CN104774329B - 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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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 pharmaceutical technology field, specifically one kind are passed for antineoplastic
The acid-sensitive macromolecule carrier sending and preparation method and load medicine application.
Background technology
Chemotherapy is still one of Main Means for the treatment of tumour at present, and traditional small molecule tumour medicine is due to water solubility
Difference, the shortage reason such as tumor tissues targeting and multi-drug resistant, lead to clinical efficacy low.By the medicine of poorly water-soluble with water-soluble
Property macromolecule carrier be connected, make Macromolecule Prodrug, the water solubility of medicine can be significantly improved, extend the plasma drug half-life,
Pass through macromolecule epr effect to accumulate in tumor tissues simultaneously, reduce drug toxicity, improve curative effect of medication.Macromolecule carrier is certainly
Since 1975 begin one's study, the macromolecule carrier of only minority enters clinical testing, including polyethylene glycol, polyglutamic
Acid, cyclodextrin.But these macromolecules all there is a problem of certain, for example, cannot be self-assembly of nano-particle in aqueous phase,
Drugloading rate is not high, lacks tumor tissues sensitiveness.
Polyglutamic acid is a kind of water-soluble, without toxicity, the boiomacromolecule being obtained using microbe fermentation method, has good
Good bioaffinity and biological degradability, can provide controlled drug release, targeting as pharmaceutical carrier, improve medicine water-soluble
Property, reduce adverse drug reaction, thus improving curative effect of medication.Poorly water-soluble, medicinal exploitation are very limited by chun li etc.
Antitumor drug paclitaxel be connected on polyglutamic acid, synthesized polyglutamic acid prodrug pga-ptx, this Macromolecule Prodrug shows
Higher water solubility, the cancer resistance of wide spectrum and good pharmacokinetic property, eliminate slow, action time prolongs in vivo
Long, bioavilability improves.Hplc analysis discloses, and in extracellular, PPX prodrug constantly discharges taxol, with
After be transported to intracellular, maintain taxol concentration in the cell, extend taxol holdup time in blood plasma, strengthen taxol
Distribution in tumor tissues.But due to carrying, medicine site (- cooh) is limited to cause drugloading rate not high it is impossible to be self-assembly of nanometer
Particle, and lack the function that fixed point in tumour cell stably discharges medicine, limit its application.
Through to existing document exploration discovery, medicine passes through the amino acid derivativges of a certain length and macromolecule connects energy
Enough make the Macromolecule Prodrug obtaining be self-assembly of nano-particle in aqueous, further enhance the water solubility of Macromolecule Prodrug
And drugloading rate.Study simultaneously and also find, compared with normal structure, tumor tissues have the microenvironment of acidity.There is acid-sensitive
The nano-particle that macromolecule carrier is formed with medicine, can realize the fixed point release of acid tumor tissues, to acidity in human body
Environment has passive target, reduces the toxic and side effect of medicine, has higher application prospect.
Content of the invention
It is an object of the invention to provide a kind of acid-sensitive macromolecule carrier and preparation method, the method is in poly- γ-paddy
On the basis of propylhomoserin (pga), each pga unit increases a carbocisteine molecule, defines each unit and contains two loads
The acid-sensitive macromolecule carrier in medicine site.
It is a further object of the present invention to provide a kind of application in antineoplastic delivery for acid-sensitive macromolecule carrier, that is,
Clinical practice for antineoplastic limits, and using above-mentioned acid-sensitive macromolecule carrier, designs, synthesizes, assembles acid-sensitive
High molecular antineoplastic prodrug, to improve curative effect and the bioavilability of medicine, under sour environment, accelerated release in vitro medicine, reduces it
Toxic and side effect, to the barrier overcoming current antineoplastic to be restricted in clinical practice.
The concrete technical scheme realizing the object of the invention is:
A kind of acid-sensitive macromolecule carrier for antineoplastic delivery, this macromolecule carrier has knot as follows
Structure:
Wherein: n is the degree of polymerization, in 30000～60000da, macromolecule carrier is with medicine even for the molecular weight of macromolecule carrier
The nano particle diameter connecing formation can control between 10～30nm, and particle diameter distribution pdi is 0.2～0.5.
