CN100430433C - Poly propenoic acid/polypeptide grafted copolymer and its preparing method and use - Google Patents
Poly propenoic acid/polypeptide grafted copolymer and its preparing method and use Download PDFInfo
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- CN100430433C CN100430433C CNB2006100289322A CN200610028932A CN100430433C CN 100430433 C CN100430433 C CN 100430433C CN B2006100289322 A CNB2006100289322 A CN B2006100289322A CN 200610028932 A CN200610028932 A CN 200610028932A CN 100430433 C CN100430433 C CN 100430433C
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Abstract
The present invention relates to a kind of polyacrylic acid/polypeptide grafted copolymer in the first as shown and its preparation process and application. The preparation process includes the main steps of: the first setting polyacrylic acid, solvent and condensing agent in reactor; and the subsequent adding peptide homoplymer to react at 15-30 deg.c to obtain the target product. The copolymer of the present invention may be used as the nanometer level release controlling carrier of hydrophobic medicine. The present invention has the advantages of pH response of the copolymer, easy preparation and capacity of controlling the relative content of the hydrophilic chain segment and the hydrophobic chain segment of the copolymer precisely.
Description
Technical field
The present invention relates to graft copolymer of a kind of polyacrylic acid and poly-peptide and its production and application.
Background technology
Amphipathic peptide multipolymer, on the formed nano-micelle narrow diameter distribution of its self-assembly, the main chain numerous peptide bond in vivo under the proteolytic enzyme effect easy fracture degraded generate nontoxic small molecules, be the multipolymer that a class is widely used in preparing nano-medicament carrier.
The existing poly-peptide multipolymer that is used to prepare nano-medicament carrier (carrier micelle), being mainly amphipathic polypeptide block multipolymer and gathering peptide with hydrophobicity is that main chain, hydrophilic segment are the poly-polypeptide grafted copolymer of side chain.The former causes by the hydrophilic segment macromole and makes, and the latter then makes by transesterification reaction, but both all lack pH responsiveness (promptly insensitive to the variation of the pH value of applied environment of living in).
Summary of the invention
One of the object of the invention is to provide a kind of poly propenoic acid/polypeptide grafted copolymer of the pH of having responsiveness;
Two of the object of the invention is to disclose a kind of method for preparing above-mentioned multipolymer;
Three of the object of the invention is to disclose a kind of purposes of above-mentioned multipolymer.
The said poly propenoic acid/polypeptide grafted copolymer of the present invention, it has structure shown in the formula (1):
In the formula (1), R is methyl, ethyl or phenmethyl (CH
2C
6H
5); M=10～20000; N=2～2000; X=5～200.
The key step for preparing above-mentioned poly propenoic acid/polypeptide grafted copolymer method is:
At first polyacrylic acid (PAA), solvent and condensing agent are placed reactor, in this reactor, add poly-peptide homopolymer then, make target compound in normal temperature (15 ℃～30 ℃) reaction;
Wherein: said poly-peptide homopolymer is: poly-γ-phenmethyl-L-glutamate (PBLG), poly-γ-ethyl-L-glutamate (PELG) or poly-γ-methyl-L-glutamate (PMLG), its preparation is referring to Synthetic polypeptides.Part II.Polyglutamic Acid., J.chem.soc., 3239,1950.
In the present invention, the solvent of recommending to use is N, dinethylformamide (DMF); The condensing agent of recommending to use is: N, N '-dicyclohexylcarbodiimide (DCC), two sec.-propyl carbodiimide (DIC), 3-ethyl-1-(3-dimethyl propyl) carbodiimide (EDC), N, two imidazoles fluoroform sulphonates (CBMIT) of N '-carbonyl or Di-tert butyl pyrocarbonate (Boc
2O) etc.
The poly propenoic acid/polypeptide grafted copolymer of the present invention's design and preparation can be used for the nano level controlled release carrier of hydrophobic class medicine.
Promptly, the said poly propenoic acid/polypeptide grafted copolymer of the present invention, hydrophobic class medicine [as (but being not limited to): Naproxen Base (naproxen), Zorubicin (adriamycin) or taxol (paclitaxel) etc.] and solvent [recommending to use N, dinethylformamide (DMF), tetrahydrofuran (THF) (THF), dimethyl sulfoxide (DMSO) (DMSO), dioxane etc.] can be made nano level carrier micelle (feed ratio of multipolymer and medicine is 10/1～10/5) by existing ultra micro dialysis technology.
