CN106943601A - Improve protein bio availability and the water miscible carrier of insoluble medicine and preparation method - Google Patents
Improve protein bio availability and the water miscible carrier of insoluble medicine and preparation method Download PDFInfo
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Abstract
Improve protein bio availability and the water miscible carrier of insoluble medicine and preparation method the present invention relates to one kind, belong to and build carrier and preparation method that joint loads pharmaceutical grade protein and dewatering medicament.Include the synthesis of polyethylene glycol poly benzyl glutamate block copolymer, the synthesis of ammonia products, the synthesis of the poly- benzyloxycarbonyl group lysine block copolymer of linear polyethylene glycol brush, the synthesis of the poly- benzyloxycarbonyl group lysine of linear polyethylene glycol brush and polylysine block copolymer；Advantage is to solve pharmaceutical grade protein bioavilability and insoluble medicine water solubility problems, so as to prepare various injections, with improve protein bio availability, the water-soluble of increase dewatering medicament, reduction frequency of injection, reduce clinical patient financial burden, enhancing drug effect the characteristics of.
Description
Technical field
Carrier and preparation method that joint loads pharmaceutical grade protein and dewatering medicament are built the present invention relates to a kind of, is especially related to
And a kind of joint that builds loads pharmaceutical grade protein and the antineoplastic control release system of dewatering medicament and method.
Background technology
In recent years, polymer molecule brush in biomedical fields wide application prospect, such as pharmaceutical carrier, gene
Carrier, protein carrier and biological sensing system etc..Lumbrokinase be a class there is antithrombotic, it is anti-oxidant, antitumor and it is immune adjust
The multienzyme complex of section effect, has been widely studied and for clinical antineoplastic treatment.It is biological but the Half-life in vivo of Lumbrokinase is short
Availability is low, and toxic and side effect is big, thus greatly limit its clinical practice.Pegylation can effectively improve the half of Lumbrokinase
Decline the phase, but pegylation reaction adds preparation difficulty and easily reduces its bioactivity；On the other hand, often by Lumbrokinase and its
Medicine (chemotherapeutics or Chinese medicine) is used in combination to reduce Lumbrokinase dosage, reduces toxic and side effect and improves antitumous effect.
To adapt to the demand for development of pharmaceutical carrier field, bio-compatible, biodegradable and target medicine carrier are prepared
Have become new development trend.
Pharmaceutical grade protein can be loaded into micella by electrostatic interaction, and loading can enter under gentle aqueous conditions
OK, efficiency of loading can reach 100%.Meanwhile, the structure of micella is adjusted, micella can be achieved and is deposited in illumination, difference pH environment and sugar
Sustained release and controlled release that dissociation reaches pharmaceutical grade protein occur under the conditions of waiting.But, a big defect of micella is pharmaceutical grade protein
Useful load and loading stability are low.It is the electrostatic interaction using micella and pharmaceutical grade protein that micella, which loads albumen, so protein
The useful load and stability of medicine are acted on by micellar charge density and pharmaceutical grade protein charge density and medium salinity.Improve
Salinity, the electrostatic interaction between micella and pharmaceutical grade protein weakens, and pharmaceutical grade protein useful load and stability decline.According to document report
Road, micella is to the useful load of protein mostly less than 10% (protein and micella mass percent).Raising micella (or protein
Medicine) charge density and crosslinking micella can improve pharmaceutical grade protein useful load and stability.
The content of the invention
The present invention provides a kind of improvement protein bio availability and the water miscible carrier of insoluble medicine, to solve to deposit at present
Protein bio availability is low, dewatering medicament poorly water-soluble the problem of.
The present invention is adopted the technical scheme that, is obtained by the following steps：
(1) polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b-PBLG synthesis；
(2) PEG-b-PBLG ammonia products PEG-b-PELG synthesis；
(3) conjunction of the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g-PZLL) of linear polyethylene glycol-brush
Into；
(4) the poly- benzyloxycarbonyl group lysine of linear polyethylene glycol-brush and polylysine block copolymer p EG-b- (PELG-
G- (PZLL-r-PLL)) synthesis；
The step (1) comprises the following steps：
1.1 prepare glutamic acid acid anhydrides and lysine acid anhydrides：It is prepared by its Glutamic Acid acid anhydrides：Equipped with 6g BLG and 0.09g
150-200mL ethyl acetate, 40-50 DEG C of oil bath, after adding drying after ethyl acetate backflow are added in the three-neck flask of activated carbon
The 1.32-1.40g triphosgenes crossed, add dried 0.16-0.21g triphosgenes, after 2 hours in reaction system after 1 hour
White BLG solids disappear, and reaction is complete；Solution is gone to the separatory funnel freezed, with the saturation NaHCO of refrigeration3Solution and