A kind of preparation method of above-mentioned macromolecule carrier, the method includes step in detail below:
1) prepare carbocisteine diformazan ester hydrochloride smcm
First carbocisteine smc is dissolved in absolute methanol (chemistry is pure), the corresponding no water beetle of 1g carbocisteine
Alcohol 10～15ml, is cooled to -5～0 DEG C under nitrogen protection, is slowly added dropwise thionyl chloride, thionyl chloride and carboxylic first half in solution
The mol ratio of cystine is 2.5:1,1 hour at 0 DEG C of keeping temperature, is warmed to room temperature reaction 5 hours after completion of dropping, concentrates, uses
A small amount of ethyl ester washing, filters, is vacuum dried to obtain transparence mucus carbocisteine diformazan ester hydrochloride smcm；
2) prepare polyglutamic carbocisteine dimethyl ester pgsmcm
By polyglutamic acid sodium (molecular weight 20000～40000, pdi is less than 1), 1- (3- dimethylamino-propyl) -3- ethyl carbon
Diimmonium salt hydrochlorate, I-hydroxybenzotriazole, carbocisteine dimethyl ester hydrochloride salt are in anhydrous n, n- dimethyl methyl
In acid amides (analysis is pure), n, n- dimethylformamide, polyglutamic acid sodium and 1- (the 3- diformazan ammonia of the corresponding 50ml of 1g polyglutamic acid sodium
Base propyl group) -3- ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole, the mol ratio of carbocisteine diformazan ester hydrochloride
For 1:3:1.2:2.2, logical nitrogen protection, 20～30 DEG C are incubated 48 hours；Solution after having reacted is poured slowly into low temperature stirring
Distilled water in, separate out white precipitate, filter, distillation water washing 3 times, 1g polyglutamic acid sodium corresponding 100ml × 3 distilled water, cold
Lyophilized dry white solid polyglutamic carbocisteine dimethyl ester pgsmcm；
3) prepare polyglutamic carbocisteine pgsmc
Polyglutamic carbocisteine dimethyl ester and 1mol/l lithium hydroxide aqueous solution are dissolved in oxolane (chemistry
Pure) in, 1g polyglutamic carbocisteine dimethyl ester corresponds to oxolane 50～60ml, polyglutamic carbocisteine dimethyl ester
Mol ratio with lithium hydroxide is 1:20, stirs 8 hours, concentrates, and adjusts reactant liquor ph to 3 with 2mol/l aqueous hydrochloric acid solution, thoroughly
Analysis, lyophilized obtain white solid polyglutamic carbocisteine pgsmc.
A kind of load medicine application of above-mentioned macromolecule carrier, this load medicine application inclusion step in detail below:
Polyglutamic carbocisteine is dissolved in anhydrous n, in n- dimethylformamide (analysis is pure), 1g polyglutamic carboxylic
First cysteine corresponds to n, n- dimethylformamide 50ml, stirs 1 hour, adds 1- (3- dimethylamino-propyl) -3- ethyl carbon
Diimmonium salt hydrochlorate, DMAP, stirring half an hour is molten clear, adds antineoplastic, wherein, polyglutamic carboxylic first half
Cystine and 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, DMAP, the rubbing of antineoplastic
Your ratio is 1:1.3:0.3:0.16, room temperature reaction 24 hours, is poured slowly into the aqueous hydrochloric acid solution of 0.2mol/l, separates out white heavy
Form sediment, 5000rpm is centrifuged 10 minutes, and the white precipitate obtaining is dissolved in the sodium bicarbonate aqueous solution of 0.5mol/l, dialysis 24 is little
When, freeze, be dried to obtain white solid pgsmc-drug；Pgsmc-drug is in aqueous by being self-assembly of nanoparticle
Son.Nano-particle pattern is observed by transmission electron microscope, and measures its particle diameter, particle diameter distribution with dynamic light scattering, inhaled with ultraviolet
Receipts method measures its drugloading rate, with the acid labile drug release performance of high effective liquid chromatography for measuring nano-particle.
Described dialysis, lyophilized refer to: selective retention molecular weight be 10000～100000 bag filter by the reaction after filtering
Liquid is placed in freeze-drying after dialysis 48～60h in deionized water.
Described load medicine application is applied to hydroxyl (- oh), the delivery of the antineoplastic of amino (- nh2).
Described hydroxyl (- oh), amino (- nh2) antineoplastic be taxol, Doxorubicin, camptothecine or Ji Xi
His shore.
The macromolecule carrying anti-tumor prodrug of the present invention promotes ester bond to crack under acidic cancer environment, antineoplastic
Discharge from carrier, so that sustained drug is accumulated in tumor tissues, the application in terms for the treatment of lung cancer, breast cancer.
The acid-sensitive Macromolecule Prodrug that the macromolecule carrier of the present invention is formed with antineoplastic can in aqueous certainly
Assembling forms nano-particle, improves the water solubility of medicine, passive target acidic cancer microenvironment, and reduction poison is secondary to greatest extent makees
With, the medicine of fixed point release simultaneously, improves curative effect and bioavilability, to overcoming chemotherapeutics clinical therapeutic efficacy undesirable
Bottleneck.
