CN104689329A - Preparation method for polyamide based polyelectrolyte nano-micelle - Google Patents
Preparation method for polyamide based polyelectrolyte nano-micelle Download PDFInfo
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- 239000003814 drug Substances 0.000 claims abstract description 32
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 15
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 15
- 239000004310 lactic acid Substances 0.000 claims abstract description 15
- 229920001897 terpolymer Polymers 0.000 claims abstract description 14
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- 239000004220 glutamic acid Substances 0.000 claims abstract description 10
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- 229920001577 copolymer Polymers 0.000 claims abstract description 9
- 235000013922 glutamic acid Nutrition 0.000 claims abstract description 9
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 claims description 7
- 229930195573 Amycin Natural products 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 238000013019 agitation Methods 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
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- 229910021642 ultra pure water Inorganic materials 0.000 claims description 4
- 239000012498 ultrapure water Substances 0.000 claims description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 108010020346 Polyglutamic Acid Proteins 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000008366 buffered solution Substances 0.000 claims description 3
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 229920002643 polyglutamic acid Polymers 0.000 claims description 3
- 229920000151 polyglycol Polymers 0.000 claims description 3
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- 239000002244 precipitate Substances 0.000 claims description 3
- 238000004064 recycling Methods 0.000 claims description 3
- 238000005070 sampling Methods 0.000 claims description 3
- 235000011150 stannous chloride Nutrition 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 150000001767 cationic compounds Chemical class 0.000 claims 1
- 238000010276 construction Methods 0.000 claims 1
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 abstract description 12
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- 239000003937 drug carrier Substances 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 229920000728 polyester Polymers 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 229940009456 adriamycin Drugs 0.000 abstract 3
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- 229920000747 poly(lactic acid) Polymers 0.000 description 1
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Landscapes
- Polyamides (AREA)
- Medicinal Preparation (AREA)
Abstract
Belonging to the technical field of carriers and sustained-release materials, the invention discloses a preparation method for a polyelectrolyte composite nano-micelle as a drug carrier. The method provided by the invention takes glutamic acid (Glu), lactic acid (LA) and mPEG as the raw materials to carry out direct copolycondensation reaction so as to obtain an amido bond containing polyelectrolyte terpolymer, and the terpolymer and adriamycin are compounded in a water solution to form adriamycin. As the main chain of the polyelectrolyte copolymer contains a polyamide chain segment structure and a polyester chain segment structure at the same time, the degradability in water is slowed down, the polymer stability is improved, and by compounding the copolymer with the anticancer drug adriamycin, the obtained nano-micelle has strengthened stability, and can be expected to improve the drug bioavailability. Drug release is controlled by pH value and ionic strength. The nano-micelle provided by the invention has the characteristics of simple synthesis, good micelle stability, no tedious synthesis step, no use of any organic solvent, no toxicity and environmental protection, and has application prospects.
Description
Technical field
The present invention relates to a kind of biodegradable preparation method based on polyamide polyelectrolyte nano-micelle, belong to carrier and slow-release material technical field.
Background technology
Polyelectrolyte composite micelle is formed by electrostatic interaction by the component of two kinds of oppositely chargeds, and an outstanding advantages of this type of micelle is can the charged medicine of load, gene or enzyme, and preparation condition is gentle simple.Research worker utilize compound polyelectrolyte can participate in the feature of the vital movement process of some complexity in life entity directly or indirectly and transplant in stimuli responsive medicine controlled releasing, cellular immunization isolation, the controlled release of polypeptide protein medicine, the field such as gene therapy and artificial vaccine conduct in-depth research and achieve major progress, this is significant for the practical value of compound polyelectrolyte.
Amycin is a kind of common anticancer chemotherapeutic agent, has obvious curative effects to kinds cancer.But the toxic and side effects of amycin is also very large.Therefore reduce its toxic and side effects, heighten the effect of a treatment be research in a difficult problem.In the research of current most of nano-micelle pharmaceutical carrier, medicine is by carrying out load with the Physical interaction or covalent attachment of carrier, keeps away unavoidable carrying drug ratio and envelop rate is low, medicine is revealed and the shortcoming of controlled release difficulty.