Saturation NaCl solution is washed 3 times respectively；Filtrate rotary evaporation, is concentrated into 60-80mL, adds petroleum ether 100-150mL, separates out white
Color is precipitated, and filter residue vacuum drying obtains white solid for 1 hour for crude product after suction filtration；Crude product with ethyl acetate 20-30mL and
Petroleum ether 6-10mL is recrystallized 3 times, and suction filtration obtains white crystal；It is prepared by lysine acid anhydrides：Equipped with 5g ZLL and 0.11g activity
110-200mL ethyl acetate is added in the three-neck flask of charcoal, 40-50 DEG C of oil bath is dried after being added after ethyl acetate backflow
1.16-1.21g triphosgenes, the white ZLL solids after 2 hours in reaction system disappear, and reaction is complete；Solution is gone to and freezed
Separatory funnel, solution refrigeration saturation NaHCO3Solution and saturation NaCl solution are washed 3 times respectively, and filtrate rotary evaporation is dense
50-60mL is reduced to, petroleum ether 100-150mL Precipitations are added, the white solid that filter residue vacuum drying is obtained is crude product；Slightly
Product is recrystallized 3 times with ethyl acetate 20-30mL and petroleum ether 6-10mL, and suction filtration obtains white crystal；
The 1.2 glutamic acid acid anhydrides obtained with step 1.1 prepare polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b-
PBLG：Weigh 0.37g PEG-NH2In 80-100mL reaction bulbs, 4-6mL dimethylformamides DMF dissolvings add 0.37g's
BLG-NCA/DMF solution；Stirring reaction 2 days at 25-30 DEG C；Ultra-pure water is added in reaction system, and is transferred to bag filter pair
Water is dialysed 2 days, and freeze-drying obtains block copolymer PEG-b-PBLG；
The step (2) includes：The polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b- obtained with step 1.2
PBLG, ammonia products PEG-b-PELG is obtained by ammonolysis：The PEG-b-PBLG for weighing 0.24g reacts in dry 80-100mL
Bottle, is dissolved with DMF, adds 0.39-0.48g 2 hydroxy pyrimidine, is added at 1.9-2.4g ethylenediamine, 27-30 DEG C and is stirred anti-
Answer 3 days.15-20ml 10% aqueous acetic acid is taken to be slowly added to reaction solution, stirring reaction 2 hours is transferred to bag filter
Water is dialysed 2 days, freeze-drying obtains PEG-b-PELG block copolymers.
The step (3) includes：Lysine anhydride reaction in the PEG-b-PELG and step 1.1 that are obtained with step (2),
Obtain the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g-PZLL) of linear polyethylene glycol-brush：Weigh 0.21g
PEG-b-PELG in dry reaction bulb, dissolved with DMF, add 0.18-0.21g lysine acid anhydrides ZLL-NCA DMF it is molten
Liquid, is stirred at room temperature reaction 3 days, and 20-30ml ultra-pure water is added in reaction solution, and is transferred to bag filter MWCO, and 7kDa is to water
Dialysis 3 days, freeze-drying obtains the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g- of linear polyethylene glycol-brush
PZLL)。
The step (4) includes：The poly- benzyloxycarbonyl group lysine block of linear polyethylene glycol-brush obtained with step (3)
The deprotection of copolymer p EG-b- (PELG-g-PZLL) parts obtains the poly- benzyloxycarbonyl group lysine of linear polyethylene glycol-brush and poly-
Lysine block copolymer PEG-b- (PELG-g- (PZLL-r-PLL))：Weigh 0.18g PEG-b- (PELG-g-PZLL) in
Dry eggplant type bottle, is dissolved in CF3COOH, is slowly added to 22-26ml HBr/CH in ice-water bath3COOH (33%) deprotections are anti-
Ying Hou, absolute ether precipitation, precipitation water dissolves, then use NaHCO3It is adjusted to after neutrality, water is dialysed 3 days, freeze-drying is obtained
Target block copolymer PEG-b- (PELG-g- (PZLL-r-PLL)).
The present invention designs and synthesizes a series of block polymers based on brush polylysine, by with pharmaceutical grade protein
Electrostatic is compound or dewatering medicament forms micella, application and internal its medicine of the research micella in terms of protein or dewatering medicament carrier
Effect, which is learned, to be evaluated.Propose to build protein carrier by basic structural unit of the brush polylysine of high amino density, the poly- bad ammonia of brush
Sour structure can strengthen the electrostatic interaction between pharmaceutical grade protein, improve protein useful load and load stability.Appropriate adjustment
Carrier structure, using hydrophobic effect, can load dewatering medicament.Based on this, the present invention is using brush polylysine as basic structure list
Member builds Lumbrokinase and its joint antineoplastic (by taking dewatering medicament taxol as an example) carrier, under mild conditions by quiet
Electro ultrafiltration and/or hydrophobic effect load Lumbrokinase and its joint antineoplastic jointly, and partly declining for Lumbrokinase is improved by being sustained
Phase and bioavilability, enrichment of the carrier/drug compound in tumor locus is improved by passive target.With liver cancer and cervical carcinoma
Nude mouse Subcutaneous transplanted model is object, and system research carrier structure, medicine composition and antitumor property relationship are built based on brush
The high efficiency anti-tumor system of shape polylysine carrier and Lumbrokinase.The carrier that the present invention is built has adjustability of structure and pervasive
Property, extend to other anti-tumor protein medicines.