Brief description
Fig. 1 is macromolecule carrier of the present invention1H nmr (d20) figure；
Fig. 2 is macromolecule carrier of the present invention1H nmr (dms0) figure；
Fig. 3 is macromolecule carrier paclitaxel loaded of the present invention1h nmr(d20)；
Fig. 4 is the grain-size graph of macromolecule carrier paclitaxel loaded of the present invention；
Fig. 5 is the transmission electron microscope picture of macromolecule carrier paclitaxel loaded of the present invention；
Fig. 6 is the different ph insoluble drug release comparison diagrams of macromolecule carrier paclitaxel loaded of the present invention；
Fig. 7 is the vitro cytotoxicity figure of macromolecule carrier paclitaxel loaded of the present invention.
Specific embodiment
In order to be better understood from the present invention, it is further elucidated with the present invention with embodiment below, but present disclosure is not
It is limited only to Examples below.
Embodiment 1
The preparation of carbocisteine diformazan ester hydrochloride
10g carbocisteine (smc) is dissolved in 100ml absolute methanol (analysis is pure), the lower ice bath of nitrogen protection is to 0 DEG C
Hereinafter, it is slowly added dropwise thionyl chloride solution, keeps 0 DEG C of system temperature one hour stirred below, be then warmed to room temperature reaction 5 little
When, 35 DEG C of rotary evaporations remove methyl alcohol and obtain mucus, are washed with ether 100ml 2 times, are vacuum dried 6 hours, obtain mucus shape under room temperature
Carbocisteine diformazan 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 carbon two is sub-
Amine hydrochlorate (15.23g, 79.45mmol), I-hydroxybenzotriazole (4.3g, 31.82mmol), carbocisteine dimethyl ester
Hydrochloride (13.77g, 56.67mmol) is dissolved in the anhydrous n of 200ml, and in n- dimethylformamide (analysis is pure), logical nitrogen is protected
Shield, 25 DEG C are stirred 48 hours.Solution after having reacted is poured slowly in the frozen water of stirring, separates out white precipitate, filter, spend
Ionized water 200ml washs 3 times, and freeze-drying obtains white solid polyglutamic carbocisteine dimethyl ester.
Embodiment 3
Prepare polyglutamic carbocisteine
Polyglutamic carbocisteine dimethyl ester (1g, every unit 3.14mmol) is dissolved in 60ml oxolane (chemistry
Pure), add 1mol/l lithium hydroxide aqueous solution 60ml, overnight revolving removes oxolane within 8 hours for stirring, and remaining aqueous solution is used
2mol/l aqueous hydrochloric acid solution adjusts ph to 3, pours dialysis 24 hours in bag filter (molecular cut off 10000) into, and period is total to more for 4 times
Change 4 liters of deionized water, the resistivity of the aqueous solution outside detection bag filter, when resistivity is less than 0.1ms/cm, collect dialysis
Surplus solution in bag, is filtered with 0.45 μm of filtering head, and freeze-drying obtains white solid polyglutamic carbocisteine.
The polyglutamic obtaining carbocisteine is dissolved with deuterated water and deuterated dimethyl sulfoxide respectively, in Brooker
Carry out hydrogen spectrum scanning, nuclear magnetic spectrum is as depicted in figs. 1 and 2 under 400000000 NMRs.
Embodiment 4
Prepare macromolecule and carry prodrugs of paclitaxel
Polyglutamic carbocisteine (1g, every unit 3.45mmol) is dissolved in the anhydrous n of 50ml, n- dimethyl formyl
Amine (analysis is pure), stirring adds 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride to completely molten clear in 1 hour
(0.86g, 4.48mmol), DMAP (126mg, 1.03mmol), stirring half an hour, to molten clear, adds taxol
(472mg, 0.552mmol), room temperature reaction 24 hours, it is poured slowly into the aqueous hydrochloric acid solution (150ml) of 0.2mol/l, separate out white
Precipitation, 5000rpm is centrifuged 10 minutes, and the white precipitate obtaining is dissolved in the sodium bicarbonate aqueous solution (150ml) of 0.5mol/l,
Pour dialysis 24 hours in bag filter (molecular cut off 10000) into, period changes 4 liters of deionized water for 4 times altogether, outside detection bag filter
The resistivity of the aqueous solution in portion, when resistivity is less than 0.1ms/cm, collects surplus solution in bag filter, dialyses 24 hours, use
0.45 μm of filtering head filters, and freeze-drying obtains macromolecule and carries prodrugs of paclitaxel pgsmc-ptx.
