CN107951839A - One kind has turnover Polyionic micella shading system of electric charge and preparation method thereof - Google Patents
One kind has turnover Polyionic micella shading system of electric charge and preparation method thereof Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
- C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
- C08G69/10—Alpha-amino-carboxylic acids
Abstract
The present invention provides one kind to have the turnover Polyionic micella shading system of electric charge, and the compound of structure is formed with platinum co-ordination as shown in formula (III).It is provided by the invention that there is the turnover Polyionic micella shading system of electric charge to support cis-platinum by coordination, not only carrier material good biocompatibility, the good nano-carrier of dissolubility is detained (EPR) effect in the enrichment of tumor tissues position by strengthening to permeate, under the pH value condition of tumor tissues position, shell with screening capacity is sloughed, expose the load cis-platinum kernel of positively charged, electropositive kernel contributes to cell endocytic, after load cis-platinum kernel enters cell, carry cis-platinum kernel and discharge the drugs Cisplatin with antitumor activity energy.
Description
Technical field
The invention belongs to polymer drug carrier technique field, and in particular to one kind has the turnover Polyionic of electric charge
Micella shading system and preparation method thereof.
Background technology
Tumour has become one of most serious disease for threatening human health.Clinically common anti-cancer therapies include
Chemotherapy, radiotherapy and operative treatment etc..Wherein, chemotherapy is most common of which and important therapy approach.But face
Antitumor drug used has the defects of many in the application on bed, such as：Water-soluble and stability is poor, and poisonous side effect of medicine is big.
In order to solve the problems, such as these, medicine can be combined with pharmaceutical carrier, to improve the water solubility of medicine and stability, and reached to medicine
The control release of thing, so that the effect of reducing the toxic side effect of medicine normal tissue, giving full play to medicine.
Cis-platinum (cis-dichlorodiamine closes platinum, cis-diamminedichloroplatinum, abbreviation CDDP) is at present should
With an extensive series antineoplastic medicament, it is found first by B.Rosenborg et al. in nineteen sixty-five.Cis-platinum have anticancer spectrum it is wide,
Effect is strong, has synergistic effect with a variety of antineoplastics and the features such as without crossing drug resistant, therefore cis-platinum is also most normal in combined chemotherapy
One of medicine.But to equally exist toxic side effect big for cis-platinum, in blood the problems such as half-life short, especially kidney poison
Property, be cis-platinum dose limiting toxicity, constrain significantly its utilization validity.For this problem, Tokyo Univ Japan
The Chen Xuesi seminar of Kataoka seminar and Changchun Institute of Applied Chemistry of the Chinese Academy of Sciences has carried out network using polyglutamic acid macromolecule to cis-platinum
Conjunction supports, and prepared macromolecule-cisplatin nano-micelle significantly reduces the toxicity of cis-platinum, and can realize in tumor locus
It is passive to build up (N.Nishiyama, et al.Cancer Research, 63 (2003) 9877-8983；Chinese patent
201210382696.X)。
Although the analog of various cis-platinums is developed to reduce toxic side effect and improve therapeutic effect, it is still
There are the problems such as the blood halflife common to small molecule platinum medicine is short, nonspecific action is obvious, and bring hemopoietic system,
The toxicity of digestive system and nervous system.As it was previously stated, macromolecule-complexing supports platinum medicine and has been proved in platinum medicine
Internal transmission in terms of there are great potential, representational NC-6004 (polyethylene glycol glutamic acid-cisplatinum complexes) is also
Tested through entering the clinical second phase.Therefore, a kind of polymer-bound platinum medicine with screen effect is prepared, can be effective
Protect medicine into the non-specific interaction after blood, extend blood circulatory half-life, and tumor locus institute can be utilized
Distinctive enhancing infiltration and retention effect (EPR effects) realize that the passive target in tumor locus is built up, therefore it is non-to play reduction
The toxic side effect of lesions position and the effect that improves tumor locus therapeutic coefficient have broad application prospects.
The content of the invention
In view of this, the technical problem to be solved in the present invention is that providing one kind has the turnover Polyionic glue of electric charge
Beam shading system and preparation method thereof, it is provided by the invention to have the turnover Polyionic micella shading system of electric charge profit
Enhancing infiltration and retention effect (EPR effects) specific to tumor locus realize that the passive target in tumor locus is built up, from
And reduce the toxic side effect of non-lesions position and improve tumor locus therapeutic coefficient.
The present invention provides one kind to have the turnover Polyionic micella shading system of electric charge, by with formula (III) institute
The compound and platinum co-ordination for showing structure form：
Wherein, 5≤x≤50,5≤y≤50,1≤a≤y, 5≤m≤20,40≤n≤120.
Present invention also offers a kind of preparation method with the turnover Polyionic micella shading system of electric charge, by having
The nanometer shell with screening capacity for having formula (I) structure is prepared with the macromolecule kernel for carrying cis-platinum；The load cis-platinum
Macromolecule kernel is made as cis-platinum with the reaction of the compound with structure shown in Formula II；
In formula (I), branched alkyls of the R selected from hydrogen, the straight chained alkyl of C1~C5 or C3~C5,5≤m≤20,40≤n≤
120；
In formula (II), 5≤x≤50,5≤y≤50.
Preferably, comprise the following steps：
The nanometer shell with screening capacity with formula (I) structure is dissolved in DMF with the macromolecule kernel for carrying cis-platinum
In, triethylamine is added, stirring, is reacted, obtained with the turnover Polyionic micella shading system of electric charge.
Preferably, the preparation method of the nanometer shell with screening capacity comprises the following steps：
A) carboxylic acid anhydrides in polyethylene glycol, benzyloxycarbonyl group lysine-N- rings and the first organic solvent are mixed, reaction, obtains
First reaction solution；
B) the first reaction solution and the second organic solvent are mixed, filtering, obtains the first solid；
C the first solid) is sloughed into benzyloxycarbonyl group, obtains the second solid；
D the second solid) is dissolved in the 3rd organic solvent, adds 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide salt
Hydrochlorate, 4-dimethylaminopyridine and methyl aconitic acid anhydride, reaction, obtain the 3rd reaction solution；
E) the 3rd reaction solution and the second organic solvent are mixed, obtain a nanometer shell.
Preferably, step A) in, the temperature of the reaction is 15 DEG C~50 DEG C, and the time of the reaction is 2~7 days；Step
Rapid D) in, the temperature of the reaction is 15 DEG C~50 DEG C, and the time of the reaction is 2~7 days.