The present invention loads pharmaceutical grade protein and dewatering medicament using the special construction of carrier, and the carrier designed, which has, to be improved
Protein bio availability, the water solubility for increasing dewatering medicament, reduction frequency of injection, the financial burden of reduction clinical patient, enhancing
The antitumor control release system of drug effect.Wherein, medicine loading operation only need to be simple to operate under the conditions of pH=7.4.
The great advantage of carrier of the present invention is that a variety of electronegative pharmaceutical grade proteins and dewatering medicament can be loaded simultaneously.
Meanwhile, this carrier load medicine stability is good, useful load is high, have slow releasing function in vivo.
Brief description of the drawings
Fig. 1 is the poly- benzyloxycarbonyl group lysine of linear polyethylene glycol-brush and polylysine block copolymer p EG-b-
The gpc analysis figure of (PELG-g- (PZLL-r-PLL))；
Fig. 2 is the poly- benzyloxycarbonyl group lysine of linear polyethylene glycol-brush and polylysine block copolymer p EG-b-
(PELG-g- (PZLL-r-PLL's))1HMR schemes；
Fig. 3 is the cell survival rate figure of the CTA of block copolymer；
Fig. 4 is the particle diameter and pattern that dynamic light scattering (DLS) and transmission electric competing (TEM) characterize polymer/drug compound
Figure；
Fig. 5 is the tumour inhibiting rate measure figure of copolymer/medicinal composition.
Embodiment
Obtained by the following steps：
(1) polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b-PBLG synthesis；
(2) PEG-b-PBLG ammonia products PEG-b-PELG synthesis；
(3) conjunction of the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g-PZLL) of linear polyethylene glycol-brush
Into；
(4) the poly- benzyloxycarbonyl group lysine of linear polyethylene glycol-brush and polylysine block copolymer p EG-b- (PELG-
G- (PZLL-r-PLL)) synthesis；
The step (1) comprises the following steps：
1.1 prepare glutamic acid acid anhydrides and lysine acid anhydrides：It is prepared by its Glutamic Acid acid anhydrides：Equipped with 6g BLG and 0.09g
150-200mL ethyl acetate, 40-50 DEG C of oil bath, after adding drying after ethyl acetate backflow are added in the three-neck flask of activated carbon
The 1.32-1.40g triphosgenes crossed, add dried 0.16-0.21g triphosgenes, after 2 hours in reaction system after 1 hour
White BLG solids disappear, and reaction is complete；Solution is gone to the separatory funnel freezed, with the saturation NaHCO of refrigeration3Solution and
Saturation NaCl solution is washed 3 times respectively；Filtrate rotary evaporation, is concentrated into 60-80mL, adds petroleum ether 100-150mL, separates out white
Color is precipitated, and filter residue vacuum drying obtains white solid for 1 hour for crude product after suction filtration；Crude product with ethyl acetate 20-30mL and
Petroleum ether 6-10mL is recrystallized 3 times, and suction filtration obtains white crystal；It is prepared by lysine acid anhydrides：Equipped with 5g ZLL and 0.11g activity
110-200mL ethyl acetate is added in the three-neck flask of charcoal, 40-50 DEG C of oil bath is dried after being added after ethyl acetate backflow
1.16-1.21g triphosgenes, the white ZLL solids after 2 hours in reaction system disappear, and reaction is complete；Solution is gone to and freezed
Separatory funnel, solution refrigeration saturation NaHCO3Solution and saturation NaCl solution are washed 3 times respectively, and filtrate rotary evaporation is dense
50-60mL is reduced to, petroleum ether 100-150mL Precipitations are added, the white solid that filter residue vacuum drying is obtained is crude product；Slightly
Product is recrystallized 3 times with ethyl acetate 20-30mL and petroleum ether 6-10mL, and suction filtration obtains white crystal；
The 1.2 glutamic acid acid anhydrides obtained with step 1.1 prepare polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b-
PBLG：Weigh 0.37g PEG-NH2In 80-100mL reaction bulbs, 4-6mL dimethylformamides DMF dissolvings add 0.37g's
BLG-NCA/DMF solution；Stirring reaction 2 days at 25-30 DEG C；Ultra-pure water is added in reaction system, and is transferred to bag filter pair
Water is dialysed 2 days, and freeze-drying obtains block copolymer PEG-b-PBLG；
The step (2) includes：The polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b- obtained with step 1.2
PBLG, ammonia products PEG-b-PELG is obtained by ammonolysis：The PEG-b-PBLG for weighing 0.24g reacts in dry 80-100mL
Bottle, is dissolved with DMF, adds 0.39-0.48g 2 hydroxy pyrimidine, is added at 1.9-2.4g ethylenediamine, 27-30 DEG C and is stirred anti-
Answer 3 days.15-20ml 10% aqueous acetic acid is taken to be slowly added to reaction solution, stirring reaction 2 hours is transferred to bag filter
Water is dialysed 2 days, freeze-drying obtains PEG-b-PELG block copolymers.