Glutamic acid (Glu) has the advantages such as reactive functional groups is many, source is relatively abundanter, relative low price, and polyglutamic acid segment contains pendant carboxy group, has the function with cation compound.Lactic acid (LA) wide material sources, cheap, its polymer has good biocompatibility and degradability, and catabolite can participate in tricarboxylic acid cycle in body and be absorbed by organism.Poly glycol monomethyl ether has good water solublity, wettability, lubricity, physiological inertia, non-stimulated to human body, gentle.
First the present invention designs and has prepared a kind of preparation method based on polyamide polyelectrolyte nano-micelle; by the design of formula, polyglutamic acid molecule is introduced copolymer; copolymer side chain is made to contain anionic group; thus effectively can form micelle with the amino in Doxorubicin molecules by the compound action of anions and canons; the hydrophobic chain segment of copolymer and Doxorubicin molecules are positioned at the kernel of micelle; the outer stability protecting micelle by hydrophilic mPEG, prevents medicine from revealing.This micelle is carried out drug release in vitro, has the advantages that drug loading is high, prevent medicine leakage and Co ntrolled release.Preparation method of the present invention simply, not with an organic solvent, micellar structure is unique, controlled release properties is good.
Summary of the invention
The object of the invention is to provide a kind of based on the preparation method of polyamide polyelectrolyte nano-micelle as pharmaceutical carrier, selects the glutamic acid of wide material sources, nontoxic non-stimulated, good biocompatibility, lactic acid and poly glycol monomethyl ether.
Technical scheme of the present invention is as follows:
(1) synthesis of amide bond polyelectrolyte terpolymer: control glutamic acid (Glu), lactic acid (LA), mPEG mol ratio is 1:0:0.5, 1:0.5:0.5, 1:1:0.5, 1:2:0.5, 1:3:0.5, two hydrated stannous chlorides are catalyst, 110 DEG C of pre-polymerization 3h, heat up 130 DEG C, vacuum maintains 0.085Mpa, heating is stopped after reaction 8h, product dissolve with ethanol, cross and filter unreacted glutamic acid, filtrate is 50 DEG C of distilling under reduced pressure, product chloroform dissolves, absolute ether precipitates, obtain light yellow viscous liquid, respectively referred to as GLP-1005, GLP-10505, GLP-1105, GLP-1205, GLP-1305, abundant drying for standby.
(2) preparation of carrier micelle: adopt polyion composite algorithm to prepare carrier micelle.By water-soluble for the PGlu-co-PLA-co-mPEG (GLP-10505) of certain mass, magnetic agitation is dissolved completely to copolymer, drip amycin aqueous solution gradually, stop when solution presents redness and has obvious Tyndall phenomenon, continue to stir 24h subsequently and carrier micelle is stablized.Polypeptide drug-loaded micelle solution being proceeded to molecular cut off is in the bag filter of 3500, and dialyse under lucifuge state 8h in ultra-pure water.
Beneficial effect of the present invention:
1. because main chain in polyelectrolyte terpolymer is simultaneously containing polyamide chains segment structure and polyester segment structure, compared with the polymer of simple polyester segment structure, in water, degradation property slows down, substantially increase polymer to stability, after itself and anticancer drugs, doxorubicin are carried out compound, gained nano-micelle stability strengthens, and is conducive to nano-micelle and circulates in vivo and be unlikely to occur that medicine is revealed, and improves the bioavailability of medicine.
2. amide bond polyelectrolyte terpolymer of the present invention can be used in art of pharmacy, method is " one-step method ", simple and convenient, whole reaction is a step only, comparatively ring-opening polymerisation legal system is for polyurethane, avoid the use of loaded down with trivial details synthesis step, expensive monomer and organic solvent, there is the advantage that " green " reacts.
3. polyion composite algorithm is adopted to prepare carrier micelle, step is simple, with ultra-pure water as solvent, asepsis environment-protecting, particularly medicine participate in the formation of micelle, and drug loading comprises the formation medicine of micelle inner core and the medicine of physically encapsulation, not only increase drug loading, also ensure that the stability of medicine, micelle has pH value and salinity sensitivity, thus makes it have excellent medicine carrying and controlled-release effect.
