CN104774329A - Acid-sensitive polymer carrier for delivering antitumor drugs, and preparation method and application thereof - Google Patents
Acid-sensitive polymer carrier for delivering antitumor drugs, and preparation method and application thereof Download PDFInfo
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- CN104774329A CN104774329A CN201510051159.0A CN201510051159A CN104774329A CN 104774329 A CN104774329 A CN 104774329A CN 201510051159 A CN201510051159 A CN 201510051159A CN 104774329 A CN104774329 A CN 104774329A
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Abstract
The invention discloses an acid-sensitive polymer carrier for delivering antitumor drugs, and a preparation method and a drug carrying application thereof. The polymer carrier is prepared through connecting sodium polyglutamate with carboxymethylcysteine through a peptide bond. The polymer carrier is used for delivering paclitaxel, doxorubicin, camptothecin and other antitumor drugs, polymer prodrugs formed through bonding the carrier with the drugs can self-assemble in water to form nanoparticles, so the water solubility and the biocompatibility of the drugs are improved, drug release is accelerated in tumor acidic environment, and the curative effects and the bioavailability of the drugs are improved.
Description
Technical field
The present invention relates to polymer chemistry and nanometer medical art, specifically a kind of acid-sensitive polymer carrier of sending for antitumor drug and preparation method and medicine carrying application.
Background technology
Current chemotherapy is still one of Main Means for the treatment of tumour, and traditional small molecules tumour medicine is due to poorly water-soluble, reason such as shortage tumor tissues targeting and multi-drug resistant etc., causes clinical efficacy low.The medicine of poorly water-soluble is connected with water-soluble polymer carrier, makes Macromolecule Prodrug, the water-soluble of medicine can be significantly improved, extend the plasma drug transformation period, accumulated at tumor tissues by polymer EPR effect simultaneously, reduce drug toxicity, improve curative effect of medication.Since polymer carrier began one's study from 1975, the polymer carrier of minority has been only had to enter clinical trial, comprising polyoxyethylene glycol, polyglutamic acid, cyclodextrin.But these polymers all exist certain problem, such as in aqueous phase, self-assembly cannot form nanoparticle, drug loading is not high, lacks tumor tissues susceptibility.
Polyglutamic acid is a kind of water-soluble, not containing toxicity, use the biopolymer that microbe fermentation method is obtained, there is good bioaffinity and biological degradability, controlled drug release, targeting can be provided as pharmaceutical carrier, improve medicine water-soluble, reduce adverse drug reaction, thus improve curative effect of medication.The antitumor drug paclitaxel that poorly water-soluble, medicinal exploitation are very limited is connected on polyglutamic acid by Chun Li etc., synthesize polyglutamic acid prodrug PGA-PTX, this Macromolecule Prodrug shows the cancer resistance of higher water-soluble, wide spectrum and good pharmacokinetic property, eliminate slowly in vivo, extended durations of action, bioavailability improves.HPLC analyzes announcement, and in extracellular, PPX prodrug constantly discharges taxol, is transported in cell subsequently, maintains taxol in intracellular concentration, extends taxol residence time in blood plasma, strengthen the distribution of taxol in tumor tissues.But cause drug loading not high because medicine carrying site (-COOH) is limited, self-assembly cannot form nanoparticle, and lack the function of fixed point Stable Release medicine in tumour cell, limit its application.
Warp is to existing document exploration discovery, and medicine is connected the Macromolecule Prodrug self-assembly formation nanoparticle in aqueous that can make to obtain by the amino acid derivative of a certain length with polymer, strengthen the water-soluble and drug loading of Macromolecule Prodrug further.Study simultaneously and also find, compared with healthy tissues, tumor tissues has acid microenvironment.There is the nanoparticle that the polymer carrier of acid-sensitive and medicine are formed, the fixed point release of acid tumor tissues can be realized in human body, to sour environment, there is passive target, reduce the toxic side effect of medicine, there is higher application prospect.
Summary of the invention
The object of the present invention is to provide a kind of acid-sensitive polymer carrier and preparation method, the method is on the basis of Polyurethane-epoxy resin (PGA), each PGA unit increases a carbocisteine molecule, defines the acid-sensitive polymer carrier of each unit containing two medicine carrying sites.
Another object of the present invention is to provide the application of a kind of acid-sensitive polymer carrier in antitumor drug is sent, namely the clinical application for antitumor drug limits, utilize above-mentioned acid-sensitive polymer carrier, design, synthesize, assemble acid-sensitive high molecular antineoplastic prodrug, to improve curative effect and the bioavailability of medicine, accelerated release in vitro medicine under sour environment, reduces its toxic side effect, to overcoming the barrier that current antitumor drug is restricted in clinical application.