The step (3) includes：Lysine anhydride reaction in the PEG-b-PELG and step 1.1 that are obtained with step (2),
Obtain the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g-PZLL) of linear polyethylene glycol-brush：Weigh 0.21g
PEG-b-PELG in dry reaction bulb, dissolved with DMF, add 0.18-0.21g lysine acid anhydrides ZLL-NCA DMF it is molten
Liquid, is stirred at room temperature reaction 3 days, and 20-30ml ultra-pure water is added in reaction solution, and is transferred to bag filter MWCO, and 7kDa is to water
Dialysis 3 days, freeze-drying obtains the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g- of linear polyethylene glycol-brush
PZLL)。
The step (4) includes：The poly- benzyloxycarbonyl group lysine block of linear polyethylene glycol-brush obtained with step (3)
The deprotection of copolymer p EG-b- (PELG-g-PZLL) parts obtains the poly- benzyloxycarbonyl group lysine of linear polyethylene glycol-brush and poly-
Lysine block copolymer PEG-b- (PELG-g- (PZLL-r-PLL))：Weigh 0.18g PEG-b- (PELG-g-PZLL) in
Dry eggplant type bottle, is dissolved in CF3COOH, is slowly added to 22-26ml HBr/CH in ice-water bath3COOH (33%) deprotections are anti-
Ying Hou, absolute ether precipitation, precipitation water dissolves, then use NaHCO3It is adjusted to after neutrality, water is dialysed 3 days, freeze-drying is obtained
Target block copolymer PEG-b- (PELG-g- (PZLL-r-PLL)).
The present invention is further illustrated by specific experiment example below.
The synthesis of glutamic acid acid anhydrides (BLG-NCA)：Added in the three-neck flask equipped with 6g BLG and 0.09g activated carbons
200mL ethyl acetate, 50 DEG C of oil baths, after adding dried 1.40g triphosgenes after ethyl acetate backflow, are added dry after 1 hour
The 0.21g triphosgenes of dry mistake, the white BLG solids after 2 hours in reaction system disappear, and reaction is complete.Solution is gone into freezing
The separatory funnel crossed, with the saturation NaHCO of refrigeration3Solution and saturation NaCl solution are washed 3 times respectively；Filtrate rotary evaporation is concentrated
To 80mL, petroleum ether 150mL is added, it is thick production to separate out filter residue vacuum drying after white precipitate, suction filtration and obtain within 1 hour white solid
Thing.Crude product is recrystallized 3 times with ethyl acetate 30mL/ petroleum ethers 10mL, and suction filtration obtains white crystal, yield 76.89%, product
With1H NMR are characterized.Reaction scheme is as follows：
The synthesis of lysine acid anhydrides (ZLL-NCA)：Added in the three-neck flask equipped with 5g ZLL and 0.11g activated carbons
200mL ethyl acetate, 50 DEG C of oil baths, after adding dried 1.21g triphosgenes, reactant after 2 hours after ethyl acetate backflow
White ZLL solids in system disappear, and reaction is complete.Solution is gone to the separatory funnel freezed, the saturation of solution refrigeration
NaHCO3Solution and saturation NaCl solution are washed 3 times respectively, and filtrate rotary evaporation is concentrated into 60mL, are added petroleum ether 150mL and are sunk
Precipitation goes out, and the white solid that filter residue vacuum drying is obtained is crude product.Crude product is tied again with ethyl acetate 30mL/ petroleum ethers 10mL
Brilliant 3 times, suction filtration obtains white crystal, yield 71.23%.Product is used1H NMR are characterized.Reaction scheme is as follows：
PEG-b-PBLG synthesis:Weigh 0.37g PEG-NH2In 100mL reaction bulbs, 6mL DMF dissolvings.Add
0.37g BLG-NCA/DMF (dimethylformamide) solution.Stirring reaction 2 days at 30 DEG C.Added in reaction system a certain amount of
Ultra-pure water, and be transferred to bag filter to water dialyse 2 days, freeze-drying obtain block copolymer PEG-b-PBLG, yield
67.83%.
PEG-b-PELG synthesis：0.24g PEG-b-PBLG is weighed in dry 100mL reaction bulbs, is dissolved with DMF,
0.48g 2 hydroxy pyrimidine is added, stirring reaction 3 days at 2.4g ethylenediamine, 30 DEG C are added.Take 20ml 10% acetic acid water
Solution is slowly added to reaction solution, and stirring reaction 2 hours is transferred to bag filter and water is dialysed 2 days, freeze-drying obtains PEG-b-
PELG block copolymers, yield 63.24%.
PEG-b- (PELG-g-PZLL) synthesis：0.21g PEG-b-PELG is weighed in dry reaction bulb, it is molten with DMF
Solution, adds the DMF solution of 0.21g lysine acid anhydrides (ZLL-NCA), and reaction 3 days is stirred at room temperature.30ml is added in reaction solution
Ultra-pure water, and be transferred to bag filter (MWCO, 7kDa) to water dialyse 3 days, freeze-drying obtain linear polyethylene glycol-brush gather
Benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g-PZLL), yield 65.18%.
