CN104788670B - A kind of double responsiveness glucosan polyamino acid block copolymer and preparation method thereof and carrier micelle - Google Patents
A kind of double responsiveness glucosan polyamino acid block copolymer and preparation method thereof and carrier micelle Download PDFInfo
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Abstract
The invention provides a kind of double responsiveness glucosan polyamino acid block copolymer, there is structure shown in formula (I), micelle can be self-assembled in water environment, for loading hydrophobic anticancer drug.Compared with prior art, the double responsiveness glucosan polyamino acid block copolymer that the present invention provides, by oxime key and disulfide bond, hydrophilic chain glucosan is connected with hydrophobic chain polyamino acid, make the double responsiveness glucosan polyamino acid block copolymer that the present invention provides while there is good pH response, there is good reduction response, prepared carrier micelle is in tumor tissues or cell, under low ph environment or homoglutathion concentration environment can rapid delivery of pharmaceuticals, thus reach enhancing drug effect and drop hypotoxic purpose.
Description
Technical field
The present invention relates to biological medical polymer material technical field, more specifically, it is to be related to a kind of double responsiveness Portugal
Polysaccharide-polyamino acid block copolymer and preparation method thereof and carrier micelle.
Background technology
Tumor has become as one of most serious disease threatening human health.At present, the treatment of cancer handss clinically commonly used
Section has chemotherapy, radiotherapy and operative treatment etc..Wherein, chemotherapy is the most frequently used and important treatment meanss.But face
On bed, antitumor drug used has many defects, such as in the application：Water solublity and stability are poor, and poisonous side effect of medicine is big
Deng.In order to solve these problems, medicine can be combined with pharmaceutical carrier, to improve water solublity and the stability of medicine, and reach
Control release to medicine, thus reducing the toxic and side effects of medicine normal tissue, gives full play to effect of medicine.
At present, conventional pharmaceutical carrier organic and/or inorganic materials nanoparticle, dendritic, liposome, polymer nanocomposite
Hydrogel and polymer micelle etc..Wherein, polymer micelle is by the amphipathic copolymerization with hydrophilic segment and hydrophobic segment
Thing spontaneous assembling in water is formed, and it has advantages below：Polymer micelle has obvious nucleocapsid structure, in self assembly
Cheng Zhong, hydrophobic block constitute micelle kernel, and hydrophilic block then around micelle inner core constitute micelle shell it will be apparent that
Nucleocapsid structure can effectively improve the water solublity of medicine；It is steady in blood circulation that polymer micelle carrier can strengthen medicine
Qualitative, extend medicine circulation time in vivo；The size of polymer micelle is controlled, and suitable size is conducive to carrying
Body, in the gathering of tumor tissues, realizes its passive target to tumor tissues, improves the bioavailability of medicine, reduces medicine
Toxic and side effects.Therefore, had a good application prospect using polymer micelle as pharmaceutical carrier.
The Chinese patent of Publication No. CN102920649A discloses a kind of medicament-carried nano micelle, is derived with Polyethylene Glycol
Thing-polylysine-poly- leucine amphipathic three block copolymer is carrier, is self-assembly of in aqueous with transmission gene
Nano-micelle with the three-decker of medicine；Wherein, the hydrophobic interaction between poly- leucine makes copolymer form micelle in water
Core, be used for containing hydrophobic drug Docetaxel；Polylysine makes nano-micelle positively charged, for reference to electronegative
Anti-apoptotic proteins siRNA；Polyethylene Glycol is used for the stability that protection is loaded with the nano-micelle of medicine and gene, extends nanometer
Micelle circulation time in vivo.But, above-mentioned carrier micelle due to macromolecular compound between chemical bond excessively stable, thus deposit
Problem in drug release lack of wisdom.
Content of the invention
In view of this, it is an object of the invention to provide a kind of double responsiveness glucosan-polyamino acid block copolymer and
Its preparation method and carrier micelle, double responsiveness glucosan-polyamino acid block copolymer that the present invention provides has good simultaneously
Good pH response and reduction response.