The invention has the advantages that:
1, poly propenoic acid/polypeptide grafted copolymer of the present invention has the pH responsiveness;
2, poly propenoic acid/polypeptide grafted copolymer of the present invention is easy to preparation, and hydrophilic, hydrophobic segmental relative content can accurately be controlled in the multipolymer;
3, based on the carrier micelle of poly propenoic acid/polypeptide grafted copolymer of the present invention, along with the difference of micellar structure, size and environment pH value, its drug loading is also different with rate of release, for the research of medicine controlled release carrier provides foundation.
Description of drawings
Fig. 1 is PAA-PBLG graft copolymer nano drug-carrying (Naproxen Base) micella transmission electron microscope picture.
Embodiment
The present invention is further elaborated by the following examples, and its purpose only is better to understand the object of the invention and unrestricted protection scope of the present invention.
Embodiment one
10 gram PAA and 41 are restrained PBLG, after dissolving fully with 100 gram DMF, add 2 gram DCC, carried out amidate action at normal temperatures 3 days, obtain the PAA-PBLG graft copolymer of following structure, wherein: m=685, n=50, x=20.
Embodiment two
4 gram PAA and 19 are restrained PBLG, after dissolving fully with 200 gram DMF, add 1 gram Boc
2O carried out amidate action 3 days under normal temperature (15 ℃～30 ℃), obtain structure PAA-PBLG graft copolymer shown in embodiment one, wherein: m=9320, n=500, x=30.
Embodiment three
20 gram PAA and 13 are restrained PELG, after dissolving fully with 200 gram DMF, add 0.2 gram CBMIT, under normal temperature (15 ℃～30 ℃), carried out amidate action 3 days, obtain the PAA-PELG graft copolymer of following structure, wherein: m=6940, n=10, x=200.
Embodiment four
5 gram PAA and 19 are restrained PELG, after dissolving fully with 150 gram DMF, add 2.5 gram EDC, under normal temperature (15 ℃～30 ℃), carry out amidate action 3 days, obtain the PAA-PELG graft copolymer of structure shown in embodiment three, wherein: m=5940, n=1000, x=10.
Embodiment five
10 gram PAA and 41 are restrained PMLG, after dissolving fully with 150 gram DMF, add 1.8 gram EDC, under normal temperature (15 ℃～30 ℃), carried out amidate action 3 days, obtain the PAA-PMLG graft copolymer of following structure, wherein: m=2638, n=140, x=20.
Embodiment six
20 gram PAA and 39 are restrained PMLG, after dissolving fully with 150 gram DMF, add 6.0 gram Boc
2O carried out amidate action 3 days under normal temperature (15 ℃～30 ℃), obtain structure PAA-PMLG graft copolymer shown in embodiment five, wherein: m=18882, n=2000, x=10.
Embodiment seven
20 gram PAA and 220 are restrained PMLG, after dissolving fully with 400 gram DMF, add 2 gram DIC, under normal temperature (15 ℃～30 ℃), carry out amidate action 3 days, obtain the PAA-PMLG graft copolymer of structure shown in embodiment five, wherein: m=260, n=15, x=100.
Embodiment eight
10 gram PAA and 15 are restrained PMLG, after dissolving fully with 150 gram DMF, add 4 gram DCC, under normal temperature (15 ℃～30 ℃), carried out amidate action 3 days, obtain structure PAA-PMLG graft copolymer shown in embodiment five, wherein: m=12, n=2, x=5.
Embodiment nine
PAA-PBLG graft copolymer and 5 gram Naproxen Base medicines with preparation among the 20 gram embodiment one, with 100 gram DMF dissolvings, after treating to dissolve fully, move into molecular weight cut-off and be in 3500 the dialysis tubing, insert in the deionized water and dialyse, after 48 hours not embedding medicinal is removed in micellar solution centrifugation in the dialysis tubing, got supernatant liquid, get the nano level carrier micelle after the lyophilize through 0.45 μ m membrane filtration.The PAA-PBLG graft copolymer nano drug-carrying micella median size that obtains is 100nm, drug loading 19.2%.Transmission electron microscope observing shows (as Fig. 1), and carrier micelle is spherical.(pH=7.4) 1 hour, 24 hours, 48 hours accumulative total burst size is respectively 19.4%, 45.2%, 62.9% in the phosphoric acid salt simulated body fluid.
Embodiment ten
The PAA-PBLG/ Naproxen Base carrier micelle that embodiment nine makes, 1 hour, 24 hours, 48 hours accumulative total burst sizes are respectively 10.9%, 37.7%, 58.4% in hydrochloric acid soln (pH=1.1).