PEG-b- (PELG-g- (PZLL-r-PLL)) synthesis：0.18g PEG-b- (PELG-g-PZLL) is weighed in dry
Dry eggplant type bottle, is dissolved in CF3COOH, is slowly added to 26ml HBr/CH in ice-water bath3COOH (33%) deprotection reaction is different
After time, absolute ether precipitation.Precipitation water dissolves, then use NaHCO3It is adjusted to after neutrality, water is dialysed 3 days, is freeze-dried
To target block copolymer PEG-b- (PELG-g- (PZLL-r-PLL)), wherein after the deprotection completely of brush lysine side-chain
The target product arrived is PEG-b- (PELG-g-PLL), yield 65.34%.1Its synthesis of HMR, gpc analysis.Target block copolymerization
Thing PEG-b- (PELG-g- (PZLL-r-PLL)) synthetic route,1HMR, gpc analysis are as follows：
The CTA of block copolymer：
The cytotoxicity of subject polymer is evaluated using CCK-8 methods.Cell (HeLa or L929) is inoculated into 96 orifice plates
(104/hole), use in 37 DEG C, 5%CO2 incubators and cultivate 24h without phenol red DMEM nutrient solutions containing 10% hyclone, treat
Cell confluency degree is added containing various concentrations polymer without phenol red DMEM nutrient solutions culture 48h up to 70~80%.Added per hole
A certain amount of CCK-8 solution continues to cultivate after 2h, and the absorbance at per hole 450nm is determined with ELIASA.Cell is calculated with following formula
Survival rate：
Cell survival rate (%)=(Asample-Ablank)/(Acontrol-Ablank) × 100%
Wherein AsampleRepresent the absorbance in the hole containing cell, CCK-8 solution and polymer samples, AblankRepresentative contains
CCK-8 solution and polymer samples but the absorbance in not celliferous hole, AcontrolRepresent containing cell and CCK-8 solution but not
The absorbance in the hole containing polymer samples.As a result Fig. 3 is seen
Loading and sign of the block copolymer to medicine：Target block copolymer PEG-b- (PELG-g-PLL) is used to load
Lumbrokinase；Target block copolymer PEG-b- (PELG-g- (PZLL-r-PLL)) is used to load Lumbrokinase and taxol jointly
(PTX).(a) loading of Lumbrokinase：Block copolymer PEG-b- (PELG-g-PLL) is in gentle PB buffer solutions to Lumbrokinase
It is loaded.Load step as follows：Target block copolymer is dissolved in PB cushioning liquid (pH7.4,0.01mol/L), obtains dense
Spend the polymer solution for 2mg/mL, the Lumbrokinase that another compound concentration is 0.1mg/mL/PB cushioning liquid (pH7.4,0.01mol/
L).Polymer solution is added in Lumbrokinase solution by a certain percentage, 30min is placed after jog.Mixed solution is taken to be transferred to
Bag (MWCO, 100kDa) is analysed, the PB cushioning liquid of same concentrations is dialysed.Meanwhile, with the Lumbrokinase of same volume same concentrations
Solution is dialysed as control under the same conditions.Dialyse after certain time, the Lumbrokinase of control group is appeared completely, now takes sample
Group extracellular fluid dialysis BCA kit measurement Lumbrokinase contents, it is that earthworm swashs that dialyzate Lumbrokinase is subtracted with Lumbrokinase total amount of feeding
Enzyme useful load, useful load is 9.78%.Investigate influence of the copolymer structure to Lumbrokinase useful load.(b) Lumbrokinase and PTX are total to
With loading：Loaded with block copolymer PEG-b- (PELG-g- (PZLL-r-PLL)) by above-mentioned steps after Lumbrokinase, add PTX
Powder, is stirred at room temperature 2h, and water is fully dialysed, and is centrifuged off unloaded PTX.Sample is freeze-dried, and PTX is extracted with ethanol, is used
Spectrophotometric determination PTX useful loads.Wherein the useful load of Lumbrokinase is that 6.28%, PTX useful loads are 7.05%.Dynamic optical dissipates
Penetrate (DLS) and transmission electric competing (TEM) characterizes the particle diameter and pattern of polymer/drug compound, as shown in Figure 4.
The release of Lumbrokinase in copolymer and medicinal composition：PTX, which is slightly soluble under water, aqueous conditions, to be difficult to be total to from block
Discharged in polymers, therefore only determine the vitro release kinetics of Lumbrokinase.
The release of Lumbrokinase：The block copolymer of brand-new/Lumbrokinase compound is loaded into bag filter (MWCO, 100kDa),
PB cushioning liquid (pH7.4) dialysis to various concentrations, changes extracellular fluid dialysis and uses BCA kits at a certain time interval
Determine extracellular fluid dialysis Lumbrokinase concentration.Dialysis time is mapped with Lumbrokinase cumulative release amount, curve is released.Investigate copolymerization
The influence of thing structure, drug load and PB buffer concentrations to release dynamics.Releasing research is released with free Lumbrokinase
Put and compare.