The invention provides a kind of double responsiveness glucosan-polyamino acid block copolymer, there is structure shown in formula (I)：
Wherein, 10≤n≤3125；10≤m≤200；
- R is selected from-H、-CH3、-CH(CH3)CH3、-CH2CH(CH3)CH3、-CH(CH3)
CH2CH3、-CH2OH、-CH2SH、 -CH
(OH)CH3、
Present invention also offers one kind has the double responsiveness glucosan-polyamino acid block copolymer of formula (I) structure
Preparation method, comprises the following steps：
A1) glucosan, 2-aminoethyl disulfide dihydrochloride and buffer solution are mixed, reacted, obtain compound shown in formula (II)；
B1) carboxylic acid anhydrides in compound shown in formula (II), aminoacid-N- and organic solvent are mixed, reacted, obtain double
Response glucosan-polyamino acid block copolymer；
Described double responsiveness glucosan-polyamino acid block copolymer has structure shown in formula (I)：
Wherein, 10≤n≤3125；10≤m≤200；
- R is selected from-H、-CH3、-CH(CH3)CH3、-CH2CH(CH3)CH3、-CH(CH3)
CH2CH3、-CH2OH、-CH2SH、 -CH
(OH)CH3、
Preferably, in described aminoacid-N-, carboxylic acid anhydrides are carboxylic acid anhydrides, γ-propine in γ-benzyl-L-Glutamic Acid ester-N-
Carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides in base-L-Glutamic Acid ester-N-, γ -2- chloroethyl-L-Glutamic Acid ester-N-, glycine-N-,
Carboxylic in carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides in L-Alanine-N-, L-Valine-N-, L-Leu-N-, L-Isoleucine-N-
Carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides in anhydride, L-phenylalanine-N-, L-Tryptophan-N-, L-Serine-N-, L-Tyrosine-
Carboxylic acid anhydrides, altheine-N- in carboxylic acid anhydrides in carboxylic acid anhydrides in N-, ε-benzyloxycarbonyl group-L-Cysteine-N-, L-Methionine-N-
Carboxylic acid anhydrides, γ-benzyl-L-aspartate ester-N- in carboxylic acid anhydrides in interior carboxylic acid anhydrides, L-Glutamine-N-, L-Threonine-N-
Carboxylic acid anhydrides in carboxylic acid anhydrides or histidine-N- in carboxylic acid anhydrides in interior carboxylic acid anhydrides, ε-benzyloxycarbonyl group -1B-N-, arginine-N-.
Preferably, the number-average molecular weight of described glucosan is 1000g/mol～500000g/mol.
Preferably, the mol ratio of described glucosan and 2-aminoethyl disulfide dihydrochloride is (0.5～1.5)：1.
Preferably, described buffer solution is acetate buffer solution；The pH value of described buffer solution is 2～7.
Preferably, step A1) described in reaction temperature be 20 DEG C～65 DEG C, the time be 12h～120h.
Preferably, step B1) described in compound shown in formula (II) with the mol ratio of carboxylic acid anhydrides in described aminoacid-N- be
1：(10～40).
Preferably, step B1) described in reaction temperature be 20 DEG C～65 DEG C, the time be 24h～120h.
Present invention also offers a kind of carrier micelle, including：Double responsiveness glucosan described in technique scheme-poly- ammonia
Double responsiveness glucosan-polyamino acid the block copolymerization of the method preparation described in base acid block copolymer or technique scheme
Thing；
It is supported on the antitumor drug on described double responsiveness glucosan-polyamino acid block copolymer；Described antitumor
Medicine is amycin, camptothecine or paclitaxel.
The invention provides a kind of double responsiveness glucosan-polyamino acid block copolymer, can be from group in water environment
Dress up micelle, for loading hydrophobic anticancer drug.Compared with prior art, the double responsiveness glucosan that the present invention provides-
Hydrophilic chain glucosan is connected with hydrophobic chain polyamino acid by polyamino acid block copolymer by oxime key and disulfide bond, wherein, two
Sulfide linkage is highly stable under the environment such as normal body temperature, pH value and oxidation, and in a certain amount of Glutathione (GSH) reductase
Or it is reduced into sulfydryl in the presence of the reducing agent such as dithiothreitol, DTT (DTT), make double responsiveness glucosan-poly- ammonia that the present invention provides
Base acid block copolymer, while having good pH response, has a good reduction response, prepared load medicine glue
Bundle in tumor tissues or cell, under low ph environment or homoglutathion concentration environment can rapid delivery of pharmaceuticals, thus reaching
To enhancing drug effect and the hypotoxic purpose of fall.
Brief description
In order to be illustrated more clearly that the embodiment of the present invention or technical scheme of the prior art, below will be to embodiment or existing
Have technology description in required use accompanying drawing be briefly described it should be apparent that, drawings in the following description be only this
Inventive embodiment, for those of ordinary skill in the art, on the premise of not paying creative work, can also basis
The accompanying drawing providing obtains other accompanying drawings.