Preferably, one kind in n,N-Dimethylformamide, dioxane and chloroform of first organic solvent or
It is a variety of；
Second organic solvent is ether；
3rd organic solvent is N,N-dimethylformamide or the mixed solution of dimethyl sulfoxide (DMSO) and dichloromethane.
Preferably, the preparation method of the macromolecule kernel for carrying cis-platinum comprises the following steps：
A) by carboxylic acid anhydrides and in carboxylic acid anhydrides in n-hexylamine, benzyloxycarbonyl group lysine-N- rings, γ benzyl glutamate-N- rings
One organic dissolution mixes, and reaction, obtains the 4th reaction solution；
B) the 4th reaction solution and the second organic solvent are mixed, filtering, obtains the 3rd solid；
C) the 3rd solid is sloughed into benzyloxycarbonyl group, obtains the 4th solid；
D) it is the 4th solid is soluble in water, add and closed with the corresponding cis-diamines dichloro of carboxyl-content in the 4th solid
Platinum, adjusts pH, reaction, obtains the 5th reaction solution；
E) the 5th reaction solution is freezed, cis-platinum macromolecule kernel must be carried.
Preferably, in step a), the temperature of the reaction is 15 DEG C~50 DEG C, and the time of the reaction is 2~7 days.
Preferably, in step d, the molar ratio that the carboxyl closes platinum with cis-diamines dichloro is 1~10：1.
Compared with prior art, the present invention provides one kind to have the turnover Polyionic micella shading system of electric charge,
The compound of structure is formed with platinum co-ordination as shown in formula (III).It is provided by the invention have electric charge it is turnover gather from
Subtype micella shading system supports cis-platinum by coordination, not only carrier material good biocompatibility, the good nanometer of dissolubility
Carrier is enriched with by strengthening infiltration delay (EPR) effect at tumor tissues position, under the pH value condition of tumor tissues position, is had
The shell of screening capacity is sloughed, and exposes the load cis-platinum kernel of positively charged, and electropositive kernel contributes to cell endocytic, when load cis-platinum
After kernel enters cell, carry cis-platinum kernel and discharge the drugs Cisplatin with antitumor activity energy.
Brief description of the drawings
Fig. 1 is N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydride nuclear magnetic spectrums prepared by embodiment 1；
Fig. 2 is the nuclear magnetic spectrum of γ-benzyl glutamate-N- ring inner-acid anhydrides prepared by embodiment 2；
Fig. 3 is the nuclear magnetic spectrum of nano-particle prepared by embodiment 10；
Fig. 4 is the nuclear magnetic spectrum of poly- (L-lysine-common poly-gamma-glutamic acid) prepared by embodiment 14；
Fig. 5 is that poly- (L-lysine-common poly-gamma-glutamic acid) that different ratios of raw materials obtains under condition of different pH connects dichloro
Diamines closes the potential of alloy platinum material；
Fig. 6 is that poly- (L-lysine-common poly-gamma-glutamic acid) that different ratios of raw materials obtains under condition of different pH connects dichloro
Diamines closes the potential of alloy platinum material；
Fig. 7 is that poly- (L-lysine-common poly-gamma-glutamic acid) that different ratios of raw materials obtains under condition of different pH connects dichloro
Diamines closes the potential of alloy platinum material；
Fig. 8 is the nuclear magnetic spectrum for the nanometer shell that embodiment 35 is prepared；
Fig. 9 is release profiles of the Polyionic micella shading system of the invention prepared in pH=7.4 and pH=5.5
Figure.
Embodiment
The present invention provides one kind to have the turnover Polyionic micella shading system of electric charge, it is characterised in that by having
The compound for having structure shown in formula (III) is formed with platinum co-ordination：
Wherein, 5≤x≤50,5≤y≤50,1≤a≤y, 5≤m≤20,40≤n≤120.
Preferably, 10≤x≤30,10≤y≤30, | x-y |≤5,1≤a≤y/2, more preferably 1≤a≤y/3.
Preferably, 10≤m≤15；80≤n≤120；It is furthermore preferred that 12≤m≤15；100≤n≤120；Most preferably, m
=14；N=117.
Present invention also offers a kind of preparation method with the turnover Polyionic micella shading system of electric charge, by having
The nanometer shell with screening capacity for having formula (I) structure is prepared with the macromolecule kernel for carrying cis-platinum；The load cis-platinum
Macromolecule kernel is made as cis-platinum with the reaction of the compound with structure shown in Formula II.
Specifically, will with the nanometer shell of formula (I) structure with screening capacity and carry cis-platinum macromolecule kernel it is molten
Solution adds triethylamine, stirring, is reacted, obtained with the turnover Polyionic micella shading system of electric charge in DMF.
In the present invention, the nanometer shell preparation method with screening capacity with formula (I) structure includes following
Step：
A) carboxylic acid anhydrides in polyethylene glycol, benzyloxycarbonyl group lysine-N- rings and the first organic solvent are mixed, reaction, obtains
First reaction solution；
B) the first reaction solution and the second organic solvent are mixed, filtering, obtains the first solid；
C the first solid) is sloughed into benzyloxycarbonyl group, obtains the second solid；
D the second solid) is dissolved in the second organic solvent, adds 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide salt
Hydrochlorate, 4-dimethylaminopyridine and methyl aconitic acid anhydride, reaction, obtain the 3rd reaction solution；
E) the 3rd reaction solution and the 3rd organic solvent are mixed, obtain a nanometer shell.
Wherein, the present invention first mixes carboxylic acid anhydrides in polyethylene glycol, benzyloxycarbonyl group lysine-N- rings and the first organic solvent
Close, reaction, obtains the first reaction solution.
Wherein, the preparation method of N (the ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides preferably includes following steps：
N (ε)-benzyloxycarbonyl group-L-lysine and double (trichloromethyl) carbonic esters are subjected to condensation reaction, obtain N (ε)-benzyl
Oxygen carbonyl-L-lysine-N- ring inner-acid anhydrides.