The concrete technical scheme realizing the object of the invention is:
For the acid-sensitive polymer carrier that antitumor drug is sent, this polymer carrier has structure as follows:
Wherein: n is the polymerization degree, the molecular weight of polymer carrier is at 30000 ~ 60000Da, and the nano particle diameter that polymer carrier and medicine are connected to form can control between 10 ~ 30nm, and size distribution PDI is 0.2 ~ 0.5.
A preparation method for above-mentioned polymer carrier, the method comprises following concrete steps:
1) carbocisteine dimethyl ester hydrochloride SMCM is prepared
First carbocisteine SMC is dissolved in anhydrous methanol (chemical pure), the corresponding anhydrous methanol 10 ~ 15ml of 1g carbocisteine, nitrogen protection borehole cooling is to-5 ~ 0 DEG C, and in solution, slowly drip thionyl chloride, the mol ratio of thionyl chloride and carbocisteine is 2.5:1, to keep at temperature 0 DEG C 1 hour, room temperature reaction is risen to 5 hours after dropwising, concentrated, wash with a small amount of ethyl ester, filter, vacuum-drying obtains transparence mucus carbocisteine dimethyl ester hydrochloride SMCM;
2) polyglutamic carbocisteine dimethyl ester PGSMCM is prepared
By polyglutamic acid sodium (molecular weight 20000 ~ 40000, PDI is less than 1), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole, carbocisteine dimethyl ester hydrochloride salt is in anhydrous N, in dinethylformamide (analytical pure), the N of the corresponding 50ml of 1g polyglutamic acid sodium, dinethylformamide, polyglutamic acid sodium and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole, the mol ratio of carbocisteine dimethyl ester hydrochloride is 1:3:1.2:2.2, logical nitrogen protection, 20 ~ 30 DEG C are incubated 48 hours, slowly pour in the distilled water of low temperature stirring by the solution after having reacted, separate out white precipitate, filter, distilled water wash 3 times, 1g polyglutamic acid sodium corresponding 100ml × 3 distilled water, lyophilize obtains white solid polyglutamic carbocisteine dimethyl ester PGSMCM,
3) polyglutamic carbocisteine PGSMC is prepared
Polyglutamic carbocisteine dimethyl ester and 1mol/L lithium hydroxide aqueous solution are dissolved in tetrahydrofuran (THF) (chemical pure), the corresponding tetrahydrofuran (THF) 50 ~ 60ml of 1g polyglutamic carbocisteine dimethyl ester, the mol ratio of polyglutamic carbocisteine dimethyl ester and lithium hydroxide is 1:20, stir 8 hours, concentrated, regulate reaction solution pH to 3 with 2mol/L aqueous hydrochloric acid, dialysis, freeze-drying obtain white solid polyglutamic carbocisteine PGSMC.
A kind of medicine carrying application of above-mentioned polymer carrier, the application of this medicine carrying comprises following concrete steps:
Polyglutamic carbocisteine is dissolved in anhydrous N, in dinethylformamide (analytical pure), the corresponding N of 1g polyglutamic carbocisteine, dinethylformamide 50ml, stir 1 hour, add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, DMAP, stirring is clearly molten for half an hour, add antitumor drug again, wherein, polyglutamic carbocisteine and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, DMAP, the mol ratio of antitumor drug is 1:1.3:0.3:0.16, room temperature reaction 24 hours, slowly pour the aqueous hydrochloric acid of 0.2mol/l into, separate out white precipitate, centrifugal 10 minutes of 5000rpm, the white precipitate obtained is dissolved in the sodium bicarbonate aqueous solution of 0.5mol/l, dialyse 24 hours, freezing, drying obtains white solid PGSMC-Drug, PGSMC-Drug forms nanoparticle by self-assembly in aqueous.By transmission electron microscope observation nanoparticle pattern, and measure its particle diameter, size distribution with dynamic light scattering, measure its drug loading with ultraviolet absorption method, with the acid labile drug release performance of high effective liquid chromatography for measuring nanoparticle.
Described dialysis, freeze-drying refer to: selective retention molecular weight be 10000 ~ 100000 dialysis tubing the reaction solution after filtering is placed in deionized water dialysis 48 ~ 60h postlyophilization.
The application of described medicine carrying is applicable to the sending of antitumor drug of hydroxyl (-OH), amino (-NH2).
Described hydroxyl (-OH), amino (-NH
2) antitumor drug be taxol, Dx, camptothecine or gemcitabine.