Double responsiveness glucosan-the b-'s poly- (γ-benzyloxy-L-Glutamic Acid ester) that Fig. 1 provides for the embodiment of the present invention 14
Infrared absorption pattern；
Double responsiveness glucosan-the b-'s poly- (γ-benzyloxy-L-Glutamic Acid ester) that Fig. 2 provides for the embodiment of the present invention 14
Hydrogen nuclear magnetic resonance spectrogram；
The carrier micelle that Fig. 3 provides for the embodiment of the present invention 17 carries out the releasing result of pH value response extracorporeal releasing test
Figure；
The carrier micelle that Fig. 4 provides for the embodiment of the present invention 17 carries out reducing the releasing result of response extracorporeal releasing test
Figure.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical scheme is clearly and completely described it is clear that institute
The embodiment of description is only a part of embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention,
The every other embodiment that those of ordinary skill in the art are obtained under the premise of not making creative work, broadly falls into this
The scope of bright protection.
The invention provides a kind of double responsiveness glucosan-polyamino acid block copolymer, there is structure shown in formula (I)：
Wherein, 10≤n≤3125；10≤m≤200；
- R is selected from-H、-CH3、-CH(CH3)CH3、-CH2CH(CH3)CH3、-CH(CH3)
CH2CH3、-CH2OH、-CH2SH、 -CH
(OH)CH3、
In the present invention, in double responsiveness glucosan-polyamino acid block copolymer that described n provides for the present invention, Portugal gathers
The degree of polymerization of sugar, in double responsiveness glucosan-polyamino acid block copolymer that described m provides for the present invention, polyamino acid is poly-
Right, wherein, 10≤n≤3125, preferably 20≤n≤2500；10≤m≤200, preferably 20≤m≤100, more preferably
20≤m≤40.
In the present invention, described-R is selected from-H、-CH3、-CH(CH3)CH3、-CH2CH
(CH3)CH3、-CH(CH3)CH2CH3、-CH2OH、-CH2SH、-CH(OH)CH3、 Excellent
Elect as
Present invention also offers one kind has the double responsiveness glucosan-polyamino acid block copolymer of formula (I) structure
Preparation method, comprises the following steps：
A1) glucosan, 2-aminoethyl disulfide dihydrochloride and buffer solution are mixed, reacted, obtain compound shown in formula (II)；
B1) carboxylic acid anhydrides in compound shown in formula (II), aminoacid-N- and organic solvent are mixed, reacted, obtain double
Response glucosan-polyamino acid block copolymer；
Described double responsiveness glucosan-polyamino acid block copolymer has structure shown in formula (I)：
Wherein, 10≤n≤3125；10≤m≤200；
- R is selected from-H、-CH3、-CH(CH3)CH3、-CH2CH(CH3)CH3、-CH(CH3)
CH2CH3、-CH2OH、-CH2SH、 -CH
(OH)CH3、
In the present invention, glucosan, 2-aminoethyl disulfide dihydrochloride and buffer solution are mixed, reacted, obtain formula (II) institute
Show compound.In the present invention, described glucosan has structure shown in formula (III)：
Wherein, n is the degree of polymerization of glucosan, 10≤n≤3125, preferably 20≤n≤2500；The number of described glucosan is equal
Molecular weight is preferably 1000g/mol～500000g/mol, more preferably 2000g/mol～100000g/mol, most preferably
5000g/mol～10000g/mol.The present invention is not particularly limited to the source of described glucosan, using those skilled in the art
Known to commercial goods.
In the present invention, described 2-aminoethyl disulfide dihydrochloride can by glucosan terminal amino group, to realize the polymerization of aminoacid,
Form oxime key and glucosan between during the course of the reaction simultaneously, and in itself structure, carry a disulfide bond, make system of the present invention
The standby double responsiveness glucosan-polyamino acid block copolymer obtaining has pH response and reduction response.The present invention is to institute
The source stating 2-aminoethyl disulfide dihydrochloride is not particularly limited, using commercial goods well known to those skilled in the art.
In the present invention, described buffer solution is preferably acetate buffer solution it is therefore an objective to make reaction stable at one
Carry out under pH environment, it is not specifically limited to this for the present invention；The pH value of described buffer solution is preferably 2～7, more preferably 4
～5.5, most preferably 5.
In the present invention, glucosan, 2-aminoethyl disulfide dihydrochloride and buffer solution are mixed, the process reacted specifically includes
Following steps：
2-aminoethyl disulfide dihydrochloride is added in buffer solution and is dissolved, add glucosan, carry out oximation reaction.
In the present invention, the mol ratio of described glucosan and 2-aminoethyl disulfide dihydrochloride is preferably (0.5～1.5)：1, more preferably
For 1：1.In the present invention, the temperature of described oximation reaction is preferably 20 DEG C～65 DEG C, more preferably 30 DEG C～60 DEG C, most preferably
For 40 DEG C；The time of described oximation reaction is preferably 12h～120h, more preferably 50h～80h, most preferably 52h.