The present invention mixes N (ε)-benzyloxycarbonyl group-L-lysine with double (trichloromethyl) carbonic esters；N (the ε)-benzyloxy
Preferably 10 DEG C~40 DEG C of the temperature that carbonyl-L-lysine is mixed with double (trichloromethyl) carbonic esters, more preferably 15 DEG C~35 DEG C,
Most preferably 20 DEG C~30 DEG C.In the present invention, N (ε)-benzyloxycarbonyl group-L-lysine and double (trichloromethyl) carbonic esters
Molar ratio be preferably 1:(0.1~1.2), more preferably 1:(0.3~1), is most preferably 1:(0.5~0.8).It is of the invention preferred
The condensation reaction of N (ε)-benzyloxycarbonyl group-L-lysine and double (trichloromethyl) carbonic esters is carried out in anhydrous conditions.The present invention is excellent
The N (ε)-benzyloxycarbonyl group-L-lysine is first dissolved in choosing in organic solvent；The organic solvent is preferably tetrahydrofuran；Institute
It is preferably (8~12) mL to state the volume of organic solvent and the mass ratio of N (ε)-benzyloxycarbonyl group-L-lysine:1g, more preferably
10mL:1g.In the present invention, the condensation reaction temperature of N (ε)-benzyloxycarbonyl group-L-lysine and double (trichloromethyl) carbonic esters
Degree is preferably 30 DEG C~80 DEG C, more preferably 35 DEG C~70 DEG C, is most preferably 40 DEG C~60 DEG C, N (ε)-benzyloxycarbonyl group-L-
When the condensation reaction time of lysine and double (trichloromethyl) carbonic esters is preferably 0.1 small~5 it is small when, more preferably 0.15 it is small when
~3 it is small when, be most preferably 0.2 it is small when~2 it is small when.
After the condensation reaction of N (ε)-benzyloxycarbonyl group-L-lysine and double (trichloromethyl) carbonic esters, the present invention
It is preferred that obtained reaction product is settled with petroleum ether, obtained sediment is separated, then wash obtained separation product,
Recrystallization, drying, obtain N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides.The present invention to washing, recrystallizing, it is dry
Method does not have special limitation, using washing well known to those skilled in the art, recrystallization, dry technical solution.
After obtaining N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides, polyethylene glycol, N (ε)-benzyloxycarbonyl group-L- are relied
Propylhomoserin-N- rings inner-acid anhydride and the mixing of the first organic solvent, reaction, obtains the first reaction solution.
In the present invention, the molar ratio of the polyethylene glycol and N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides is excellent
Elect 1 as：(10~15), more preferably 1：(12~15), are most preferably 1：14.
The present invention preferably carries out polyethylene glycol and N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides in a nitrogen atmosphere
Reaction.The present invention preferably carries out acid in polyethylene glycol and N (ε)-benzyloxycarbonyl group-L-lysine-N- rings under conditions of stirring
The reaction of acid anhydride.In the present invention, the temperature that polyethylene glycol and N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides are reacted
Preferably 15 DEG C~50 DEG C, more preferably 20 DEG C~40 DEG C, most preferably 25 DEG C~35 DEG C；Polyethylene glycol and N (ε)-benzyloxycarbonyl group-
The time that L-lysine-N- ring inner-acid anhydrides are reacted is elected as 2 days~7 days, more preferably 3 days~5 days, is most preferably 4 days.Institute
State one or more of first organic solvent in N,N-dimethylformamide, dioxane and chloroform.
After obtaining the first reaction solution, the present invention preferably mixes the first reaction solution and the second organic solvent, and filtering, obtains
To the first solid.In the present invention, second organic solvent is preferably ether.
The product being obtained by filtration preferably is dried in vacuo by the present invention, obtains the first solid.In the present invention, the mistake
The temperature for filtering obtained product vacuum drying is preferably 20 DEG C~40 DEG C, more preferably 25 DEG C~35 DEG C；It is described to be obtained by filtration
The time of product vacuum drying is preferably 12h~24h, more preferably 18h~24h.
After obtaining the first solid, first solid is sloughed benzyloxycarbonyl group and obtains the second solid by the present invention.The present invention is excellent
Solid is dissolved in the 4th organic solvent by choosing sloughs benzyloxycarbonyl group again；4th organic solvent is preferably trifluoroacetic acid or two
Monoxone, more preferably trifluoroacetic acid；The volume of 4th organic solvent and the mass ratio of solid are preferably (8~12) mL:
1g, more preferably 10mL:1g.In the present invention, the solid is sloughed benzyloxycarbonyl group and is preferably carried out in acid condition；The acid
Property condition preferably by hydrogen bromide acetic acid solution provide；The volume ratio of hydrogen bromide and acetic acid is excellent in the acetic acid solution of the hydrogen bromide
Elect 0.5 as:1~5:1, more preferably 2:1.
The present invention carries out solid preferably under conditions of stirring and sloughs benzyloxycarbonyl group.In the present invention, the solid is sloughed
The temperature of benzyloxycarbonyl group is preferably 20 DEG C~50 DEG C, more preferably 30 DEG C~35 DEG C；The solid sloughs the time of benzyloxycarbonyl group
Preferably 0.5h~4h, more preferably 1h~2h, are most preferably 1h.
After completion solid sloughs the reaction of benzyloxycarbonyl group, the present invention is preferably placed reaction liquid into ether and filtered, will
Obtained solid matter with deionized water dissolving is filtered, is then dialysed, is freezed, obtain the second solid nanoparticles kernel.This hair
It is bright preferably to use molecular cut off to go to dialyse for 3500 bag filter；The time of the dialysis is 4 days, changes per 4h and once dialyses
Liquid.The present invention does not have special limitation to lyophilized method, using freeze drying technology scheme well known to those skilled in the art；
The lyophilized temperature is preferably -20 DEG C, and the lyophilized time is preferably 72h.
After obtaining the second solid, the second solid is dissolved in the 3rd organic solvent, adds 1- (3- dimethylamino-propyls) -3- second
Base carbodiimide hydrochloride, 4-dimethylaminopyridine and methyl aconitic acid anhydride, reaction, obtain the 3rd reaction solution.Institute of the present invention
It is preferably the one or more in n,N-Dimethylformamide, dioxane and chloroform to state the 3rd organic solvent, more preferably N,
Dinethylformamide and chloroform；The ratio of N,N-dimethylformamide and chloroform is preferably 1 in 3rd organic solvent:
(0.5~1.2), more preferably 1:1；The cumulative volume of 3rd organic solvent and the mass ratio of solid are preferably (8~12) mL:
1g, more preferably 10mL:1g.The temperature of the reaction is preferably 15 DEG C~50 DEG C, more preferably 20 DEG C~40 DEG C, most preferably 25
DEG C~35 DEG C；The time of the reaction is elected as 2 days~7 days, more preferably 3 days~5 days, is most preferably 4 days.
After completing reaction, the 3rd reaction solution is preferably placed in ether by the present invention to be filtered, the solid that suction filtration is obtained
Product is dried in vacuo, and obtains a nanometer shell.In the present invention, the temperature of the product vacuum drying being obtained by filtration is preferred
For 20 DEG C~40 DEG C, more preferably 25 DEG C~35 DEG C；It is described be obtained by filtration product vacuum drying time be preferably 12h~
24h, more preferably 18h~24h.
