CN100588666C - Polypeptide-polyacrylic acid copolymer and its prepn process - Google Patents
Polypeptide-polyacrylic acid copolymer and its prepn process Download PDFInfo
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- CN100588666C CN100588666C CN200710041593A CN200710041593A CN100588666C CN 100588666 C CN100588666 C CN 100588666C CN 200710041593 A CN200710041593 A CN 200710041593A CN 200710041593 A CN200710041593 A CN 200710041593A CN 100588666 C CN100588666 C CN 100588666C
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Abstract
The present invention relates to one kind of biodegradable polypeptide-polyacrylic acid copolymer in the structure as shown and its preparation process. The block copolymer is prepared through the first acylating polypeptide as the initial material, the subsequent atom transferring free radical polymerization of the acylated polypeptide and tert-butyl acrylate or tert-butyl methacrylate, and finalhydrolysis of the obtained polymer to obtain the target product. The biodegradable polypeptide-polyacrylic acid block copolymer may be used as the nanometer level release-controlling carrier of hydrophobic medicine. Compared with available polypeptide copolymer, the present invention has the advantages of precisely controlled hydrophilic component content and hydrophobic component content, simplepreparation and low cost.
Description
Technical field
The present invention relates to a kind of biodegradable polypeptide-polyacrylic acid copolymer and preparation method thereof.
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), (Chinese Pharmaceutical Journal .2002,37 (7): 509-512) with the hydrophilic segment polyacrylic acid is the poly-polypeptide grafted copolymer (as the poly propenoic acid/polypeptide grafted copolymer of CN 1900144A report) that the poly-peptide of main chain, hydrophobicity is a side chain to be mainly amphipathic polyethers/poly-polypeptide block multipolymer.The former exists the insensitive defective of variation to the pH value of applied environment of living in, and the latter has polyacrylic molecular weight to be difficult to the effectively problem of regulation and control.
Therefore the poly-peptide multipolymer that a kind of novel being used to prepare nano-medicament carrier-both contained pH responsiveness segment need be researched and developed in this area, but the poly-peptide multipolymer of accuracy controlling molecular weight again.
Summary of the invention
The object of the invention is, but provides a kind of degradable, contain the polypeptide-polyacrylic acid segmented copolymer of pH responsiveness segment and molecular weight accuracy controlling, overcomes the defective of prior art with this;
Two of the object of the invention is, discloses a kind of method for preparing above-mentioned segmented copolymer.
The said polypeptide-polyacrylic acid segmented copolymer of the present invention, it has structure shown in the formula (1):
In the formula (1), R
1Be methyl, ethyl or benzyl (CH
2C
6H
5); R
2, R
3Be selected from H or C respectively
1～C
6A kind of in the alkyl; R
4Be H or methyl; M=10～20,000, n=10～20,000.
In an optimal technical scheme of the present invention, R
2, R
3Be selected from C respectively
1～C
3A kind of in the alkyl.
The method for preparing the said segmented copolymer of the present invention; its key step is: with poly-peptide homopolymer [compound shown in the formula (2)] is starting raw material; at first the amino in the compound shown in the formula (2) is carried out acidylate [acylating reagent is alpha-halogen carboxylic acid halides (compound shown in the formula (3))]; acylate [compound shown in the formula (4)] with gained carries out atom transfer radical polymerization (ATRP) with tert-butyl acrylate or methacrylic tert-butyl acrylate [compound shown in the formula (5)] then, at last resulting polymers is got target compound after hydrolysis.
Synthetic route is as follows:
Wherein: R
1, R
2, R
3, R
4, the implication of m and n with before chat identical; X is halogen (F, Cl, Br or I).
Description of drawings
The segmented copolymer of Fig. 1 embodiment 1 preparation and hydrolysate thereof
1The H-NMR spectrogram.
Wherein: (1) is the poly-peptide-polyacrylic acid tert-butyl ester segmented copolymer (PBLG-b-PtBA, structure is suc as formula shown in (6-1)) of embodiment 1 preparation
1The H-NMR spectrogram;
A, b, b
1, b
11, c, d, e, f and g exist for H not of the same race
1Identification marking in H-NMR-(1) spectrogram
(2) be the hydrolysate (PBLG/PAA, structure is suc as formula shown in (6-2)) of the PBLG-b-PtBA of embodiment 1 preparation
1The H-NMR spectrogram;
A, b, b
1, b
11, c, d, e, f and g exist for H not of the same race
1Identification marking in H-NMR-(2) spectrogram
Embodiment
In the present invention, said poly-peptide homopolymer is poly-γ-phenmethyl-L-glutamate (PBLG), poly-γ-ethyl-L-glutamate (PELG) or poly-γ-methyl-L-glutamate (PMLG), their preparation is referring to Synthetic polypeptides.PartII.Polyglutamic Acid., J.chem.soc., 3239,1950.