In the present invention, glucosan, 2-aminoethyl disulfide dihydrochloride and buffer solution are mixed, after being reacted, preferably also include
The product that reaction is obtained is dialysed and lyophilizing successively, obtains compound shown in formula (II).In the present invention, described dialysis is adopted
The bag filter being 3500Dalton with molecular cut off well known to those skilled in the art, it is not specifically limited to this for the present invention.
The pH value of described dialysis is preferably 5～8.5, more preferably 7.4；The temperature of described dialysis is preferably 4 DEG C～20 DEG C, more preferably
15℃；The time of described dialysis is preferably 24h～72h, more preferably 48h.
In the present invention, described lyophilizing for technological means well known to those skilled in the art it is therefore an objective to obtain formula (II) institute
Show compound to be reacted further, it is not specifically limited to this for the present invention.
In the present invention, carboxylic acid anhydrides in compound shown in formula (II), aminoacid-N- and organic solvent are mixed, carry out anti-
Should, obtain double responsiveness glucosan-polyamino acid block copolymer.In the present invention, in described aminoacid-N-, carboxylic acid anhydrides are preferred
For carboxylic acid anhydrides, γ -2- chloroethene in carboxylic acid anhydrides in γ-benzyl-L-Glutamic Acid ester-N-, γ-propinyl-L-Glutamic Acid ester-N-
In carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides in base-L-Glutamic Acid ester-N-, glycine-N-, L-Alanine-N-, L-Valine-N-
Carboxylic acid anhydrides, L- color ammonia in carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides, L-Leu-N-, L-Isoleucine-N-, L-phenylalanine-N-
Carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides in acid-N-, L-Serine-N-, L-Tyrosine-N-, ε-benzyloxycarbonyl group-L-Cysteine-
Carboxylic acid anhydrides, L- in carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides in N-, L-Methionine-N-, altheine-N-, L-Glutamine-N-
In carboxylic acid anhydrides in carboxylic acid anhydrides in threonine-N-, γ-benzyl-L-aspartate ester-N-, ε-benzyloxycarbonyl group -1B-N-
Carboxylic acid anhydrides in carboxylic acid anhydrides or histidine-N- in carboxylic acid anhydrides, arginine-N-, in more preferably γ-benzyl-L-Glutamic Acid ester-N-
Carboxylic acid anhydrides in carboxylic acid anhydrides or L-phenylalanine-N- in carboxylic acid anhydrides, ε-benzyloxycarbonyl group -1B-N-.The present invention is to described amino
In acid-N-, the source of carboxylic acid anhydrides is not particularly limited, using commercial goods well known to those skilled in the art.
In the present invention, the effect of described organic solvent is carboxylic acid in compound shown in dissolving formula (II) and aminoacid-N-
Acid anhydride, thus providing media environment for polyreaction, it is not specifically limited to this for the present invention, preferably anhydrous dimethyl base sulfone.
In the present invention, carboxylic acid anhydrides in compound shown in formula (II), aminoacid-N- and organic solvent are mixed, carry out anti-
The process answered specifically includes following steps：
Compound shown in formula (II) is carried out pre-treatment, add carboxylic acid anhydrides and organic solvent in aminoacid-N- carry out molten
Solution, polyreaction, sedimentation, obtain double responsiveness glucosan-polyamino acid block copolymer.
In the present invention, the purpose that compound shown in described (II) by formula carries out pre-treatment is eliminating water, and the present invention does not have to this
There is particular restriction, such as can adopt the technical scheme of toluene azeotropic water removing well known to those skilled in the art.
In the present invention, compound shown in described formula (II) and the mol ratio of carboxylic acid anhydrides in described aminoacid-N- are preferably
1：(10～40), more preferably 1：(20～30).In the present invention, the temperature of described polyreaction is preferably 20 DEG C～65 DEG C,
More preferably 25 DEG C；The time of described polyreaction is preferably 24h～120h, more preferably 72h.
In the present invention, described it is settled into technological means well known to those skilled in the art it is therefore an objective to obtain double responsiveness
Glucosan-polyamino acid block copolymer, it is not specifically limited to this for the present invention.
Present invention also offers a kind of carrier micelle, including：Double responsiveness glucosan described in technique scheme-poly- ammonia
Double responsiveness glucosan-polyamino acid the block copolymerization of the method preparation described in base acid block copolymer or technique scheme
Thing；
It is supported on the antitumor drug on described double responsiveness glucosan-polyamino acid block copolymer；Described antitumor
Medicine is amycin, camptothecine or paclitaxel.
In the present invention, described double responsiveness glucosan-polyamino acid block copolymer is described in technique scheme
The double responsiveness Portugal of the method preparation described in double responsiveness glucosan-polyamino acid block copolymer or technique scheme gathers
Sugar-polyamino acid block copolymer, will not be described here.Described antitumor drug is amycin, camptothecine or paclitaxel, preferably
For amycin.