In formula (I), R is selected from the branched alkyl of hydrogen, the straight chained alkyl of C1~C5 or C3~C5, is preferably hydrogen, C1~C2
Straight chained alkyl；The most preferably straight chained alkyl of C1.5≤m≤20,40≤n≤120；Preferably, 10≤m≤15；80≤n≤
120；It is furthermore preferred that 12≤m≤15；100≤n≤120；Most preferably, m=14；N=117.
In the present invention, the macromolecule kernel for carrying cis-platinum is reacted as cis-platinum with the compound with structure shown in Formula II
It is made, its preparation method comprises the following steps：
A) by carboxylic acid anhydrides and in carboxylic acid anhydrides in n-hexylamine, benzyloxycarbonyl group lysine-N- rings, γ benzyl glutamate-N- rings
One organic dissolution mixes, and reaction, obtains the 4th reaction solution；
B) the 4th reaction solution and the second organic solvent are mixed, filtering, obtains the 3rd solid；
C) the 3rd solid is sloughed into benzyloxycarbonyl group, obtains the 4th solid；
D) it is the 4th solid is soluble in water, add and closed with the corresponding cis-diamines dichloro of carboxyl-content in the 4th solid
Platinum, adjusts pH, reaction, obtains the 5th reaction solution；
E) the 5th reaction solution is freezed, cis-platinum macromolecule kernel must be carried.
The present invention is first by carboxylic in carboxylic acid anhydrides in n-hexylamine, benzyloxycarbonyl group lysine-N- rings, γ benzyl glutamate-N- rings
Acid anhydrides and the mixing of the first organic dissolution, reaction, obtains the 4th reaction solution.
Wherein, N (the ε)-benzyloxycarbonyl group-L-lysine-N- rings inner-acid anhydride and N (ε)-benzyl described in above-mentioned technical proposal
The source of oxygen carbonyl-L-lysine-N- ring inner-acid anhydrides is identical with preparation method, and details are not described herein.
The preparation method of the γ-benzyl glutamate-N- ring inner-acid anhydrides preferably includes following steps：
γ-benzyl glutamate and double (trichloromethyl) carbonic esters are subjected to condensation reaction, obtain γ-benzyl glutamate-N-
Ring inner-acid anhydride.
The present invention mixes γ-benzyl glutamate with double (trichloromethyl) carbonic esters；γ-the benzyl glutamate with it is double
Preferably 10 DEG C~40 DEG C of the temperature of (trichloromethyl) carbonic ester mixing, more preferably 15 DEG C~35 DEG C, are most preferably 20 DEG C~30
℃.In the present invention, the molar ratio of the γ-benzyl glutamate and double (trichloromethyl) carbonic esters is preferably 1:(0.1~
1.2), it is more preferably 1:(0.3~1), is most preferably 1:(0.5~0.8).The present invention preferably carries out γ-benzyl in anhydrous conditions
The condensation reaction of base glutamic acid and double (trichloromethyl) carbonic esters.The present invention preferably first dissolves the γ-benzyl in organic solvent
Base glutamic acid；The organic solvent is preferably tetrahydrofuran；The volume of the organic solvent and the mass ratio of γ-benzyl glutamate
Preferably (8~12) mL:1g, more preferably 10mL:1g.In the present invention, the γ-benzyl glutamate and double (trichloromethyls)
The setting-up point of carbonic ester is preferably 30 DEG C~80 DEG C, more preferably 35 DEG C~70 DEG C, is most preferably 40 DEG C~60 DEG C, institute
State γ-benzyl glutamate and the condensation reaction time of double (trichloromethyl) carbonic esters when being preferably 0.1 small~5 it is small when, more preferably
For 0.15 it is small when~3 it is small when, be most preferably 0.2 it is small when~2 it is small when.
After the condensation reaction of the γ-benzyl glutamate and double (trichloromethyl) carbonic esters, the present invention preferably incites somebody to action
To reaction product settled with petroleum ether, by obtained sediment separate, then by obtained separation product washing, recrystallization,
It is dry, obtain γ-benzyl glutamate-N- ring inner-acid anhydrides.The present invention does not have special limit to the method washed, recrystallize, dried
System, using washing well known to those skilled in the art, recrystallization, dry technical solution.
In the present invention, the n-hexylamine, N (ε)-benzyloxycarbonyl group-L-lysine-N- rings inner-acid anhydride and γ-benzyl paddy ammonia
The molar ratio of acid-N- ring inner-acid anhydrides is preferably 1：(5~50)：(5~50), more preferably 1：(10~30)：(10~30), it is optimal
Elect 1 as：25：25.
The present invention preferably carries out n-hexylamine, N (ε)-benzyloxycarbonyl group-L-lysine-N- rings and γ-benzyl in a nitrogen atmosphere
The reaction of glutamic acid-N- ring inner-acid anhydride inner-acid anhydrides.The present invention carries out n-hexylamine, N (ε)-benzyloxy carbonyl preferably under conditions of stirring
The reaction of base-L-lysine-N- rings inner-acid anhydride and γ-benzyl glutamate-N- ring inner-acid anhydrides.In the present invention, n-hexylamine, N
(ε)-benzyloxycarbonyl group-L-lysine-N- rings inner-acid anhydride and the temperature that γ-benzyl glutamate-N- ring inner-acid anhydrides are reacted are preferred
For 15 DEG C~50 DEG C, more preferably 20 DEG C~40 DEG C, most preferably 25 DEG C~35 DEG C；The time of the reaction is elected as 2 days~7 days,
More preferably 3 days~5 days, be most preferably 4 days.
The present invention preferably mixes the first reaction solution and the second organic solvent after obtaining the first reaction solution, and filtering, obtains
To the 3rd solid.In the present invention, second organic solvent is preferably ether.
The product being obtained by filtration preferably is dried in vacuo by the present invention, obtains the 3rd solid.In the present invention, the mistake
The temperature for filtering obtained product vacuum drying is preferably 20 DEG C~40 DEG C, more preferably 25 DEG C~35 DEG C；It is described to be obtained by filtration
The time of product vacuum drying is preferably 12h~24h, more preferably 18h~24h.
After obtaining the 3rd solid, the 3rd solid is sloughed benzyloxycarbonyl group and obtains the 4th solid by the present invention.The present invention is excellent
4th solid is dissolved in the 4th organic solvent by choosing sloughs benzyloxycarbonyl group again；4th organic solvent is preferably trifluoroacetic acid
Or dichloroacetic acid, it is more preferably trifluoroacetic acid；The volume of 4th organic solvent and the volume mass ratio of the 3rd solid are preferred
For (8~12) mL:1g, more preferably 10mL:1g.In the present invention, the 3rd solid sloughs benzyloxycarbonyl group preferably in acidity
Under the conditions of carry out；The acid condition is preferably provided by the acetic acid solution of hydrogen bromide；Bromination in the acetic acid solution of the hydrogen bromide
The volume ratio of hydrogen and acetic acid is preferably 0.5:1~5:1, more preferably 2:1.