Accompanying drawing explanation
Fig. 1 is based on the structural representation of polyamide polyelectrolyte and amycin composite Nano micelle.
Fig. 2 amide bond polyelectrolyte terpolymer PGlu-co-PLA-co-mPEG infrared spectrum.
The SEM photo of Fig. 3 medicament-carried nano micelle (GLP105-DOX).
Fig. 4 medicament-carried nano micelle (GLP105-DOX) is at PBS buffer Chinese medicine release profiles.a：pH=8.0PBS；b：pH=7.4PBS；c：pH=7.0PBS；d：pH=6.0PBS；e：pH=5.0PBS。
Detailed description of the invention
Below in conjunction with example, the present invention is described in more detail, but the present invention is not limited thereto.
Embodiment 1
The synthesis of amide bond polyelectrolyte terpolymer: by 1.5gL-glutamic acid, 4gmPEG mix homogeneously, adding 0.02g bis-hydrated stannous chloride is catalyst, 110 DEG C of pre-polymerization 3h, heat up 130 DEG C, vacuum maintains 0.085Mpa, stops heating, product dissolve with ethanol after reaction 8h, cross and filter unreacted glutamic acid, filtrate is 50 DEG C of distilling under reduced pressure, and product chloroform dissolves, and absolute ether precipitates, obtain light yellow viscous liquid, abundant drying for standby.
The preparation of carrier micelle: adopt polyion composite algorithm to prepare carrier micelle.The PGlu-co-PLA-co-mPEGG (LP105-DOX) of 0.2g is dissolved in 20g water, magnetic agitation is dissolved completely to copolymer, drip amycin aqueous solution gradually, stop when solution presents redness and has obvious Tyndall phenomenon, continue to stir 24h subsequently and carrier micelle is stablized.Polypeptide drug-loaded micelle solution being proceeded to molecular cut off is in the bag filter of 3500, and dialyse under lucifuge state 8h in ultra-pure water.
The releasing research of carrier micelle in different medium: the carrier micelle of having dialysed is got 5mL in bag filter, to be placed in 250mL medium be respectively 0.01M pH be 5.0,6.0,7.0,7.4,8.0 phosphate buffered solution (PBS), with 37 ± 0.5 DEG C of constant temperature magnetic agitation at a slow speed, separated in time sampling 4mL the fresh dissolution medium adding the identical temperature of same volume are to keep liquor capacity constant, and ultraviolet spectrophotometer tests the A of dialysis solution
483, recycling formulae discovery cumulative release medication amount also draws In-vitro release curves.
Embodiment 2
The mol ratio of Glu, LA and mPEG is 1:0.5:0.5, and other building-up processes are identical with embodiment 1.
Embodiment 3
The mol ratio of Glu, LA and mPEG is 1:1:0.5, and other building-up processes are identical with embodiment 1.
Embodiment 4
The mol ratio of Glu, LA and mPEG is 1:2:0.5, and other building-up processes are identical with embodiment 1.
The mol ratio of Glu, LA and mPEG is 1:3:0.5, and other building-up processes are identical with embodiment 1.
Embodiment 5
Respectively GLP-1005, GLP-10505, GLP-1105, GLP-1205, GLP-1305 are dissolved in ethanol, adopt KBr salt sheet coating method, test after drying.With Fourier infrared spectrograph at 4000 ~ 500cm
-1wave-number range in carry out INFRARED ABSORPTION scanning, obtain infrared spectrum.Fig. 2 is the infrared spectrum of respective polymer, and as can be seen from the figure, it is basically identical that abcde goes out peak position.1640cm
-1amide groups C=O stretching vibration peak, 3300cm
-1be N-H stretching vibration, prove the existence of-CONH group in copolymer, it can thus be appreciated that polyamide reaction occurs.
Embodiment 6
By GLP-1005, GLP-10505, GLP-1105, GLP-1205, GLP-1305 respectively compound concentration be the THF solution of 8mg/mL, take PEG as standard specimen, with the molecular weight and molecualr weight distribution of GPC method working sample.Along with the increase of LA rate of charge, the increase of polylactic acid chain segment content, the molecular weight of polymer increases gradually, and esterification causes productive rate lower.