In the present invention, the preparation method of described carrier micelle is preferably specially：
Described double responsiveness glucosan-polyamino acid block copolymer is dissolved in DMF, obtains
Solution A；Meanwhile, described antitumor drug is dissolved in buffer solution, obtains solution B；Again solution B is slowly dropped to solution
In A, stirring a period of time under the conditions of uniform temperature, dialysis, lyophilizing, obtain carrier micelle.
In the present invention, described buffer solution is preferably disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution it is therefore an objective to make institute
State antitumor drug to be dissolved in the environment of pH stable, it is not specifically limited to this for the present invention；The pH value of described buffer solution
It is preferably 5～8, more preferably 7.4.
In the present invention, the mass ratio of described double responsiveness glucosan-polyamino acid block copolymer and antitumor drug
It is preferably (0.05～0.5)：1, more preferably (0.1～0.4)：1.In the present invention, the temperature of described stirring be preferably 4 DEG C～
20 DEG C, more preferably 15 DEG C；The time of described stirring is preferably 8h～30h, more preferably 24h.
In the present invention, described dialysis is the saturating of 3500Dalton using molecular cut off well known to those skilled in the art
Analysis bag, it is not specifically limited to this for the present invention.The pH value of described dialysis is preferably 5～8.5, more preferably 7.4；Described dialysis
Temperature is preferably 4 DEG C～20 DEG C, more preferably 15 DEG C；The time of described dialysis is preferably 4h～16h, more preferably 12h.
In the present invention, described lyophilizing be technological means well known to those skilled in the art it is therefore an objective to obtain carrier micelle,
It is not specifically limited to this for the present invention.
The invention provides a kind of double responsiveness glucosan-polyamino acid block copolymer, can be from group in water environment
Dress up micelle, for loading hydrophobic anticancer drug.Compared with prior art, the double responsiveness glucosan that the present invention provides-
Hydrophilic chain glucosan is connected with hydrophobic chain polyamino acid by polyamino acid block copolymer by oxime key and disulfide bond, wherein, two
Sulfide linkage is highly stable under the environment such as normal body temperature, pH value and oxidation, and in a certain amount of Glutathione (GSH) reductase
Or it is reduced into sulfydryl in the presence of the reducing agent such as dithiothreitol, DTT (DTT), make double responsiveness glucosan-poly- ammonia that the present invention provides
Base acid block copolymer, while having good pH response, has a good reduction response, prepared load medicine glue
Bundle in tumor tissues or cell, under low ph environment or homoglutathion concentration environment can rapid delivery of pharmaceuticals, thus reaching
To enhancing drug effect and the hypotoxic purpose of fall.
In order to further illustrate the present invention, it is described in detail below by following examples.
Embodiment 1～4
Prepare the acetate buffer solution of pH=5, the buffer respectively measuring 50mL configuration is respectively placed in 4 round-bottomed flasks
In, it is separately added into 0.225g 2-aminoethyl disulfide dihydrochloride in each flask, after stirring and dissolving, then add 5g Portugal to gather in each flask
Sugar, the number-average molecular weight of described glucosan is 5000g/mol, then seals each reaction bulb, according to the reaction temperature bar of table 1
Part, reacts 52h, after reaction terminates, adjusts each reactant liquor pH to 7.4 with sodium bicarbonate solution, then with molecular cut off be
The bag filter dialysis 48h of 3500Dalton, lyophilizing after filtration, respectively obtain compound shown in formula (II).Experimental result is shown in Table 1,
Table 1 is the reaction condition of the embodiment of the present invention 1～4 and the yield of products therefrom.
The reaction condition of table 1 embodiment of the present invention 1～4 and the yield of products therefrom
| Embodiment | Temperature/DEG C | Yield (%) |
| 1 | 30 | 75.4 |
| 2 | 40 | 93.2 |
| 3 | 50 | 88.5 |
| 4 | 60 | 75.3 |
Embodiment 5～8
PH value condition according to table 2 prepares acetate buffer solution respectively, and respectively measures the buffer of 50mL configuration respectively
It is placed in 4 round-bottomed flasks, be separately added into 0.225g 2-aminoethyl disulfide dihydrochloride in each flask, after stirring and dissolving, then to each
5g glucosan is added, the number-average molecular weight of described glucosan is 5000g/mol, then seals each reaction bulb, anti-in flask
Under conditions of answering temperature to be 40 DEG C, react 52h, after reaction terminates, adjust each reactant liquor pH to 7.4 with sodium bicarbonate solution,
Then the bag filter dialysis 48h being 3500Dalton with molecular cut off, lyophilizing after filtration, respectively obtain chemical combination shown in formula (II)
Thing.Experimental result is shown in Table 2, and table 2 is the reaction condition of the embodiment of the present invention 5～8 and the yield of products therefrom.