The blood concentration detection of copolymer/medicinal composition：Nude mouse is randomly divided into 4 groups：Normal group, free Lumbrokinase
Group, polyethylene glycol Lumbrokinase group, polymer/Lumbrokinase/PTX groups, every group 6.Normal group is left intact, other groups of difference
0.2mL free Lumbrokinase, polyethylene glycol Lumbrokinase, polymer/Lumbrokinase/PTX parenteral solutions are injected, Lumbrokinase dosage is
10000IU, PTX dosage are 0.1mg.Mouse tail vein blood is taken in different time, anticoagulant heparin, centrifuging and taking supernatant is placed in -20 DEG C
Freezen protective.Sample is taken out from refrigerator before test, placed to room temperature, sample dilution is added according to different extension rates
Liquid, Lumbrokinase blood concentration is determined according to the operating procedure in Lumbrokinase kit specification.Copolymer structure is studied to blood medicine
The influence of concentration, and contrasted with polyethylene glycol Lumbrokinase, carry out bioequivalence analysis.
The tumour inhibiting rate of copolymer/medicinal composition is determined：Liver cancer and cervical cancer cell are inoculated into nude mouse subcutaneously, set up
Replanting model mice.After certain time, mouse is randomly divided into 5 groups：Normal group, control group, free Lumbrokinase group, polyethylene glycol
Lumbrokinase group, polymer/Lumbrokinase/PTX groups, every group 10.Normal group not modeling, it is not administered, control group modeling but is not administered,
Free Lumbrokinase, polyethylene glycol Lumbrokinase, polymer/Lumbrokinase/PTX parenteral solutions are injected after other groups of modelings respectively, is observed small
Mouse Subcutaneous Tumor Growth situation.After certain time, mouse is put to death, knurl body is peeled off, scales/electronic balance weighing calculates tumor suppression with following formula
Rate, as shown in Figure 5：
Tumour inhibiting rate (100%)=(the average knurl weight of the average knurl weight-experimental group of control group) average knurl weight × 100% of/control group.
Claims (10)
1. one kind improves protein bio availability and the water miscible carrier of insoluble medicine, it is characterised in that obtained by the following steps
Arrive：
(1) polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b-PBLG synthesis；
(2) PEG-b-PBLG ammonia products PEG-b-PELG synthesis；
(3) synthesis of the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g-PZLL) of linear polyethylene glycol-brush；
(4) the poly- benzyloxycarbonyl group lysine of linear polyethylene glycol-brush and polylysine block copolymer p EG-b- (PELG-g-
(PZLL-r-PLL) synthesis).
2. a kind of improvement protein bio availability according to claim 1 and the water miscible carrier of insoluble medicine, it is special
Levy and be, the step (1) comprises the following steps：
1.1 prepare glutamic acid acid anhydrides and lysine acid anhydrides：It is prepared by its Glutamic Acid acid anhydrides：Equipped with 6g BLG and 0.09g activity
150-200mL ethyl acetate is added in the three-neck flask of charcoal, 40-50 DEG C of oil bath is dried after being added after ethyl acetate backflow
1.32-1.40g triphosgenes, add dried 0.16-0.21g triphosgenes, the white after 2 hours in reaction system after 1 hour
BLG solids disappear, and reaction is complete；Solution is gone to the separatory funnel freezed, with the saturation NaHCO of refrigeration3Solution and saturation
NaCl solution is washed 3 times respectively；Filtrate rotary evaporation, is concentrated into 60-80mL, adds petroleum ether 100-150mL, separates out white heavy
Form sediment, filter residue vacuum drying obtains white solid for 1 hour for crude product after suction filtration；Crude product ethyl acetate 20-30mL and oil
Ether 6-10mL is recrystallized 3 times, and suction filtration obtains white crystal；It is prepared by lysine acid anhydrides：Equipped with 5g ZLL and 0.11g activated carbons
110-200mL ethyl acetate, 40-50 DEG C of oil bath, after adding dried 1.16- after ethyl acetate backflow are added in three-neck flask
1.21g triphosgenes, the white ZLL solids after 2 hours in reaction system disappear, and reaction is complete；Solution is gone to point freezed
Liquid funnel, the saturation NaHCO of solution refrigeration3Solution and saturation NaCl solution are washed 3 times respectively, and filtrate rotary evaporation is concentrated into
50-60mL, adds petroleum ether 100-150mL Precipitations, and the white solid that filter residue vacuum drying is obtained is crude product；Crude product
Recrystallized 3 times with ethyl acetate 20-30mL and petroleum ether 6-10mL, suction filtration obtains white crystal；
The 1.2 glutamic acid acid anhydrides obtained with step 1.1 prepare polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b-
PBLG：Weigh 0.37g PEG-NH2In 80-100mL reaction bulbs, 4-6mL dimethylformamides DMF dissolvings add 0.37g's
BLG-NCA/DMF solution；Stirring reaction 2 days at 25-30 DEG C；Ultra-pure water is added in reaction system, and is transferred to bag filter pair
Water is dialysed 2 days, and freeze-drying obtains block copolymer PEG-b-PBLG.
3. a kind of improvement protein bio availability according to claim 1 and the water miscible carrier of insoluble medicine, it is special
Levy and be, the step (2) includes：Polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b-PBLG is used, is obtained by ammonolysis
To ammonia products PEG-b-PELG：0.24g PEG-b-PBLG is weighed in dry 80-100mL reaction bulbs, is dissolved with DMF, plus
Enter 0.39-0.48g 2 hydroxy pyrimidine, add stirring reaction 3 days at 1.9-2.4g ethylenediamine, 27-30 DEG C.Take 15-20ml
10% aqueous acetic acid be slowly added to reaction solution, stirring reaction 2 hours is transferred to bag filter and water is dialysed 2 days, freezing
It is dried to obtain PEG-b-PELG block copolymers.