The acylation reaction of said poly-peptide homopolymer is performed such: compound shown in compound shown in the formula (2) and the formula (3) is placed under the anhydrous tetrahydro furan (THF); adding (as catalyzer) such as triethylamine, 4-Dimethylamino pyridine (DMAP) or pyridines reacts; temperature of reaction is-15 ℃～100 ℃ (0 ℃～80 ℃ of preferable reaction temperature), reaction times to be 0.1 hour～48 hours (the preferred reaction time is 0.5 hour～24 hours); get compound shown in the formula (4), compound shown in the purifying gained formula (4) (mainly removing unreacted raw material) is standby.
With compound shown in the above-mentioned purified formula (4), in inert atmosphere (as the stable gas of chemical property such as nitrogen or argon gas), have under the condition of catalyzer and coordination agent existence, carry out the ATRP polymerization with compound shown in the formula (5), the ATRP polymerization temperature is that-70 ℃～160 ℃ (preferred 20 ℃～160 ℃), ATRP polymerization times are several minutes extremely about 65 hours (preferred 10 minutes～about 48 hours), and the gained polymerisate gets target compound after the hydrolysis through trifluoroacetic acid down at normal temperature (15 ℃～30 ℃).
Wherein, said catalyzer is transition metal or transition metal low price ionic halogenide, as Cu, Fe, CuCl, CuBr, FeCl
2Or FeBr
2In a kind of, or two or more mixture; Said coordination agent is the existing nitrogenous compound of ATRP polymeric coordination agent one that is used for, as 2, a kind of in the amino Soxylat A 25-7 of 2 '-bipyridine, pentamethyl-diethylenetriamine (PMDETA), o-phenanthroline or derivatives thereof, Tetramethyl Ethylene Diamine or its many methyl polyamines, a two dimethyl amine benzyl ethyl ether or tetramethyl-, or two or more mixture.
The mol ratio of catalyzer and coordination agent is 1: (1.5～5.0), preferred mol ratio are 1: (2.0～4.0).
The halogen shown in the formula (4) in the compound and the mol ratio of catalyzer are 1: (0.1～3.0), preferred mol ratio are 1: (0.5～2.0).
Poly-peptide-the acrylic block copolymer of the present invention's design and preparation can be used for the nano level controlled release carrier of hydrophobic class medicine.Compare with the existing poly-peptide multipolymer that is used for the nano level controlled release carrier, have (a) and can accurately control hydrophilic, hydrophobic segmental molecular weight and relative content; (b) have preparation and simply reach advantages such as with low cost.
The invention will be further described by the following examples, and its purpose only is better to understand content of the present invention, and unrestricted protection scope of the present invention:
Embodiment 1
20 gram γ-phenmethyl-L-glutamate (PBLG) and 11g 4-Dimethylamino pyridine (DMAP) are added in the there-necked flask with 50ml anhydrous tetrahydro furan (THF), stirring is up to dissolving fully, cryosel is bathed and is passed through slowly Dropwise 5 ml α-bromine isobutyl acylbromide in above-mentioned solution of constant pressure funnel down, and constantly stir, have white precipitate and generate this moment, then stirring reaction 20 hours at room temperature.With sedimentation and filtration, filtrate was 3,500 dialysis tubing deionized water dialysis three days with molecular weight cut-off, changed one time deionized water every three hours, and last lyophilize obtains white powdery solid, i.e. macromole evocating agent PBLG-Br.
Get synthetic dry good macromole evocating agent PBLG-Br, macromole evocating agent as synthetic Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock, with cuprous bromide/pentamethyl-diethylenetriamine (CuBr/PMDETA) is catalyst system, under 80 ℃, carry out the body ATRP polymerization of tert-butyl acrylate, prepared PBLG-b-PtBA segmented copolymer (structure is suc as formula shown in (6-1)).Concrete prescription is: macromole evocating agent PBLG-Br is 0.23g (brominated 0.2mmol), and tert-butyl acrylate 5.1g, CuBr are 0.03g, and PMDETA is 0.03g.That is to say: tert-butyl acrylate: PBLG-Br: the mol ratio of CuBr:PMDETA is 200: 1: 1: 2, obtain poly-peptide-polyacrylic acid tert-butyl ester segmented copolymer (PBLG-b-PtBA).