The reaction condition of table 2 embodiment of the present invention 5～8 and the yield of products therefrom
| Embodiment | PH value | Yield (%) |
| 5 | 4 | 92.5 |
| 6 | 4.5 | 91.9 |
| 7 | 5 | 94.8 |
| 8 | 5.5 | 92.9 |
Embodiment 9～12
Prepare the acetate buffer solution of pH=5, the buffer respectively measuring 50mL configuration is respectively placed in 4 round-bottomed flasks
In, it is separately added into 0.225g 2-aminoethyl disulfide dihydrochloride in each flask, after stirring and dissolving, then add Portugal to gather in each flask
Sugar, the number-average molecular weight of described glucosan is shown in Table 3, then seals each reaction bulb, under conditions of reaction temperature is 40 DEG C, instead
Answer 52h, after reaction terminates, adjust each reactant liquor pH to 7.4 with sodium bicarbonate solution, then with molecular cut off be
The bag filter dialysis 48h of 3500Dalton, lyophilizing after filtration, respectively obtain compound shown in formula (II).Experimental result is shown in Table 3,
Table 3 is the reaction condition of the embodiment of the present invention 9～12 and the yield of products therefrom.
The reaction condition of table 3 embodiment of the present invention 9～12 and the yield of products therefrom
Embodiment 13～16
The each 1g of compound shown in formula (II) that Example 2 prepares respectively, is respectively placed in 4 reaction bulbs, then divides
Not Jia Ru 80mL dry toluene, 125 DEG C of heated and stirred of oil bath, azeotropic 2h, pick out toluene, extract residual toluene out with oil pump, by table 4
The compound shown in formula (II) providing and carboxylic acid anhydrides mol ratio in γ-benzyloxy-L-Glutamic Acid ester-N-, addition γ-benzyloxy-
Carboxylic acid anhydrides in L-Glutamic Acid ester-N-, and add anhydrous dimethyl sulphoxide 50mL to dissolve, stir under the conditions of 25 DEG C in a nitrogen environment
72h, carries out polyreaction.After polyreaction terminates, with ether sedimentation, then with DMF dissolving obtain consolidate
Body, is settled with ether again, the product obtaining is carried out with sucking filtration, and vacuum drying obtains the double responsiveness with formula (IV) structure
Glucosan-b- poly- (γ-benzyloxy-L-Glutamic Acid ester)；
Compound shown in formula (II) and carboxylic in γ-benzyloxy-L-Glutamic Acid ester-N- in table 4 embodiment of the present invention 13～16
Anhydride molar ratio
| Embodiment | Compound shown in formula (II) and carboxylic acid anhydrides mol ratio in γ-benzyloxy-L-Glutamic Acid ester-N- |
| 13 | 1：10 |
| 14 | 1：20 |
| 15 | 1：30 |
| 16 | 1：40 |
Embodiment 17
The double-bang firecracker that Example 14 prepares answers glucosan-b- poly- (γ-benzyloxy-L-Glutamic Acid ester) 0.1g to be added to
In 20mL DMF, dissolving is stirred at room temperature, obtains solution A；Meanwhile, 1g amycin is dissolved in 10mL
In the disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution of pH=7.4, obtain solution B；Again solution B is slowly dropped to solution A
In, stir 24h under the conditions of 15 DEG C；The bag filter dialysis 12h being finally 3500Dalton with molecular cut off, lyophilizing, obtain
Carrier micelle.
Embodiment 18
(1) each 1g of compound shown in formula (II) that Example 2 prepares, is placed in reaction bulb, adds 80mL no
Water-toluene, 125 DEG C of heated and stirred of oil bath, azeotropic 2h, pick out toluene, extract residual toluene out with oil pump, chemical combination as shown in formula (II)
Thing and carboxylic acid anhydrides mol ratio 1 in ε-benzyloxycarbonyl group -1B-N-：20, add carboxylic acid in ε-benzyloxycarbonyl group -1B-N-
Acid anhydride, and add anhydrous dimethyl sulphoxide 50mL to dissolve, stir 72h under the conditions of 25 DEG C in a nitrogen environment, carry out polyreaction.Poly-
After conjunction reaction terminates, settled with ether, then the solid being obtained with DMF dissolving, settled with ether again, right
The product obtaining carries out sucking filtration, vacuum drying, obtains the poly- (ε-benzyloxy carbonyl of double responsiveness glucosan-b- with formula (V) structure
Base -1B)；
(2) above-mentioned double responsiveness glucosan-b- poly- (ε-benzyloxycarbonyl group -1B) 0.1g is taken to be added to 20mLN, N- bis-
In methylformamide, dissolving is stirred at room temperature, obtains solution A；Meanwhile, 1g amycin is dissolved in the phosphorus of 10mL pH=7.4
In sour disodium hydrogen-potassium dihydrogen phosphate buffer solution, obtain solution B；Again solution B is slowly dropped in solution A, in 15 DEG C of conditions
Lower stirring 24h；The bag filter dialysis 12h being finally 3500Dalton with molecular cut off, lyophilizing, obtain carrier micelle.