4. a kind of improvement protein bio availability according to claim 1 and the water miscible carrier of insoluble medicine, it is special
Levy and be, the step (3) includes：Lysine anhydride reaction in the PEG-b-PELG and step 1.1 that are obtained with step (2),
Obtain the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g-PZLL) of linear polyethylene glycol-brush：Weigh 0.21g
PEG-b-PELG in dry reaction bulb, dissolved with DMF, add 0.18-0.21g lysine acid anhydrides ZLL-NCA DMF it is molten
Liquid, is stirred at room temperature reaction 3 days, and 20-30ml ultra-pure water is added in reaction solution, and is transferred to bag filter MWCO, and 7kDa is to water
Dialysis 3 days, freeze-drying obtains the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g- of linear polyethylene glycol-brush
PZLL)。
5. a kind of improvement protein bio availability according to claim 1 and the water miscible carrier of insoluble medicine, it is special
Levy and be, the step (4) includes：The poly- benzyloxycarbonyl group lysine block of linear polyethylene glycol-brush obtained with step (3) is total to
The deprotection of polymers PEG-b- (PELG-g-PZLL) parts obtains the poly- benzyloxycarbonyl group lysine of linear polyethylene glycol-brush and poly- bad
Propylhomoserin block copolymer PEG-b- (PELG-g- (PZLL-r-PLL))：0.18g PEG-b- (PELG-g-PZLL) is weighed in dry
Dry eggplant type bottle, is dissolved in CF3COOH, is slowly added to 22-26ml HBr/CH in ice-water bath3COOH (33%) deprotection reaction
Afterwards, absolute ether is precipitated, precipitation water dissolves, then uses NaHCO3It is adjusted to after neutrality, water is dialysed 3 days, freeze-drying obtains mesh
Mark block copolymer PEG-b- (PELG-g- (PZLL-r-PLL)).
6. a kind of improve the preparation method of protein bio availability and the water miscible carrier of insoluble medicine, it is characterised in that bag
Include the following steps：
(1) polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b-PBLG synthesis；
(2) PEG-b-PBLG ammonia products PEG-b-PELG synthesis；
(3) synthesis of the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g-PZLL) of linear polyethylene glycol-brush；
(4) the poly- benzyloxycarbonyl group lysine of linear polyethylene glycol-brush and polylysine block copolymer p EG-b- (PELG-g-
(PZLL-r-PLL) synthesis).
7. the preparation of a kind of improvement protein bio availability according to claim 6 and the water miscible carrier of insoluble medicine
Method, it is characterised in that the step (1) comprises the following steps：
1.1 prepare glutamic acid acid anhydrides and lysine acid anhydrides：It is prepared by its Glutamic Acid acid anhydrides：Equipped with 6g BLG and 0.09g activity
150-200mL ethyl acetate is added in the three-neck flask of charcoal, 40-50 DEG C of oil bath is dried after being added after ethyl acetate backflow
1.32-1.40g triphosgenes, add dried 0.16-0.21g triphosgenes, the white after 2 hours in reaction system after 1 hour
BLG solids disappear, and reaction is complete；Solution is gone to the separatory funnel freezed, with the saturation NaHCO of refrigeration3Solution and saturation
NaCl solution is washed 3 times respectively；Filtrate rotary evaporation, is concentrated into 60-80mL, adds petroleum ether 100-150mL, separates out white heavy
Form sediment, filter residue vacuum drying obtains white solid for 1 hour for crude product after suction filtration；Crude product ethyl acetate 20-30mL and oil
Ether 6-10mL is recrystallized 3 times, and suction filtration obtains white crystal；It is prepared by lysine acid anhydrides：Equipped with 5g ZLL and 0.11g activated carbons
110-200mL ethyl acetate, 40-50 DEG C of oil bath, after adding dried 1.16- after ethyl acetate backflow are added in three-neck flask
1.21g triphosgenes, the white ZLL solids after 2 hours in reaction system disappear, and reaction is complete；Solution is gone to point freezed
Liquid funnel, the saturation NaHCO of solution refrigeration3Solution and saturation NaCl solution are washed 3 times respectively, and filtrate rotary evaporation is concentrated into
50-60mL, adds petroleum ether 100-150mL Precipitations, and the white solid that filter residue vacuum drying is obtained is crude product；Crude product
Recrystallized 3 times with ethyl acetate 20-30mL and petroleum ether 6-10mL, suction filtration obtains white crystal；
The 1.2 glutamic acid acid anhydrides obtained with step 1.1 prepare polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b-
PBLG：Weigh 0.37g PEG-NH2In 80-100mL reaction bulbs, 4-6mL dimethylformamides DMF dissolvings add 0.37g's
BLG-NCA/DMF solution；Stirring reaction 2 days at 25-30 DEG C；Ultra-pure water is added in reaction system, and is transferred to bag filter pair
Water is dialysed 2 days, and freeze-drying obtains block copolymer PEG-b-PBLG.