It is 36% that the macromolecule obtaining carries prodrugs of paclitaxel ultraviolet spectrophotometry measurement drugloading rate, maximum dissolving in water
Spend for 60mg/ml.
The macromolecule obtaining is carried the deuterated water dissolves of prodrugs of paclitaxel pgsmc-ptx, in Brooker 400,000,000 nuclear magnetic resonance
Carry out hydrogen spectrum scanning, nuclear magnetic spectrum is as shown in Figure 3 under instrument.
Embodiment 5
Configuration macromolecule carries prodrugs of paclitaxel 1mg/ml, stands 2 minutes, use Malvern laser particle analyzer after ultrasonic 5 minutes
Measure its particle size and particle diameter distribution, Fig. 4 display nano particle footpath narrowly distributing, particle size about 15nm.
Embodiment 6
Macromolecule carries the Release Performance of prodrugs of paclitaxel
By the macromolecule being obtained carry prodrugs of paclitaxel be respectively placed in ph be 7.4, in 6.5,5.0 buffer solution, in 37 DEG C
Constant temperature oscillation, takes out 1ml buffer solution at regular intervals, is extracted with ethyl acetate, is spin-dried for, purple with high effective liquid chromatography for measuring
The cumulative release concentration of China fir alcohol.As shown in fig. 6, macromolecule carries prodrugs of paclitaxel obvious sustained drug release effect, and
Under acid condition, rate of releasing drug is accelerated, and shows that this Macromolecule Prodrug is woven with certain fixed-point drug releasing function to acid tumor group.
Embodiment 7
The nano-particle transmission electron microscope picture that acid-sensitive Macromolecule Prodrug is self-assembly of refers to Fig. 5, and Fig. 5 shows nano-particle
Be shaped as spherical and a size of 20nm.
Embodiment 8
Macromolecule carries the Cytotoxic evaluation of prodrugs of paclitaxel
Using cck8 method, by non-small cell lung cancer h460 good for growth conditions with certain density kind in 96 orifice plates, 37
DEG C, 5%co2Constant incubator in culture add a series of ptx of concentration, pgsmc-ptx sample after 24 hours, continue culture
After 48h, every hole adds 10 microlitres of cck8 solution, places 4h in 37 DEG C of isothermal vibration casees, measures each hole on 96 orifice plates with ELIASA thin
The absorbance (od) of cytosol, cell survival rate is calculated according to below equation:
Cell survival rate=(od sample/od comparison) х 100%
Od sample: for adding the absorbance of the cell liquid of each concentration samples
Od compares: for the absorbance of blank nutrient solution
Each sample arranges 6 Duplicate Samples, and cell survival rate is as shown in fig. 7, explanation macromolecule load prodrugs of paclitaxel is compared
In active compound, obvious reduction is had on cytotoxicity.
Claims (6)
1. a kind of acid-sensitive macromolecule carrier for antineoplastic delivery it is characterised in that this macromolecule carrier have as follows
Shown structure:
Wherein: n is the degree of polymerization, and in 30000～60000da, macromolecule carrier is connected shape with medicine to the molecular weight of macromolecule carrier
The nano particle diameter becoming can control between 10～30nm, and particle diameter distribution pdi is 0.2～0.5.
2. a kind of preparation method of macromolecule carrier described in claim 1 is it is characterised in that the method includes step in detail below:
1) prepare carbocisteine diformazan ester hydrochloride smcm
First carbocisteine smc is dissolved in absolute methanol, 1g carbocisteine corresponds to absolute methanol 10～15ml, nitrogen
It is cooled to -5～0 DEG C under gas shielded, be slowly added dropwise thionyl chloride, the mol ratio of thionyl chloride and carbocisteine in solution
For 2.5:1,1 hour at 0 DEG C of keeping temperature, after completion of dropping, it is warmed to room temperature reaction 5 hours, concentrates, washed with a small amount of ether, mistake
Filter, is vacuum dried to obtain transparence mucus carbocisteine diformazan ester hydrochloride smcm；
2) prepare polyglutamic carbocisteine dimethyl ester pgsmcm
Polyglutamic acid sodium, 1- (3- dimethylamino-propyl) -3- ethyl carbon two Asia that molecular weight 20000～40000, pdi are less than 1
Amine hydrochlorate, I-hydroxybenzotriazole, carbocisteine dimethyl ester hydrochloride salt are in anhydrous n, n- dimethylformamide
In, n, n- dimethylformamide, polyglutamic acid sodium and 1- (3- the dimethylamino-propyl) -3- second of the corresponding 50ml of 1g polyglutamic acid sodium
Base carbodiimide hydrochloride, I-hydroxybenzotriazole, the mol ratio of carbocisteine diformazan ester hydrochloride are 1:3:1.2:
2.2, logical nitrogen protection, 20～30 DEG C are incubated 48 hours；Solution after having reacted is poured slowly in the distilled water of low temperature stirring,
Separate out white precipitate, filter, distillation water washing 3 times, 1g polyglutamic acid sodium corresponding 100ml × 3 distilled water, freeze-drying obtains white
Solid polyglutamic carbocisteine dimethyl ester pgsmcm；
3) prepare polyglutamic carbocisteine pgsmc
Polyglutamic carbocisteine dimethyl ester and 1mol/l lithium hydroxide aqueous solution are dissolved in the pure oxolane of chemistry,
1g polyglutamic carbocisteine dimethyl ester corresponds to oxolane 50～60ml, polyglutamic carbocisteine dimethyl ester and hydrogen-oxygen
The mol ratio of change lithium is 1:20, stirs 8 hours, concentrates, and adjusts reactant liquor ph to 3 with 2mol/l aqueous hydrochloric acid solution, dialyses, is lyophilized
Obtain white solid polyglutamic carbocisteine pgsmc.