The present invention carries out the 3rd solid preferably under conditions of stirring and sloughs benzyloxycarbonyl group.In the present invention, the solid
The temperature for sloughing benzyloxycarbonyl group is preferably 20 DEG C~50 DEG C, more preferably 30 DEG C~35 DEG C；The solid sloughs benzyloxycarbonyl group
Time is preferably 0.5h~4h, more preferably 1h~2h, is most preferably 1h.
Complete after the 3rd solid sloughs the reaction of benzyloxycarbonyl group, the present invention is preferably placed reaction liquid into ether and taken out
Filter, the solid matter with deionized water that suction filtration is obtained are dissolved, then dialysed, and are freezed, are obtained the 4th solid.The present invention preferably adopts
Go to dialyse with the bag filter that molecular cut off is 3500；The time of the dialysis is 4 days, and a dialyzate is changed per 4h.The present invention
There is no special limitation to lyophilized method, using freeze drying technology scheme well known to those skilled in the art；It is described lyophilized
Temperature be preferably -20 DEG C, the lyophilized time is preferably 72h.
4th solid is soluble in water, add and close platinum with the corresponding cis-diamines dichloro of carboxyl-content in the 4th solid,
PH is adjusted, reaction, obtains the 5th reaction solution.In the present invention, the molar ratio that the carboxyl closes platinum with cis-diamines dichloro is (1
~10)：1, it is preferably 4:1~8:1, it is most preferably 6:1.The pH value is preferably 8~10, is most preferably 9.
5th reaction solution is freezed, cis-platinum macromolecule kernel must be carried.The present invention does not have special limit to lyophilized method
System, using freeze drying technology scheme well known to those skilled in the art；The lyophilized temperature is preferably -20 DEG C, lyophilized
Time is preferably 72h.
After obtaining the macromolecule kernel with formula (II) structure, the present invention is by described in formula (I) structure with masking
The nanometer shell of ability and the macromolecule kernel of load cis-platinum are dissolved in dimethyl sulfoxide (DMSO), add triethylamine, reaction.And then it can make
There must be the turnover Polyionic micella shading system of electric charge of formula (III) structure.Wherein, it is described with formula (I) structure
The molar ratio of nanometer shell and the macromolecule kernel with formula (II) structure for being loaded with cis-platinum with screening capacity is 1:2~
10, it is more preferably 1:2~5, it is most preferably 1:5.The volume of the dimethyl sulfoxide (DMSO) and with formula (I) structure with masking energy
The total mass ratio of the nanometer shell of power and the macromolecule kernel of load cis-platinum is preferably (8~12) mL:1g, more preferably 10mL:1g.
The reaction temperature is 20~30 DEG C, is preferably 22~27 DEG C, optimal is 25 DEG C.Reaction time is 2~12h, preferably 4~
10h, optimal is 8h.
In formula (II), 5≤x≤50,5≤y≤50, it is preferred that 10≤x≤30,10≤y≤30, | x-y |≤5.
It is provided by the invention that there is the turnover Polyionic micella shading system of electric charge to support cis-platinum by coordination,
Not only carrier material good biocompatibility, the good nano-carrier of dissolubility are detained (EPR) effect in tumor group by strengthening to permeate
Position enrichment is knitted, under the pH value condition of tumor tissues position, the shell with screening capacity is sloughed, and exposes the load cis-platinum of positively charged
Kernel, electropositive kernel contribute to cell endocytic, after load cis-platinum kernel enters cell, carry cis-platinum kernel and discharge with anti-
The drugs Cisplatin of tumour performance.
For a further understanding of the present invention, with reference to embodiment to it is provided by the invention have electric charge it is turnover gather from
Subtype micella shading system and preparation method thereof illustrates, and protection scope of the present invention is not limited by the following examples.
Embodiment 1：The preparation of N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides
N- benzyloxycarbonyl groups-L-lysine described in 1g is mixed with double (trichloromethyl) carbonic esters of 0.6g at 25 DEG C, is added
Tetrahydrofuran, is heated to 50 DEG C of reaction 2h, after reaction, reaction mixture is settled in excessive oil ether, separates, wash
Wash, recrystallize, N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides are obtained after drying, for nuclear magnetic spectrum referring to Fig. 1, Fig. 1 is real
Apply N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydride nuclear magnetic spectrums of the preparation of example 1.
Embodiment 2：The preparation of γ-benzyl glutamate-N- ring inner-acid anhydrides
γ-benzyl glutamate described in 1g is mixed with double (trichloromethyl) carbonic esters of 0.6g at 25 DEG C, adds tetrahydrochysene furan
Mutter, be heated to 50 DEG C of reaction 2h, after reaction, reaction mixture settled in excessive oil ether, separates, wash, tie again
γ-benzyl glutamate-N- ring inner-acid anhydrides are obtained after brilliant, dry, for nuclear magnetic spectrum referring to Fig. 2, Fig. 2 is γ-benzyl prepared by embodiment 2
The nuclear magnetic spectrum of base glutamic acid-N- ring inner-acid anhydrides.
Embodiment 3：The preparation of the poly glycol monomethyl ether of different molecular weight-poly- N (ε)-benzyloxycarbonyl group-L-lysine
1g polyethylene glycol is put into monomethyl ether in dry reaction bulb, 10mL n,N-Dimethylformamide is added, adds
N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides prepared by 0.5g embodiments 1, in a nitrogen atmosphere stirring reaction.Obtain
N ' the dinethylformamide solution of poly glycol monomethyl ether-N (ε)-benzyloxycarbonyl group-L-lysine.It is equal that its number is calculated by nuclear-magnetism
Molecular weight is 7500.
Embodiment 4：The preparation of the poly glycol monomethyl ether of different molecular weight-poly- N (ε)-benzyloxycarbonyl group-L-lysine
1g poly glycol monomethyl ethers are placed in dry reaction bulb, add 10mL n,N-Dimethylformamide, add
N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides prepared by 1g embodiments 1, in a nitrogen atmosphere stirring reaction.Gathered
N ' the dinethylformamide solution of glycol monoethyl ether-N (ε)-benzyloxycarbonyl group-L-lysine.Its number is calculated by nuclear-magnetism to divide equally
Son amount is 9900.