Polymer carrying anti-tumor prodrug of the present invention impels ester bond cracking under acidic cancer environment, and antitumor drug discharges from carrier, and sustained drug is accumulated at tumor tissues, the application in treatment lung cancer, mammary cancer.
The acid-sensitive Macromolecule Prodrug that polymer carrier of the present invention and antitumor drug are formed self-assembly can form nanoparticle in aqueous, improve the water-soluble of medicine, passive target acidic cancer microenvironment, reduce toxic side effect to greatest extent, the medicine of fixed point release simultaneously, improve curative effect and bioavailability, to overcoming the undesirable bottleneck of chemotherapeutics clinical therapeutic efficacy.
Accompanying drawing explanation
Fig. 1 is polymer carrier of the present invention
1h NMR (D20) figure;
Fig. 2 is polymer carrier of the present invention
1h NMR (DMS0) figure;
Fig. 3 is polymer carrier paclitaxel loaded of the present invention
1h NMR (D20);
Fig. 4 is the grain-size graph of polymer carrier paclitaxel loaded of the present invention;
Fig. 5 is the transmission electron microscope picture of polymer carrier paclitaxel loaded of the present invention;
Fig. 6 is the different pH drug release comparison diagrams of polymer carrier paclitaxel loaded of the present invention;
Fig. 7 is the vitro cytotoxicity figure of polymer carrier paclitaxel loaded of the present invention.
Embodiment
For a better understanding of the present invention, illustrate the present invention further by embodiment below, but content of the present invention is not only confined to example below.
Embodiment 1
The preparation of carbocisteine dimethyl ester hydrochloride
10g carbocisteine (SMC) is dissolved in 100ml anhydrous methanol (analytical pure); under nitrogen protection below ice bath to 0 DEG C; slow dropping thionyl chloride solution; system temperature less than 0 DEG C is kept to stir one hour; then rise to room temperature reaction 5 hours, 35 DEG C of rotary evaporation removing methyl alcohol obtain mucus, wash 2 times with ether 100ml; dry 6 hours of ambient temperature in vacuum, obtains mucus shape carbocisteine dimethyl ester hydrochloride.
Embodiment 2
Prepared by polyglutamic carbocisteine dimethyl ester
By polyglutamic acid sodium (molecular weight 35000; 4g, 26.4mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (15.23g; 79.45mmol); I-hydroxybenzotriazole (4.3g, 31.82mmol), carbocisteine dimethyl ester hydrochloride (13.77g; 56.67mmol) be dissolved in the anhydrous N of 200ml; in dinethylformamide (analytical pure), logical nitrogen protection, 25 DEG C are stirred 48 hours.Slowly poured in the frozen water of stirring by solution after having reacted, separate out white precipitate, filter, wash 3 times with deionized water 200ml, lyophilize obtains white solid polyglutamic carbocisteine dimethyl ester.
Embodiment 3
Prepare polyglutamic carbocisteine
By polyglutamic carbocisteine dimethyl ester (1g, every unit 3.14mmol) be dissolved in 60ml tetrahydrofuran (THF) (chemical pure), add 1mol/L lithium hydroxide aqueous solution 60ml, stir 8 hr overnight, revolve and steam removing tetrahydrofuran (THF), remaining aqueous solution 2mol/L aqueous hydrochloric acid regulates PH to 3, pour in dialysis tubing (molecular weight cut-off 10000) and dialyse 24 hours, period changes deionized water 4 liters 4 times altogether, detect the resistivity of the aqueous solution of dialysis tubing outside, when resistivity is lower than 0.1mS/cm, collect surplus solution in dialysis tubing, filter with 0.45 μm of filtering head, lyophilize obtains white solid polyglutamic carbocisteine.
Dissolved with deuterated water and deuterated dimethyl sulfoxide respectively by the polyglutamic carbocisteine obtained, under Brooker 400,000,000 nuclear magnetic resonance analyser, carry out the scanning of hydrogen spectrum, nuclear magnetic spectrum as depicted in figs. 1 and 2.
Embodiment 4
Prepare polymer and carry prodrugs of paclitaxel
By polyglutamic carbocisteine (1g, every unit 3.45mmol) be dissolved in the anhydrous N of 50ml, dinethylformamide (analytical pure), stir 1 little of complete clearly molten, add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.86g, 4.48mmol), DMAP (126mg, 1.03mmol), stir half an hour to clearly molten, add taxol (472mg, 0.552mmol), room temperature reaction 24 hours, slowly pour the aqueous hydrochloric acid (150ml) of 0.2mol/l into, separate out white precipitate, centrifugal 10 minutes of 5000rpm, the white precipitate obtained is dissolved in the sodium bicarbonate aqueous solution (150ml) of 0.5mol/l, pour in dialysis tubing (molecular weight cut-off 10000) and dialyse 24 hours, period changes deionized water 4 liters 4 times altogether, detect the resistivity of the aqueous solution of dialysis tubing outside, when resistivity is lower than 0.1mS/cm, collect surplus solution in dialysis tubing, dialyse 24 hours, filter with 0.45 μm of filtering head, lyophilize obtains polymer and carries prodrugs of paclitaxel PGSMC-PTX.