In the formula (6-2): m=685, n=15; A, b, b
1, b
11, c, d, e, f and g exist for H not of the same race
1Identification marking in H-NMR-(1) spectrogram.
Get refined PBLG-b-PtBA segmented copolymer, with a certain amount of methylene dichloride (CH
2Cl
2) dissolving, cryosel is bathed slowly to drip while stirring down and is equivalent to 5 times of normal trifluoroacetic acids of the tert-butyl ester (TFA), stirs 20 hours under the room temperature.Methylene dichloride and excessive trifluoroacetic acid are removed by rotatory evaporator, vacuum-drying is 2 days under the gray solid room temperature that obtains, use dimethyl formamide (DMF) dissolving then, with molecular weight cut-off is 3, deionized water was changed one time in 500 dialysis tubing deionized water dialysis three days every three hours, last lyophilize obtains gray solid, be the PBLG/PAA segmented copolymer, structure as the formula (6).
In the formula (6-2): m=685, n=15; A, b, b
1, b
11, c, d, e, f and g exist for H not of the same race
1Identification marking in H-NMR-(2) spectrogram.
Prepared poly-peptide-polyacrylic acid tert-butyl ester segmented copolymer (PBLG-b-PtBA, compound shown in the formula (6-1)) and hydrolysate (PBLG/PAA, compound shown in the formula (6-2))
1The H-NMR spectrogram is seen Fig. 1.
Among Fig. 1,8.34ppm absorption peak is in the coiled strand molecular structure-proton peak in the NH group, 7.25ppm be the feature proton absorption peak of side-chain benzene ring, 5.07ppm be the proton peak of side chain phenmethyl, 3.98ppm be on the main chain on the α position-the proton absorption peak of CH-group, 1.45ppm is the strong proton absorption peak of the tertiary butyl in the tert-butyl acrylate.Have the characteristic peak of PBLG and PtBA in the multipolymer concurrently, illustrate that the molecular structure of the synthetic PBLG-b-PtBA of institute is correct.Simultaneously, as can be seen from Figure 1, tert-butyl acrylate block on the segmented copolymer side chain tertiary butyl under certain condition can be hydrolyzed and obtains vinylformic acid block (fracture of other ester bonds does not take place in the hydrolytic process), thereby obtains amphipathic PBLG-b-PAA segmented copolymer.We find that the methyl peak has disappeared substantially on the tertiary butyl from nuclear magnetic spectrogram, and hydrolysis is complete basically thereby determine the tertiary butyl.
Adopt method similar to Example 1 can make following segmented copolymer (shown in embodiment 2～embodiment 5), be summarized as follows respectively:
Embodiment 2
20 gram γ-methyl-L-glutamate (PMLG) and 10g pyridine are dissolved with 50ml anhydrous tetrahydro furan (THF), after treating to dissolve fully, add 5ml bromine butyryl bromide and carry out amidate action synthetic macromolecule initiator PMLG-Br, add tert-butyl acrylate, (coordination agent is 2 by atom transfer radical polymerization to adopt bulk process, 2 '-bipyridine, catalyzer is CuCl) obtain poly-peptide-polyacrylic acid tert-butyl ester segmented copolymer, remove the tert-butyl ester with trifluoroacetic acid hydrolysis then and obtain the PBLG-PAA segmented copolymer, structure as the formula (7).
M=50 in the formula (7), n=126.
Embodiment 3
20 gram γ-ethyl-L-glutamate (PELG) and 8g triethylamine are dissolved with 50ml anhydrous tetrahydro furan (THF), after treating to dissolve fully, add the 5ml bromopropionyl bromide and carry out amidate action synthetic macromolecule initiator PELG-Br, add tert-butyl acrylate, (coordination agent is pentamethyl-diethylenetriamine (PMDETA) by atom transfer radical polymerization to adopt bulk process, catalyzer is CuCl) obtain poly-peptide-polyacrylic acid tert-butyl ester segmented copolymer, remove the tert-butyl ester with trifluoroacetic acid hydrolysis then and obtain the PBLG-PAA segmented copolymer, structure as the formula (8).
M=645 in the formula (8), n=68.
Embodiment 4
20 gram γ-methyl-L-glutamate (PMLG) and 11g 4-Dimethylamino pyridine (DMAP) are dissolved with 50ml anhydrous tetrahydro furan (THF), after treating to dissolve fully, add the 5ml bromopropionyl bromide and carry out amidate action synthetic macromolecule initiator PMLG-Br, add tert-butyl acrylate, adopting THF is that (coordination agent is pentamethyl-diethylenetriamine (PMDETA) by atom transfer radical polymerization for the solution polymerization process of solvent, catalyzer is CuCl) obtain poly-peptide-polyacrylic acid tert-butyl ester segmented copolymer, remove the tert-butyl ester with trifluoroacetic acid hydrolysis then and obtain the PBLG-PAA segmented copolymer, structure as the formula (9).