3. a kind of load medicine application of macromolecule carrier described in claim 1 is it is characterised in that the application of this load medicine is included in detail below
Step:
Polyglutamic carbocisteine is dissolved in anhydrous n, in n- dimethylformamide, 1g polyglutamic carbocisteine pair
Answer n, n- dimethylformamide 50ml, stir 1 hour, addition 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride,
DMAP, stirring half an hour is molten clear, adds antineoplastic, polyglutamic carbocisteine and 1- (3- diformazan ammonia
Base propyl group) -3- ethyl-carbodiimide hydrochloride, DMAP, antineoplastic mol ratio be 1:1.3:0.3:
0.16, room temperature reaction 24 hours, it is poured slowly in the aqueous hydrochloric acid solution of 0.2mol/l, separate out white precipitate, 5000rpm centrifugation 10
Minute, the white precipitate obtaining is dissolved in the sodium bicarbonate aqueous solution of 0.5mol/l, dialyses 24 hours, freeze-drying obtains white
Color solid pgsmc-drug；Pgsmc-drug is in aqueous by being self-assembly of nano-particle；Observed by transmission electron microscope
Nano-particle pattern, and measure its particle diameter, particle diameter distribution with dynamic light scattering, measure its drugloading rate with ultraviolet absorption method, use
The acid labile drug release performance of high effective liquid chromatography for measuring nano-particle.
4. preparation method according to claim 2 is it is characterised in that described dialysis, lyophilized refer to: selective retention molecular weight
Reactant liquor after filtering is placed in freeze-drying after dialysis 48～60h in deionized water by the bag filter for 10000～100000.
5. the medicine that carries according to claim 3 is applied it is characterised in that the application of this load medicine is applied to hydroxyl, the anti-of amino swells
The delivery of tumor medicine.
6. the medicine that carries according to claim 5 is applied it is characterised in that the antineoplastic of described hydroxyl, amino is Japanese yew
Alcohol, Doxorubicin, camptothecine or gemcitabine.
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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 |
| CN107050462B (en) * | 2017-03-09 | 2021-03-30 | 中山大学 | Solution-particle phase transition type anti-tumor drug delivery 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 |
| 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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| US5059542A (en) * | 1988-10-12 | 1991-10-22 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | Artificial carrier particles and method for preparation thereof |
| CN102083468A (en) * | 2008-03-06 | 2011-06-01 | 日东电工株式会社 | Polymer paclitaxel conjugates and methods for treating cancer |
| CN102933225A (en) * | 2010-02-27 | 2013-02-13 | 斯坦陵布什大学 | Surfactant composition |
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| JP2589431B2 (en) * | 1991-05-13 | 1997-03-12 | 株式会社ディ・ディ・エス研究所 | Sugar-modified polyglutamic acid derivative and production method thereof |
| US20040057958A1 (en) * | 2002-05-17 | 2004-03-25 | Waggoner David W. | Immunogenicity-enhancing carriers and compositions thereof and methods of using the same |
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|---|---|---|---|---|
| US5059542A (en) * | 1988-10-12 | 1991-10-22 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | Artificial carrier particles and method for preparation thereof |
| CN102083468A (en) * | 2008-03-06 | 2011-06-01 | 日东电工株式会社 | Polymer paclitaxel conjugates and methods for treating cancer |
| CN102933225A (en) * | 2010-02-27 | 2013-02-13 | 斯坦陵布什大学 | Surfactant composition |
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