Embodiment 5：The preparation of the poly glycol monomethyl ether of different molecular weight-poly- N (ε)-benzyloxycarbonyl group-L-lysine
1g poly glycol monomethyl ethers are placed in dry reaction bulb, add 10mL n,N-Dimethylformamide, add
N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides prepared by 1.5g embodiments 1, in a nitrogen atmosphere stirring reaction.Obtain
N ' the dinethylformamide solution of poly glycol monomethyl ether-N (ε)-benzyloxycarbonyl group-L-lysine.It is equal that its number is calculated by nuclear-magnetism
Molecular weight is 12400.
Embodiment 6：The preparation of poly- N (ε)-benzyloxycarbonyl group-L-lysine of different molecular weight
1g polyethylene glycol is placed in dry reaction bulb, adds 10mL n,N-Dimethylformamide, add 2g implementations
N (ε)-benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides prepared by example 1, in a nitrogen atmosphere stirring reaction.Obtain polyethylene glycol
N ' the dinethylformamide solution of monomethyl ether-N (ε)-benzyloxycarbonyl group-L-lysine.Calculating its number-average molecular weight by nuclear-magnetism is
14800。
Embodiment 7：The preparation of the polyaminoacid nano-particle of different content
The N (ε) that γ prepared by 2.27g embodiments 2-benzyl glutamate-N- rings inner-acid anhydride is prepared with 2.64g embodiments 1-
Benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides are uniformly mixed, and are added to the n,N-Dimethylformamide containing 0.087g n-hexylamines
In solution, stirring reaction 3 days, solution after reaction is poured into 100mL anhydrous ethers under nitrogen atmosphere, and suction filtration takes solid, very
Sky is dry, obtains polyaminoacid nano-particle, average each n-hexylamine polymerize upper 10 γ-benzyl glutamates and 10 N (ε)-
Benzyloxycarbonyl group-L-lysine.
Embodiment 8：The preparation of the polyaminoacid nano-particle of different content
The N (ε) that γ prepared by 2.27g embodiments 2-benzyl glutamate-N- rings inner-acid anhydride is prepared with 2.64g embodiments 1-
Benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides are uniformly mixed, and are added to the n,N-Dimethylformamide containing 0.035g n-hexylamines
In solution, stirring reaction 3 days, solution after reaction is poured into 100mL anhydrous ethers under nitrogen atmosphere, and suction filtration takes solid, very
Sky is dry, obtains polyaminoacid nano-particle, average each n-hexylamine polymerize upper 25 γ-benzyl glutamates and 25 N (ε)-
Benzyloxycarbonyl group-L-lysine.
Embodiment 9：The preparation of the polyaminoacid nano-particle of different content
The N (ε) that γ prepared by 2.27g embodiments 2-benzyl glutamate-N- rings inner-acid anhydride is prepared with 2.64g embodiments 1-
Benzyloxycarbonyl group-L-lysine-N- ring inner-acid anhydrides are uniformly mixed, and are added to the n,N-Dimethylformamide containing 0.017g n-hexylamines
In solution, stirring reaction 3 days, solution after reaction is poured into 100mL anhydrous ethers under nitrogen atmosphere, and suction filtration takes solid, very
Sky is dry, obtains polyaminoacid nano-particle, average each n-hexylamine polymerize upper 50 γ-benzyl glutamates and 50 N (ε)-
Benzyloxycarbonyl group-L-lysine.
Embodiment 10~13：The poly glycol monomethyl ether of different molecular weight-polyaminoacid nano-particle deprotection
The poly glycol monomethyl ether of the different molecular weight prepared in 1g embodiments 3~6-polyaminoacid nano-particle is put into
In 50mL round-bottomed flasks, add the dissolving of 10mL trifluoroacetic acids, add 3mL hydrogen bromides acetic acid solution (hydrogen bromide and acetic acid
Volume ratio is 2:1).Reaction 1h is stirred at room temperature；Then reaction solution is poured into 100mL ether, filtered, obtained solid is with water-soluble
Solution, is dialysed 3 days in deionized water with the bag filter that molecular cut off is 3500, and a dialyzate is changed per 4h；Resulting solution is frozen
Nano-particle is obtained after dry, for nuclear magnetic spectrum referring to Fig. 3, Fig. 3 is the nuclear magnetic spectrum of nano-particle prepared by embodiment 10.Nuclear-magnetism meter
The number-average molecular weight for calculating the nano-particle of embodiment 10~13 is respectively 6500,8000,9500,11000.
Embodiment 14~16：Poly- (N (ε)-benzyloxycarbonyl group-L-lysine-copolymerization-γ-benzyl glutamate) prepared is sloughed
N- benzyloxycarbonyl groups and benzyl
Weigh respectively the poly glycol monomethyl ether that is prepared in 1g embodiments 7~9-poly- (N (ε)-benzyloxycarbonyl group-L-lysine-
Copolymerization-γ-benzyl glutamate) it is dissolved in 10mL trifluoroacetic acids, the acetic acid solution of 3mL hydrogen bromides is added, reaction is stirred at room temperature
1h, reaction solution is poured into 100mL ether, is filtered, and obtained solid is dissolved with water, with the bag filter that molecular cut off is 3500
Dialyse 3d in deionized water, changes a dialyzate per 4h, resulting solution obtains poly- (L-lysine-copolymerization-γ-paddy after freezing
Propylhomoserin), for nuclear magnetic spectrum referring to Fig. 4, Fig. 4 is the nuclear-magnetism figure of poly- (L-lysine-common poly-gamma-glutamic acid) prepared by embodiment 14
Spectrum, the number-average molecular weight that poly- (L-lysine-common poly-gamma-glutamic acid) prepared by embodiment 14~16 is calculated by nuclear-magnetism are distinguished
For 2700,6500,13000.
Embodiment 17~22：Prepare poly- (L-lysine-common poly-gamma-glutamic acid) and connect dichlorodiamine conjunction platinum
Poly- (L-lysine-common poly-gamma-glutamic acid) for weighing the preparation of 50mg embodiments 14 is dissolved in deionized water, is used
It is 8 that 1mol/L sodium hydroxide solutions, which adjust its pH value, weighs 60mg, 30mg, 15mg, 10mg, 7.5mg, the dichloro two of 6mg respectively
Amine closes platinum and adds in reaction system, wherein, carboxyl closes platinum in platinum with dichlorodiamine in poly- (L-lysine-common poly-gamma-glutamic acid)
Molar ratio be respectively 1:1、2:1、4:1、6:1、8:1 and 10:After 1,37 DEG C of isothermal vibration reaction 3d, dialyse, freeze, gathered
(L-lysine-common poly-gamma-glutamic acid) connects dichlorodiamine and closes alloy platinum material.