It is 36% that the polymer obtained carries prodrugs of paclitaxel ultraviolet spectrophotometry measurement drug loading, and in water, maxima solubility is 60mg/ml.
The polymer obtained is carried the deuterated water dissolution of prodrugs of paclitaxel PGSMC-PTX, under Brooker 400,000,000 nuclear magnetic resonance analyser, carry out the scanning of hydrogen spectrum, nuclear magnetic spectrum as shown in Figure 3.
Embodiment 5
Configuration polymer carries prodrugs of paclitaxel 1mg/ml, and leave standstill 2 minutes after ultrasonic 5 minutes, measure its size and size distribution with Malvern laser particle analyzer, Fig. 4 shows nano particle footpath narrowly distributing, and size is about 15nm.
Embodiment 6
Polymer carries the Release Performance of prodrugs of paclitaxel
Obtained polymer is carried prodrugs of paclitaxel and be placed in the damping fluid that pH is 7.4,6.5,5.0 respectively, constant temperature oscillation in 37 DEG C, takes out 1ml damping fluid at regular intervals, is extracted with ethyl acetate, be spin-dried for, by the cumulative release concentration of Taxol Power by HPLC.As shown in Figure 6, polymer carries prodrugs of paclitaxel obvious sustained drug release effect, and rate of releasing drug is accelerated in acid condition, shows that the tumor group of this Macromolecule Prodrug to acidity is woven with certain fixed-point drug releasing function.
Embodiment 7
The nanoparticle transmission electron microscope picture that the self-assembly of acid-sensitive Macromolecule Prodrug is formed consults Fig. 5, and the shape that Fig. 5 shows nanoparticle is that class is spherical and be of a size of about 20nm.
Embodiment 8
Polymer carries the Cytotoxic evaluation of prodrugs of paclitaxel
Adopt CCK8 method, by nonsmall-cell lung cancer H460 good for growth conditions with certain density kind in 96 orifice plates, 37 DEG C, 5%CO
2constant incubator in cultivate the PTX adding a series of concentration after 24 hours, PGSMC-PTX sample, after continuing to cultivate 48h, every hole adds 10 microlitre CCK8 solution, 4h is placed in 37 DEG C of isothermal vibration casees, measure the absorbancy (OD) of each porocyte liquid on 96 orifice plates by microplate reader, cell survival rate is calculated according to following formula:
Cell survival rate=(OD sample/OD contrast) х 100%
OD sample: for adding the absorbancy of the enchylema of each concentration samples
OD contrasts: be the absorbancy of blank nutrient solution
Each sample arranges 6 Duplicate Samples, and cell survival rate as shown in Figure 7, illustrates that polymer carries prodrugs of paclitaxel compared to former medicine, cytotoxicity has obvious reduction.
Claims (6)
1., for the acid-sensitive polymer carrier that antitumor drug is sent, it is characterized in that this polymer carrier has structure as follows:
Wherein: n is the polymerization degree, the molecular weight of polymer carrier is at 30000 ~ 60000Da, and the nano particle diameter that polymer carrier and medicine are connected to form can control between 10 ~ 30nm, and size distribution PDI is 0.2 ~ 0.5.