Embodiment 11
The PAA-PBLG/ Naproxen Base carrier micelle that embodiment nine makes, 1 hour, 24 hours, 48 hours accumulative total burst sizes are respectively 24.3%, 60.4%, 85.9% in sodium bicarbonate-yellow soda ash buffered soln (pH=10.0).
Embodiment 12
PAA-PELG graft copolymer and 5 gram Naproxen Base medicines with preparation among the 20 gram embodiment four, with 100 gram DMSO dissolvings, after treating to dissolve fully, in the immigration dialysis tubing, insert in the deionized water and dialyse, after 48 hours not embedding medicinal is removed in micellar solution centrifugation in the dialysis tubing, got supernatant liquid, get the nano level carrier micelle after the lyophilize through 0.45 μ m membrane filtration.The PAA-PELG graft copolymer nano drug-carrying micella median size that obtains is 130nm, drug loading 10.0%.Electron microscope showed, carrier micelle are spherical.(pH=7.4) 1 hour, 24 hours, 48 hours accumulative total burst size is respectively 20.7%, 57.8%, 75.3% in the phosphoric acid salt simulated body fluid.
Embodiment 13
PAA-PMLG graft copolymer and 5 gram Naproxen Base medicines with preparation among the 20 gram embodiment seven, with 100 gram dioxane dissolvings, after treating to dissolve fully, in the immigration dialysis tubing, insert in the deionized water and dialyse, after 48 hours not embedding medicinal is removed in micellar solution centrifugation in the dialysis tubing, got supernatant liquid, get the nano level carrier micelle after the lyophilize through 0.45 μ m membrane filtration.The PAA-PMLG graft copolymer nano drug-carrying micella median size that obtains is 90nm, drug loading 15.3%.Electron microscope showed, carrier micelle are spherical.(pH=7.4) 1 hour, 24 hours, 48 hours accumulative total burst size is respectively 14.5%, 40.3%, 57.6% in the phosphoric acid salt simulated body fluid.
Embodiment 14
PAA-PBLG graft copolymer and 3 gram Zorubicin medicines with preparation among the 20 gram embodiment two, with 100 gram DMF dissolvings, after treating to dissolve fully, in the immigration dialysis tubing, insert in the deionized water and dialyse, after 48 hours not embedding medicinal is removed in micellar solution centrifugation in the dialysis tubing, got supernatant liquid, get the nano level carrier micelle after the lyophilize through 0.45 μ m membrane filtration.The PAA-PBLG graft copolymer nano drug-carrying micella median size that obtains is 150nm, drug loading 15.8%.Electron microscope showed, carrier micelle are spherical.(pH=7.4) 1 hour, 24 hours, 48 hours accumulative total burst size is respectively 18.3%, 45.6%, 59.8% in the phosphoric acid salt simulated body fluid.
Embodiment 15
PAA-PMLG graft copolymer and 3 gram Zorubicin medicines with preparation among the 20 gram embodiment five, with 100 gram THF dissolvings, after treating to dissolve fully, in the immigration dialysis tubing, insert in the deionized water and dialyse, after 48 hours not embedding medicinal is removed in micellar solution centrifugation in the dialysis tubing, got supernatant liquid, get the nano level carrier micelle after the lyophilize through 0.45 μ m membrane filtration.The PAA-PMLG graft copolymer nano drug-carrying micella median size that obtains is 140nm, drug loading 6.1%.Electron microscope showed, carrier micelle are spherical.(pH=7.4) 1 hour, 24 hours, 48 hours accumulative total burst size is respectively 23.5%, 56.9%, 71.2% in the phosphoric acid salt simulated body fluid.
Embodiment 16
PAA-PELG graft copolymer and 2 gram taxol drug with preparation among the 20 gram embodiment three, with 100 gram DMF dissolvings, after treating to dissolve fully, in the immigration dialysis tubing, insert in the deionized water and dialyse, after 48 hours not embedding medicinal is removed in micellar solution centrifugation in the dialysis tubing, got supernatant liquid, get the nano level carrier micelle after the lyophilize through 0.45 μ m membrane filtration.The PAA-PELG graft copolymer nano drug-carrying micella median size that obtains is 110nm, drug loading 7.0%.Electron microscope showed, carrier micelle are spherical.(pH=7.4) 1 hour, 24 hours, 48 hours accumulative total burst size is respectively 37.4%, 75.3%, 87.8% in the phosphoric acid salt simulated body fluid.