Each sample takes 2ml to adjust pH respectively to 5.0,5.5,6.0,6.5,6.8,7.4,8.0 respectively afterwards.Test afterwards
Its potential and particle diameter, as a result referring to Fig. 5 and table 1, Fig. 5 be under condition of different pH different ratios of raw materials obtain poly- (L- relies ammonia
Acid-common poly-gamma-glutamic acid) connect the potential that dichlorodiamine closes alloy platinum material.
Poly- (L-lysine-common poly-gamma-glutamic acid) that different ratios of raw materials obtains under conditions of table 1pH is 7.4 connects dichloro
Diamines closes the particle size results of alloy platinum material
Similarly, under conditions of pH5.0,5.5,6.0,6.5,6.8 and 8.0, obtain it is poly- (L-lysine-copolymerization-γ-
Glutamic acid) connect dichlorodiamine close alloy platinum material change it is little.The change of pH value is little to the grain diameter influence of material.
Embodiment 23~28：Prepare poly- (L-lysine-common poly-gamma-glutamic acid) and connect dichlorodiamine conjunction platinum
Poly- (L-lysine-common poly-gamma-glutamic acid) for weighing the preparation of 50mg embodiments 15 is dissolved in deionized water, is used
It is 8 that 1mol/L sodium hydroxide solutions, which adjust its pH value, weighs 60mg, 30mg, 15mg, 10mg, 7.5mg, the dichloro two of 6mg respectively
Amine closes platinum and adds in reaction system, wherein, carboxyl closes platinum in platinum with dichlorodiamine in poly- (L-lysine-common poly-gamma-glutamic acid)
Molar ratio be respectively 1:1、2:1、4:1、6:1、8:1 and 10:After 1,37 DEG C of isothermal vibration reaction 3d, dialyse, freeze, gathered
(L-lysine-common poly-gamma-glutamic acid) connects dichlorodiamine and closes alloy platinum material.
Each sample takes 2ml to adjust pH respectively to 5.0,5.5,6.0,6.5,6.8,7.4,8.0 respectively afterwards.Test afterwards
Its potential and particle diameter, as a result referring to Fig. 6 and table 2, Fig. 6 be under condition of different pH different ratios of raw materials obtain poly- (L- relies ammonia
Acid-common poly-gamma-glutamic acid) connect the potential that dichlorodiamine closes alloy platinum material.
Poly- (L-lysine-common poly-gamma-glutamic acid) that different ratios of raw materials obtains under conditions of table 2pH is 7.4 connects dichloro
Diamines closes the particle size results of alloy platinum material
Similarly, under conditions of pH5.0,5.5,6.0,6.5,6.8 and 8.0, obtain it is poly- (L-lysine-copolymerization-γ-
Glutamic acid) connect dichlorodiamine close alloy platinum material change it is little.The change of pH value is little to the grain diameter influence of material.
Embodiment 29~34：Prepare poly- (L-lysine-common poly-gamma-glutamic acid) and connect dichlorodiamine conjunction platinum
Poly- (L-lysine-common poly-gamma-glutamic acid) for weighing the preparation of 50mg embodiments 16 is dissolved in deionized water, is used
It is 8 that 1mol/L sodium hydroxide solutions, which adjust its pH value, weighs 60mg, 30mg, 15mg, 10mg, 7.5mg, the dichloro two of 6mg respectively
Amine closes platinum and adds in reaction system, wherein, carboxyl closes platinum in platinum with dichlorodiamine in poly- (L-lysine-common poly-gamma-glutamic acid)
Molar ratio be respectively 1:1、2:1、4:1、6:1、8:1 and 10:After 1,37 DEG C of isothermal vibration reaction 3d, dialyse, freeze, gathered
(L-lysine-common poly-gamma-glutamic acid) connects dichlorodiamine and closes alloy platinum material.
Each sample takes 2ml to adjust pH respectively to 5.0,5.5,6.0,6.5,6.8,7.4,8.0 respectively afterwards.Test afterwards
Its potential and particle diameter, as a result referring to Fig. 7 and table 3, Fig. 7 be under condition of different pH different ratios of raw materials obtain poly- (L- relies ammonia
Acid-common poly-gamma-glutamic acid) connect the potential that dichlorodiamine closes alloy platinum material.
Poly- (L-lysine-common poly-gamma-glutamic acid) that different ratios of raw materials obtains under conditions of table 3pH is 7.4 connects dichloro
Diamines closes the particle size results of alloy platinum material
Similarly, under conditions of pH5.0,5.5,6.0,6.5,6.8 and 8.0, obtain it is poly- (L-lysine-copolymerization-γ-
Glutamic acid) connect dichlorodiamine close alloy platinum material change it is little.The change of pH value is little to the grain diameter influence of material.
Embodiment 35~38：Prepare poly glycol monomethyl ether-polyaminoacid nano-particle of methyl aconitic acid anhydride grafting：
Poly glycol monomethyl ether-polyaminoacid nano-particle of 100mg embodiments 10~13 is weighed, is dissolved in N, N- diformazans
Base formamide and chloroform 1:In 1 solvent, 130mg n-hydroxysuccinimides, 360mg 1- (3- dimethylaminos third are added
Base) -3- ethyl-carbodiimide hydrochlorides, 60mg methyl aconitic acid anhydrides, react 3d, after settled with ether, obtain a nanometer shell, nuclear-magnetism
For collection of illustrative plates referring to Fig. 8, Fig. 8 is the nuclear magnetic spectrum for the nanometer shell that embodiment 35 is prepared.
Embodiment 39~56：Preparation with the turnover Polyionic micella shading system of electric charge
Poly- (L-lysine-common poly-gamma-glutamic acid) for weighing the preparation of 50mg embodiments 17~34 connects dichlorodiamine conjunction platinum product
Material, is dissolved in dimethyl sulfoxide (DMSO), adds the polyethyleneglycol first of methyl aconitic acid anhydride grafting prepared by 50.0mg embodiments 36
Ether-polyaminoacid shell, reacts 3d, and ether sedimentation can be obtained with the turnover Polyionic micella shading system of electric charge.
Embodiment 57~74：Preparation with the turnover Polyionic micella shading system of electric charge
Poly- (L-lysine-common poly-gamma-glutamic acid) for weighing the preparation of 50mg embodiments 17~34 connects dichlorodiamine conjunction platinum product
Material, is dissolved in dimethyl sulfoxide (DMSO), and the poly glycol monomethyl ether that methyl aconitic acid anhydride prepared by addition 30mg embodiments 37 is grafted-
Polyaminoacid shell, reacts 3d, and ether sedimentation can be obtained with the turnover Polyionic micella shading system of electric charge.