Embodiment 19
(1) each 1g of compound shown in formula (II) that Example 2 prepares, is placed in reaction bulb, adds 80mL no
Water-toluene, 125 DEG C of heated and stirred of oil bath, azeotropic 2h, pick out toluene, extract residual toluene out with oil pump, chemical combination as shown in formula (II)
Thing and carboxylic acid anhydrides mol ratio 1 in L-phenylalanine-N-：20, add carboxylic acid anhydrides in L-phenylalanine-N-, and add anhydrous dimethyl
Base sulfoxide 50mL dissolves, and stirs 72h under the conditions of 25 DEG C in a nitrogen environment, carries out polyreaction.After polyreaction terminates, use second
Ether settles, then the solid being obtained with DMF dissolving, is settled with ether again, the product obtaining is taken out
Filter, vacuum drying, obtain the double responsiveness glucosan-b- poly- (L-phenylalanine) with formula (VI) structure；
(2) above-mentioned double responsiveness glucosan-b- poly- (L-phenylalanine) 0.1g is taken to be added to 20mL N, N- dimethyl formyl
In amine, dissolving is stirred at room temperature, obtains solution A；Meanwhile, 1g amycin is dissolved in the phosphoric acid hydrogen two of 10mL pH=7.4
In sodium-potassium dihydrogen phosphate buffer solution, obtain solution B；Again solution B is slowly dropped in solution A, stirs under the conditions of 15 DEG C
24h；The bag filter dialysis 12h being finally 3500Dalton with molecular cut off, lyophilizing, obtain carrier micelle.
Double responsiveness glucosan-the b- poly- (γ-benzyloxy-L-Glutamic Acid ester) that the embodiment of the present invention 14 is provided carries out red
Outer absorption detecting and magnetic resonance detection, testing result is shown in Fig. 1 and Fig. 2；Wherein, Fig. 1 for the embodiment of the present invention 14 provide double
The infrared absorption pattern of response glucosan-b- poly- (γ-benzyloxy-L-Glutamic Acid ester)；Fig. 2 provides for the embodiment of the present invention 14
Double responsiveness glucosan-b- poly- (γ-benzyloxy-L-Glutamic Acid ester) hydrogen nuclear magnetic resonance spectrogram.From Fig. 1 and Fig. 2, this
Invention has prepared double responsiveness glucosan-b- poly- (γ-benzyloxy-L-Glutamic Acid ester).
To the embodiment of the present invention 17 provide carrier micelle divide carry out pH value response and reduction response release in vitro examination
Test, result of the test is shown in Fig. 3 and Fig. 4；Wherein, the carrier micelle that Fig. 3 provides for the embodiment of the present invention 17 carries out pH value response gonosome
The releasing result figure of outer release test；The carrier micelle that Fig. 4 provides for the embodiment of the present invention 17 carries out reduction response to be released in vitro
Put the releasing result figure of test.From Fig. 3 and Fig. 4, the carrier micelle that the present invention provides is in low ph environment or high gluathione
Under peptide concentration environment can rapid delivery of pharmaceuticals, thus reach enhancing drug effect and drop hypotoxic purpose.
The described above of the disclosed embodiments, makes professional and technical personnel in the field be capable of or uses the present invention.Right
Multiple modifications of these embodiments will be apparent from for those skilled in the art, and as defined herein one
As principle can realize in other embodiments without departing from the spirit or scope of the present invention.Therefore, the present invention will
Will not be intended to be limited to the embodiments shown herein, and be to fit to consistent with principles disclosed herein and features of novelty
Scope the widest.
