOAc) in the mixed solution of 0.7 gram of trifluoroacetic acid (TFA) and 4.8 grams of HBr/HOAc, after 0 DEG C of lower magnetic force stirs 1h, get 2 grams of reactant liquors, add doxorubicin hydrochloride (DOXHCl) powder 10mg wherein, dropwise distilled water is added wherein again after stirring 1h, until solution is pale red and has obvious Tyndall effect, lucifuge magnetic agitation 12h, after solution being transferred to bag filter (molecular cut off 3500) middle lucifuge dialysis 24h, be transferred to standardize solution in volumetric flask to keep in Dark Place.
2. the preparation method of a kind of PLGA-b-Polyethylene Glycol medicament-carried nano micelle according to claim 1, it is characterized in that in step 1) in, mercaptoethylmaine (AET) is 1:30 ~ 1:50 with the molar ratio of Pidolidone-γ-benzyl ester-N-carboxylic acid anhydrides (BLG-NCA); The two is dissolved in dichloromethane solvent, and reactant total concentration is 10w%.
3. the preparation method of a kind of PLGA-b-Polyethylene Glycol medicament-carried nano micelle according to claim 1, is characterized in that in step 2) in, the molecular weight of polyethylene glycol methacrylate-styrene polymer used is M
nthe molar ratio of=475g/mol, PLT and polyethylene glycol methacrylate-styrene polymer is 1:1 ~ 1:1.5, and the two is dissolved in DMF solvent, and reactant total concentration is 15w%.
4. the preparation method of a kind of PLGA-b-Polyethylene Glycol medicament-carried nano micelle according to claim 1, it is characterized in that in step 3) in, 1:1,2:1,4:1 feed intake in molar ratio respectively for cystamine and PLE, the two is dissolved in DMF solvent, reactant total concentration is 12w%, obtain three kinds of medicine carryings by above-mentioned three kinds of ingredient proportions synthesis and be cross-linked micelle, called after PLS-1, PLS-2, PLS-3 respectively.
5. a PLGA-b-Polyethylene Glycol medicament-carried nano micelle, it is characterized in that method synthesis according to claim 1, define the nano-micelle of nucleocapsid structure, wherein the carboxyl of PLGA side chain passes through electrostatic interaction load drug adriamycin.
6. the application of a PLGA-b-Polyethylene Glycol medicament-carried nano micelle, it is characterized in that medicament-carried nano micelle described in claim 5 being placed in glutathion (GSH) solution that concentration is 10mM, drug release is carried out, medicament-carried nano micelle display reduction and pH doubling sensitivity under the mild acid conditions of pH=5.0 ~ 6.0.
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| CN115894905A (en) * | 2022-08-30 | 2023-04-04 | 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 methoxypolyethylene glycol-poly (L-sodium glutamate) |
| 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) |
| CN115197433A (en) * | 2022-09-13 | 2022-10-18 | 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) |
| 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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