M=105 in the formula (9), n=669.
Embodiment 5
23 gram γ-phenmethyl-L-glutamate (PBLG) and 9g triethylamine are dissolved with 50ml anhydrous tetrahydro furan (THF), after treating to dissolve fully, add the 5ml bromopropionyl bromide and carry out amidate action synthetic macromolecule initiator PBLG-Br, add tert-butyl acrylate, (coordination agent is pentamethyl-diethylenetriamine (PMDETA) by atom transfer radical polymerization to adopt bulk process, catalyzer is CuCl) obtain poly-peptide-polyacrylic acid tert-butyl ester segmented copolymer, remove the tert-butyl ester with trifluoroacetic acid hydrolysis then and obtain the PBLG-PAA segmented copolymer, structure as the formula (10).
M=43 in the formula (10), n=824.
Claims (10)
1, a kind of polypeptide-polyacrylic acid segmented copolymer, it has structure shown in the formula (1):
In the formula (1), R
1Be methyl, ethyl or benzyl; R
2, R
3Be selected from H or C respectively
1～C
6A kind of in the alkyl; R
4Be H or methyl; M=10～20,000, n=10～824.
2, polypeptide-polyacrylic acid segmented copolymer as claimed in claim 1 is characterized in that, wherein R
2, R
3Be selected from C respectively
1～C
3A kind of in the alkyl.
3, a kind of method for preparing polypeptide-polyacrylic acid segmented copolymer as claimed in claim 1 or 2, it is characterized in that, described preparation method's key step is: be that acylating reagent carries out acidylate to the amino in the compound shown in the formula (2) with compound shown in the formula (3) at first, then compound shown in compound shown in the formula (4) of gained and the formula (5) is carried out atom transfer radical polymerization, at last resulting polymers is got target compound after hydrolysis;
Wherein: X is a halogen.
4, preparation method as claimed in claim 3 is characterized in that, it is-15 ℃～100 ℃ that compound shown in compound shown in its Chinese style (2) and the formula (3) carries out the temperature of acylation reaction.
5, preparation method as claimed in claim 3, it is characterized in that, wherein under the condition that has catalyzer and coordination agent to exist, it is-70 ℃～160 ℃ that compound shown in compound shown in the formula (4) and the formula (5) carries out the polymerization temperature of atom transfer radical polymerization, and polymerization time is 10 minutes to 48 hours.
6, preparation method as claimed in claim 5, it is characterized in that, compound carries out in the atom transfer radical polymerization shown in compound shown in its Chinese style (4) and the formula (5), and the halogen shown in the formula (4) in the compound and the mol ratio of catalyzer are 1: (0.1～3.0).
7, preparation method as claimed in claim 6 is characterized in that, wherein said catalyzer is Cu, Fe, CuCl, CuBr, FeCl
2Or/and FeBr
2
8, preparation method as claimed in claim 5 is characterized in that, compound carries out in the atom transfer radical polymerization shown in compound shown in the formula (4) and the formula (5), and the mol ratio of catalyst system therefor and used coordination agent is 1: (1.5～5.0).
9, preparation method as claimed in claim 8 is characterized in that, wherein said catalyzer is Cu, Fe, CuCl, CuBr, FeCl
2Or/and FeBr
2
10, preparation method as claimed in claim 8, it is characterized in that, wherein said coordination agent is 2, one or two or more kinds mixture in the amino Soxylat A 25-7 of 2 '-bipyridine, pentamethyl-diethylenetriamine, o-phenanthroline or derivatives thereof, Tetramethyl Ethylene Diamine, a two dimethyl amine benzyl ethyl ether or tetramethyl-.
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Non-Patent Citations (3)
| Title |
|---|
| Synthesis of poly(γ-benzyl-L-glutamate) graft copolymers. Ben，Jin，Liu，Feng，，Gao，Yun，，Lin，Jiaping.合成橡胶工业，第30卷第1期. 2007 * |
| Synthesis of poly(γ-benzyl-L-glutamate)graft copolymers. Ben,Jin,Liu,Feng,Gao,Yun,Lin,Jiaping.合成橡胶工业，第30卷第1期. 2007 * |
| 聚丙烯酸及其接枝/嵌段共聚物的合成与表征. 贲进.华东理工大学硕士学位论文. 2007 * |
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