2. a preparation method for polymer carrier described in claim 1, is characterized in that the method comprises following concrete steps:
1) carbocisteine dimethyl ester hydrochloride SMCM is prepared
First carbocisteine SMC is dissolved in anhydrous methanol, the corresponding anhydrous methanol 10 ~ 15ml of 1g carbocisteine, nitrogen protection borehole cooling is to-5 ~ 0 DEG C, and in solution, slowly drip thionyl chloride, the mol ratio of thionyl chloride and carbocisteine is 2.5:1, to keep at temperature 0 DEG C 1 hour, room temperature reaction is risen to 5 hours after dropwising, concentrated, use a small amount of washed with diethylether, filter, vacuum-drying obtains transparence mucus carbocisteine dimethyl ester hydrochloride SMCM;
2) polyglutamic carbocisteine dimethyl ester PGSMCM is prepared
By polyglutamic acid sodium (molecular weight 20000 ~ 40000, PDI is less than 1), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole, carbocisteine dimethyl ester hydrochloride salt is in anhydrous N, in dinethylformamide, the N of the corresponding 50ml of 1g polyglutamic acid sodium, dinethylformamide, polyglutamic acid sodium and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole, the mol ratio of carbocisteine dimethyl ester hydrochloride is 1:3:1.2:2.2, logical nitrogen protection, 20 ~ 30 DEG C are incubated 48 hours, slowly pour in the distilled water of low temperature stirring by the solution after having reacted, separate out white precipitate, filter, distilled water wash 3 times, 1g polyglutamic acid sodium corresponding 100ml × 3 distilled water, lyophilize obtains white solid polyglutamic carbocisteine dimethyl ester PGSMCM,
3) polyglutamic carbocisteine PGSMC is prepared
Polyglutamic carbocisteine dimethyl ester and 1mol/L lithium hydroxide aqueous solution are dissolved in chemical pure tetrahydrofuran (THF), the corresponding tetrahydrofuran (THF) 50 ~ 60ml of 1g polyglutamic carbocisteine dimethyl ester, the mol ratio of polyglutamic carbocisteine dimethyl ester and lithium hydroxide is 1:20, stir 8 hours, concentrated, regulate reaction solution pH to 3 with 2mol/L aqueous hydrochloric acid, dialysis, freeze-drying obtain white solid polyglutamic carbocisteine PGSMC.
3. the medicine carrying application of polymer carrier described in a claim 1, is characterized in that the application of this medicine carrying comprises following concrete steps:
Polyglutamic carbocisteine is dissolved in anhydrous N, in dinethylformamide, the corresponding N of 1g polyglutamic carbocisteine, dinethylformamide 50ml, stir 1 hour, add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, DMAP, stirring is clearly molten for half an hour, add antitumor drug, polyglutamic carbocisteine and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, DMAP, the mol ratio of antitumor drug is 1:1.3:0.3:0.16, room temperature reaction 24 hours, slowly pour in the aqueous hydrochloric acid of 0.2mol/l, separate out white precipitate, centrifugal 10 minutes of 5000rpm, the white precipitate obtained is dissolved in the sodium bicarbonate aqueous solution of 0.5mol/l, dialyse 24 hours, lyophilize obtains white solid PGSMC-Drug, PGSMC-Drug forms nanoparticle by self-assembly in aqueous.By transmission electron microscope observation nanoparticle pattern, and measure its particle diameter, size distribution with dynamic light scattering, measure its drug loading with ultraviolet absorption method, with the acid labile drug release performance of high effective liquid chromatography for measuring nanoparticle.
4. preparation method according to claim 2, is characterized in that described dialysis, freeze-drying refers to: selective retention molecular weight be 10000 ~ 100000 dialysis tubing the reaction solution after filtering is placed in deionized water dialysis 48 ~ 60h postlyophilization.
5. medicine carrying according to claim 3 application, is characterized in that the application of this medicine carrying is applicable to hydroxyl, the sending of amino antitumor drug.
6. medicine carrying according to claim 5 application, is characterized in that described hydroxyl, amino antitumor drug is taxol, Dx, camptothecine or gemcitabine.
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Cited By (4)
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| CN105497912A (en) * | 2016-01-21 | 2016-04-20 | 华东师范大学 | Preparation method and application of erythrocyte membrane-coated acid-sensitive polymer prodrug nano drug delivery system |
| CN107050462A (en) * | 2017-03-09 | 2017-08-18 | 中山大学 | Solution particles phase in version type antineoplastic transmission system and preparation method thereof |
| CN107383362A (en) * | 2017-06-30 | 2017-11-24 | 华东师范大学 | Hydrotropy polymer carrier and preparation method and application for insoluble drug delivering |
| CN111643674A (en) * | 2020-07-02 | 2020-09-11 | 中国药科大学 | Polyamino acid carrier with middle acid-sensitive connecting arm and preparation method and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105497912A (en) * | 2016-01-21 | 2016-04-20 | 华东师范大学 | Preparation method and application of erythrocyte membrane-coated acid-sensitive polymer prodrug nano drug delivery system |
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| CN107383362A (en) * | 2017-06-30 | 2017-11-24 | 华东师范大学 | Hydrotropy polymer carrier and preparation method and application for insoluble drug delivering |
| CN111643674A (en) * | 2020-07-02 | 2020-09-11 | 中国药科大学 | Polyamino acid carrier with middle acid-sensitive connecting arm and preparation method and application thereof |
| CN111643674B (en) * | 2020-07-02 | 2022-03-25 | 中国药科大学 | Polyamino acid carrier with middle acid-sensitive connecting arm and preparation method and application thereof |
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