Embodiment 74~91：Preparation with the turnover Polyionic micella shading system of electric charge
Poly- (L-lysine-common poly-gamma-glutamic acid) for weighing the preparation of 50mg embodiments 17~34 connects dichlorodiamine conjunction platinum product
Material, is dissolved in dimethyl sulfoxide (DMSO), and the poly glycol monomethyl ether that methyl aconitic acid anhydride prepared by addition 15mg embodiments 38 is grafted-
Polyaminoacid shell, reacts 3d, and ether sedimentation can be obtained with the turnover Polyionic micella shading system of electric charge.
Embodiment 92:Release with the turnover Polyionic micella shading system of electric charge
Under conditions of 37 DEG C, 5mg Polyionic micella shading systems are weighed respectively, and being dissolved in 5mL0.01M pH value is
7.4 phosphate and pH value is in 5.5 acetate buffer solution, is then transferred to bag filter, the molecular cut off of bag filter
For 3500, dialysed with the buffer solution of the corresponding pH value of 40mL, in the separately sampled 3mL of 12h, 24h, 48h, 72h and 120h, and added
Enter the buffer solution of respective amount；Using inductivity coupled plasma mass spectrometry carry out quantitative analysis, obtain cumulative percentage release with
Time increased variation relation, releasing result are as shown in Figure 5.Fig. 9 is that Polyionic micella shading system prepared by the present invention exists
Releasing curve diagram during pH=7.4 and pH=5.5, as shown in Figure 9, Polyionic micella shading system have slow-release capability and acid
Property pH under accelerate release feature.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (9)
1. one kind has the turnover Polyionic micella shading system of electric charge, it is characterised in that by with knot formula (III) Suo Shi
The compound of structure is formed with platinum co-ordination：
Wherein, 5≤x≤50,5≤y≤50,1≤a≤y, 5≤m≤20,40≤n≤120.
2. a kind of preparation method with the turnover Polyionic micella shading system of electric charge, it is characterised in that by with formula
(I) the nanometer shell with screening capacity of structure is prepared with the macromolecule kernel for carrying cis-platinum；The high score for carrying cis-platinum
Sub- kernel is made as cis-platinum with the reaction of the compound with structure shown in Formula II；
In formula (I), R is selected from the branched alkyl of hydrogen, the straight chained alkyl of C1~C5 or C3~C5,5≤m≤20,40≤n≤120；
In formula (II), 5≤x≤50,5≤y≤50.
3. preparation method according to claim 2, it is characterised in that comprise the following steps：
The nanometer shell with screening capacity with formula (I) structure is dissolved in DMF with the macromolecule kernel for carrying cis-platinum, is added
Enter triethylamine, stir, reacted, obtained with the turnover Polyionic micella shading system of electric charge.
4. preparation method according to claim 2, it is characterised in that the system of the nanometer shell with screening capacity
Preparation Method comprises the following steps：
A) carboxylic acid anhydrides in polyethylene glycol, benzyloxycarbonyl group lysine-N- rings and the first organic solvent are mixed, reaction, obtains first
Reaction solution；
B) the first reaction solution and the second organic solvent are mixed, filtering, obtains the first solid；
C the first solid) is sloughed into benzyloxycarbonyl group, obtains the second solid；
D the second solid) is dissolved in the 3rd organic solvent, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides,
4-dimethylaminopyridine and methyl aconitic acid anhydride, reaction, obtain the 3rd reaction solution；
E) the 3rd reaction solution and the second organic solvent are mixed, obtain a nanometer shell.
5. preparation method according to claim 4, it is characterised in that step A) in, the temperature of the reaction for 15 DEG C~
50 DEG C, the time of the reaction is 2~7 days；Step D) in, the temperature of the reaction is 15 DEG C~50 DEG C, the reaction when
Between be 2~7 days.
6. preparation method according to claim 4, it is characterised in that first organic solvent is selected from N, N- dimethyl methyls
One or more in acid amides, dioxane and chloroform；
Second organic solvent is ether；
3rd organic solvent is N,N-dimethylformamide or the mixed solution of dimethyl sulfoxide (DMSO) and dichloromethane.
7. preparation method according to claim 2, it is characterised in that the preparation method of the macromolecule kernel for carrying cis-platinum
Comprise the following steps：
A) carboxylic acid anhydrides and first in carboxylic acid anhydrides in n-hexylamine, benzyloxycarbonyl group lysine-N- rings, γ benzyl glutamate-N- rings is had
Machine dissolving mixing, reaction, obtains the 4th reaction solution；
B) the 4th reaction solution and the second organic solvent are mixed, filtering, obtains the 3rd solid；
C) the 3rd solid is sloughed into benzyloxycarbonyl group, obtains the 4th solid；
D) it is the 4th solid is soluble in water, add and close platinum with the corresponding cis-diamines dichloro of carboxyl-content in the 4th solid, adjust
PH is saved, reaction, obtains the 5th reaction solution；
E) the 5th reaction solution is freezed, cis-platinum macromolecule kernel must be carried.
8. preparation method according to claim 7, it is characterised in that in step a), the temperature of the reaction for 15 DEG C~
50 DEG C, the time of the reaction is 2~7 days.
9. preparation method according to claim 7, it is characterised in that in step d, the carboxyl and cis-diamines dichloro
The molar ratio for closing platinum is 1~10：1.
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| CN109438715A (en) * | 2018-12-24 | 2019-03-08 | 中国科学院长春应用化学研究所 | A kind of cis-dichlorodiamine platinum complex, preparation method and application with ROS response |
| CN109481695A (en) * | 2018-12-24 | 2019-03-19 | 中国科学院长春应用化学研究所 | A kind of cis-dichlorodiamine platinum complex, preparation method and application with pH response |
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| CN109134778A (en) * | 2018-08-16 | 2019-01-04 | 西南民族大学 | Charge flip type polymer micelle, carrier micelle and preparation method thereof |
| CN109134778B (en) * | 2018-08-16 | 2021-03-09 | 西南民族大学 | Charge inversion type polymer micelle, drug-loaded micelle and preparation method thereof |
| CN109438715A (en) * | 2018-12-24 | 2019-03-08 | 中国科学院长春应用化学研究所 | A kind of cis-dichlorodiamine platinum complex, preparation method and application with ROS response |
| CN109481695A (en) * | 2018-12-24 | 2019-03-19 | 中国科学院长春应用化学研究所 | A kind of cis-dichlorodiamine platinum complex, preparation method and application with pH response |
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