Claims (10)
1. a kind of double responsiveness glucosan-polyamino acid block copolymer, has structure shown in formula (I)：
Wherein, 10≤n≤3125；10≤m≤200；
- R is selected from-H、-CH3、-CH(CH3)CH3、-CH2CH(CH3)CH3、-CH(CH3)
CH2CH3、-CH2OH、-CH2SH、-CH(OH)
CH3、
2. one kind has the preparation method of the double responsiveness glucosan-polyamino acid block copolymer of formula (I) structure, including following
Step：
A1) glucosan, 2-aminoethyl disulfide dihydrochloride and buffer solution are mixed, reacted, obtain compound shown in formula (II)；
B1) carboxylic acid anhydrides in compound shown in formula (II), aminoacid-N- and organic solvent are mixed, reacted, obtaining double-bang firecracker should
Property glucosan-polyamino acid block copolymer；
Described double responsiveness glucosan-polyamino acid block copolymer has structure shown in formula (I)：
Wherein, 10≤n≤3125；10≤m≤200；
- R is selected from-H、-CH3、-CH(CH3)CH3、-CH2CH(CH3)CH3、-CH(CH3)
CH2CH3、-CH2OH、-CH2SH、-CH(OH)
CH3、
3. preparation method according to claim 2 it is characterised in that in described aminoacid-N- carboxylic acid anhydrides be γ-benzene first
Carboxylic acid anhydrides, γ -2- chloroethyl-L-Glutamic Acid in carboxylic acid anhydrides in base-L-Glutamic Acid ester-N-, γ-propinyl-L-Glutamic Acid ester-N-
In carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides in ester-N-, glycine-N-, L-Alanine-N-, L-Valine-N-, carboxylic acid anhydrides, L- are bright
Carboxylic acid in carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides in propylhomoserin-N-, L-Isoleucine-N-, L-phenylalanine-N-, L-Tryptophan-N-
Carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides in acid anhydride, L-Serine-N-, L-Tyrosine-N-, ε-benzyloxycarbonyl group-L-Cysteine-N-,
In carboxylic acid anhydrides in carboxylic acid anhydrides in carboxylic acid anhydrides in L-Methionine-N-, altheine-N-, L-Glutamine-N-, L-Threonine-N-
Carboxylic acid anhydrides, smart ammonia in carboxylic acid anhydrides in carboxylic acid anhydrides, γ-benzyl-L-aspartate ester-N-, ε-benzyloxycarbonyl group -1B-N-
Carboxylic acid anhydrides in carboxylic acid anhydrides or histidine-N- in acid-N-.
4. preparation method according to claim 2 is it is characterised in that the number-average molecular weight of described glucosan is 1000g/
Mol～500000g/mol.
5. preparation method according to claim 2 is it is characterised in that the mol ratio of described glucosan and 2-aminoethyl disulfide dihydrochloride
For (0.5～1.5)：1.
6. preparation method according to claim 2 is it is characterised in that described buffer solution is acetate buffer solution；Institute
The pH value stating buffer solution is 2～7.
7. preparation method according to claim 2 is it is characterised in that step A1) described in reaction temperature be 20 DEG C～
65 DEG C, the time is 12h～120h.
8. preparation method according to claim 2 is it is characterised in that step B1) described in compound shown in formula (II) with
In described aminoacid-N-, the mol ratio of carboxylic acid anhydrides is 1：(10～40).
9. preparation method according to claim 2 is it is characterised in that step B1) described in reaction temperature be 20 DEG C～
65 DEG C, the time is 24h～120h.
10. a kind of carrier micelle, including：Double responsiveness glucosan-polyamino acid block copolymer described in claim 1 or power
Profit requires double responsiveness glucosan-polyamino acid block copolymer prepared by the method described in 2～9 any one；
It is supported on the antitumor drug on described double responsiveness glucosan-polyamino acid block copolymer；Described antitumor drug
For amycin, camptothecine or paclitaxel.
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| CN106008964B (en) * | 2016-05-20 | 2018-07-03 | 中国科学院长春应用化学研究所 | A kind of water-soluble amino acid block copolymer and its preparation method and application |
| CN106496571B (en) * | 2016-10-17 | 2019-10-11 | 江苏师范大学 | Restore responsiveness Amphipathilic block polymer and nano-micelle and application |
| CN110950970B (en) * | 2019-12-12 | 2022-03-15 | 江南大学 | Environment-responsive glucosyl nanoparticles and processing method thereof |
| CN111821512B (en) * | 2020-06-19 | 2022-06-14 | 上海大学 | Enzyme-response drug release poly-L-glutamic acid/chitosan porous composite microcarrier, and preparation method and application thereof |
| CN112618728B (en) * | 2020-12-18 | 2022-07-29 | 绍兴文理学院 | Dual-response prodrug containing polysialic acid group, synthetic method thereof and application thereof in pharmaceutical preparation |
| CN113456611A (en) * | 2021-06-11 | 2021-10-01 | 淮阴工学院 | Double-response rapid controlled release nano-carrier and preparation method of nano-drug formed by nano-carrier |
| CN113603806B (en) * | 2021-07-16 | 2022-09-02 | 武汉纳乐吉生命科技有限公司 | Cysteamine derivative based on dextran modification, preparation and application thereof |
| CN115721628B (en) * | 2021-09-01 | 2024-02-06 | 中国科学院上海硅酸盐研究所 | PH/GGT enzyme double-response modified glucan self-assembly body |
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