8. the preparation of a kind of improvement protein bio availability according to claim 6 and the water miscible carrier of insoluble medicine
Method, it is characterised in that the step (2) includes：Polyethylene glycol-polybenzyl-L-glutamate block copolymer PEG-b-PBLG is used,
Ammonia products PEG-b-PELG is obtained by ammonolysis：0.24g PEG-b-PBLG is weighed in dry 80-100mL reaction bulbs, is used
DMF dissolves, and adds 0.39-0.48g 2 hydroxy pyrimidine, adds stirring reaction 3 days at 1.9-2.4g ethylenediamine, 27-30 DEG C.
15-20ml 10% aqueous acetic acid is taken to be slowly added to reaction solution, stirring reaction 2 hours is transferred to bag filter saturating to water
Analysis 2 days, freeze-drying obtains PEG-b-PELG block copolymers.
9. the preparation of a kind of improvement protein bio availability according to claim 6 and the water miscible carrier of insoluble medicine
Method, it is characterised in that the step (3) includes：Lysine in the PEG-b-PELG and step 1.1 that are obtained with step (2)
Anhydride reaction, obtains the poly- benzyloxycarbonyl group lysine block copolymer PEG-b- (PELG-g-PZLL) of linear polyethylene glycol-brush：
0.21g PEG-b-PELG is weighed in dry reaction bulb, is dissolved with DMF, 0.18-0.21g lysine acid anhydrides ZLL- is added
NCA DMF solution, is stirred at room temperature reaction 3 days, and 20-30ml ultra-pure water is added in reaction solution, and is transferred to bag filter
MWCO, 7kDa dialyse 3 days to water, and freeze-drying obtains the poly- benzyloxycarbonyl group lysine block copolymer of linear polyethylene glycol-brush
PEG-b-(PELG-g-PZLL)。
10. the system of a kind of improvement protein bio availability according to claim 6 and the water miscible carrier of insoluble medicine
Preparation Method, it is characterised in that the step (4) includes：The poly- benzyloxycarbonyl group of linear polyethylene glycol-brush obtained with step (3)
The deprotection of lysine block copolymer PEG-b- (PELG-g-PZLL) parts obtains the poly- benzyloxycarbonyl group of linear polyethylene glycol-brush
Lysine and polylysine block copolymer p EG-b- (PELG-g- (PZLL-r-PLL))：Weigh 0.18g PEG-b- (PELG-
G-PZLL) in dry eggplant type bottle, it is dissolved in CF3COOH, is slowly added to 22-26ml HBr/CH in ice-water bath3COOH (33%)
After deprotection reaction, absolute ether precipitation, precipitation water dissolves, then use NaHCO3It is adjusted to after neutrality, water is dialysed 3 days, freezing
It is dried to obtain target block copolymer PEG-b- (PELG-g- (PZLL-r-PLL)).
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| CN110483764A (en) * | 2018-01-02 | 2019-11-22 | 温州医科大学 | Charge drives the anti-oxidant nanoparticle of self assembly and its application as fruit and vegetable fresh-keeping agent and lichee fresh-keeping |
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| CN113512200A (en) * | 2021-06-10 | 2021-10-19 | 广州市第一人民医院（广州消化疾病中心、广州医科大学附属市一人民医院、华南理工大学附属第二医院） | Molecular brush polymer with poly-L-glutamic acid ester as main chain, and preparation method and application thereof |
| CN115161728A (en) * | 2022-05-23 | 2022-10-11 | 南通赛可特电子有限公司 | Pore-finishing agent for pore metallization, preparation method and application |
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| CN110483764A (en) * | 2018-01-02 | 2019-11-22 | 温州医科大学 | Charge drives the anti-oxidant nanoparticle of self assembly and its application as fruit and vegetable fresh-keeping agent and lichee fresh-keeping |
| CN110483764B (en) * | 2018-01-02 | 2022-05-03 | 温州医科大学 | Charge-driven self-assembled antioxidant nano particles and application thereof as fruit and vegetable preservative and litchi preservative |
| CN110693831A (en) * | 2019-09-18 | 2020-01-17 | 温州医科大学 | Preparation method of long-ocular-surface retention and high-corneal-permeability drug-loaded nano-micelle |
| CN110693831B (en) * | 2019-09-18 | 2021-07-30 | 温州医科大学 | Preparation method of long-ocular-surface retention and high-corneal-permeability drug-loaded nano-micelle |
| CN113512200A (en) * | 2021-06-10 | 2021-10-19 | 广州市第一人民医院（广州消化疾病中心、广州医科大学附属市一人民医院、华南理工大学附属第二医院） | Molecular brush polymer with poly-L-glutamic acid ester as main chain, and preparation method and application thereof |
| CN115161728A (en) * | 2022-05-23 | 2022-10-11 | 南通赛可特电子有限公司 | Pore-finishing agent for pore metallization, preparation method and application |
| CN115161728B (en) * | 2022-05-23 | 2023-10-20 | 南通赛可特电子有限公司 | Pore-forming agent for pore metallization, preparation method and application |
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