Embodiment 7
By dry to GLP-1005, GLP-10505, GLP-1105, GLP-1205, GLP-1305 post analysis, it is elementary composition.
Embodiment 8
Get carrier micelle (GLP105-DOX) 5mL in bag filter, to be placed in 250mL medium be respectively 0.01M pH be 5.0,6.0,7.0,7.4,8.0 phosphate buffered solution (PBS), with 37 ± 0.5 DEG C of constant temperature magnetic agitation at a slow speed, separated in time sampling 4mL the fresh dissolution medium adding the identical temperature of same volume are to keep liquor capacity constant, and ultraviolet spectrophotometer tests the A of dialysis solution
483, recycling formulae discovery cumulative release medication amount also draws In-vitro release curves.
Fig. 4 is carrier micelle (GLP105-DOX) drug release patterns in PBS buffer.Drug release result shows: carrier micelle has obviously slowly releasing effect and stronger pH sensitivity.PH=5.0,6.0,7.0,7.4, in the buffer solutions of 8.0, the rate of release of medicine slows down successively, illustrates that the release of medicine is strongly depend on pH value.
Above-described embodiment is used for explaining and the present invention is described, instead of limits the invention, and in the protection domain of spirit of the present invention and claim, any amendment make the present invention and change, all fall into protection scope of the present invention.
Table 1 direct polycondensation method prepares amide bond polyelectrolyte terpolymer
Table 2 gathers (glutamic acid-co-lactic acid-co-mPEG) terpolymer elementary analysis
Claims (4)
1. a preparation for amide bond polyelectrolyte terpolymer, is characterized in that using glutamic acid, lactic acid, poly glycol monomethyl ether as raw material, by direct copolycondensation, obtains the amphiphilic polyelectrolyte terpolymer of amide bond.Containing-COOH the group hung on the polyglutamic acid construction unit of copolymer, there is the function of carrying out compound with cationic compound.
2. the preparation method of amide bond polyelectrolyte terpolymer according to claim 1 and condition, it is characterized in that: glutamic acid (Glu), lactic acid (LA), mPEG mol ratio is respectively 1:0:0.5, 1:0.5:0.5, 1:1:0.5, 1:2:0.5, 1:3:0.5, under two hydrated stannous chloride catalysis, 110 DEG C of pre-polymerization 3h, heat up 130 DEG C, vacuum maintains 0.085Mpa, heating is stopped after reaction 8h, product dissolve with ethanol, cross and filter unreacted glutamic acid, filtrate is 50 DEG C of distilling under reduced pressure, product chloroform dissolves, absolute ether precipitates, obtain light yellow viscous liquid, abundant drying for standby.
3., based on a preparation method for polyamide polyelectrolyte nano-micelle, it is characterized in that amide bond polyelectrolyte terpolymer according to claim 1 and amycin to carry out compound to prepare.The PGlu-co-PLA-co-mPEG (GLP-10505) of 0.2g is dissolved in 20g water, magnetic agitation is dissolved completely to copolymer, drip amycin aqueous solution gradually, stop when solution presents redness and has obvious Tyndall phenomenon, continue to stir 24h subsequently and carrier micelle is stablized.Polypeptide drug-loaded micelle solution being proceeded to molecular cut off is in the bag filter of 3500, and dialyse under lucifuge state 8h in ultra-pure water.The structure of this polyelectrolyte terpolymer medicament-carried nano micelle as shown in Figure 1.
4. the application of nano-micelle according to claim 3.It is characterized in that: the carrier micelle of having dialysed is got 5mL in bag filter, to be placed in 250mL medium be respectively 0.01M pH be 5.0,6.0,7.0,7.4,8.0 phosphate buffered solution (PBS), with 37 ± 0.5 DEG C of constant temperature magnetic agitation at a slow speed, separated in time sampling 4mL the fresh dissolution medium adding the identical temperature of same volume are to keep liquor capacity constant, and ultraviolet spectrophotometer tests the A of dialysis solution
483, recycling formulae discovery cumulative release medication amount also draws In-vitro release curves.
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