Embodiment 17
Poly-polypeptide grafted copolymer of PAA-PMLG and 2 gram taxol drug with preparation among the 20 gram embodiment six, with 100 gram DMF dissolvings, after treating to dissolve fully, in the immigration dialysis tubing, insert in the deionized water and dialyse, after 48 hours not embedding medicinal is removed in micellar solution centrifugation in the dialysis tubing, got supernatant liquid, get the nano level carrier micelle after the lyophilize through 0.45 μ m membrane filtration.The PAA-PMLG graft copolymer nano drug-carrying micella median size that obtains is 90nm, drug loading 7.5%.Electron microscope showed, carrier micelle are spherical.(pH=7.4) 1 hour, 24 hours, 48 hours accumulative total burst size is respectively 28.7%, 70.2%, 81.3% in the phosphoric acid salt simulated body fluid.
Claims (5)
1, a kind of poly propenoic acid/polypeptide grafted copolymer, it has structure shown in the formula (1):
In the formula (1), R is methyl, ethyl or phenmethyl; M=10～20000; N=2～2000; X=5～200.
2, a kind of preparation is as the method for the said poly propenoic acid/polypeptide grafted copolymer of claim 1, it is characterized in that, said preparation method's key step is: at first polyacrylic acid, solvent and condensing agent are placed reactor, in this reactor, add poly-peptide homopolymer then, make target compound 15 ℃～30 ℃ reactions;
Wherein: said poly-peptide homopolymer is: poly-γ-phenmethyl-L-glutamate, poly-γ-ethyl-L-glutamate or poly-γ-methyl-L-glutamate, said solvent is N, dinethylformamide.
3, as the said preparation method of claim 2, it is characterized in that, wherein said condensing agent is: N, N '-dicyclohexylcarbodiimide, two sec.-propyl carbodiimide, 3-ethyl-1-(3-dimethyl propyl) carbodiimide, N, two imidazoles fluoroform sulphonates of N '-carbonyl or Di-tert butyl pyrocarbonate.
4, the nano level controlled release carrier that is used for hydrophobic class medicine as the said poly propenoic acid/polypeptide grafted copolymer of claim 1.
As the said purposes of claim 4, it is characterized in that 5, wherein said hydrophobic class medicine is: Naproxen Base (naproxen), Zorubicin (adriamycin) or taxol (paclitaxel).
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| CN104559216A (en) * | 2015-01-06 | 2015-04-29 | 山东理工大学 | Method for improving hydrophily and flexibility of polypeptide membrane by poly(trimethylene carbonate) and polyacrylic acid |
| CN111875721B (en) * | 2020-07-24 | 2023-04-07 | 广西民族大学 | Modified polyacrylic acid copolymer and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1163627A (en) * | 1994-07-22 | 1997-10-29 | 弗拉基米尔·费恩戈尔德 | Biocompatible optically transparent polymeric material based upon collagen and method of making |
| CN1268879A (en) * | 1997-05-28 | 2000-10-04 | 斯塔尔外科公司 | Biocompatible, optically transparent, ultraviolet light absorbing, polymeric material based upon collagen and method of making |
| JP2002241430A (en) * | 2001-02-21 | 2002-08-28 | Kao Corp | Polyamino acid graft (co)polymer |
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2006
- 2006-07-14 CN CNB2006100289322A patent/CN100430433C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1163627A (en) * | 1994-07-22 | 1997-10-29 | 弗拉基米尔·费恩戈尔德 | Biocompatible optically transparent polymeric material based upon collagen and method of making |
| CN1268879A (en) * | 1997-05-28 | 2000-10-04 | 斯塔尔外科公司 | Biocompatible, optically transparent, ultraviolet light absorbing, polymeric material based upon collagen and method of making |
| JP2002241430A (en) * | 2001-02-21 | 2002-08-28 | Kao Corp | Polyamino acid graft (co)polymer |
Non-Patent Citations (4)
| Title |
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| 13CNMR法研究乙烯基类单体与胶原蛋白水解多肽的接枝共聚反应. 杨晓峰，李曼尼，佟永志.内蒙古大学学报(自然科学版)，第36卷第2期. 2005 |
| 13CNMR法研究乙烯基类单体与胶原蛋白水解多肽的接枝共聚反应. 杨晓峰，李曼尼，佟永志.内蒙古大学学报(自然科学版)，第36卷第2期. 2005 * |
| 多肽-丙烯酸酯接枝共聚制备皮革涂饰剂. 张景斌，张鹏戈，王万兴，隋智慧.日用化学工业，第3期. 1996 |
| 多肽-丙烯酸酯接枝共聚制备皮革涂饰剂. 张景斌，张鹏戈，王万兴，隋智慧.日用化学工业，第3期. 1996 * |
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