CN105801847A - Hydrotropy macromolecular carrier for antitumor drug delivery and preparing method - Google Patents
Hydrotropy macromolecular carrier for antitumor drug delivery and preparing method Download PDFInfo
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Abstract
The invention discloses a hydrotropy macromolecular carrier for antitumor drug delivery, preparation and drug loading application.The macromolecular carrier is formed by connecting poly-glutamoyl glutamine and hydrotropy micromolecule N,N-diethylnicotinamide through chemical bonds.The macromolecular carrier is used for delivering hydrophobic antitumor drugs and can form hydrotropy polymer nanoparticles with the drugs in a water phase through self assembling, the possible toxic and side effect produced on the body after direct drug administration of monomer cosolvent DENA is avoided, the problem that dilution stability of hydrotropy polymetic micelle PEG-g-pDENA is poor can be solved, and the drug water solubility and bioavailability are improved.An effective approach is provided for studying and developing a series of personalized carrier materials suitable for different drugs and is conductive to promoting development of the field of pharmaceutic adjuvant studies in China.
Description
Technical field
The present invention relates to polymer chemistry and nanometer pharmaceutical technology field, a kind of for helping that antitumor drug delivers
Soluble high molecular carrier and preparation method and medicine carrying are applied.
Background technology
Cosolvent is that a kind of to increase medicine by forming the forms such as complex, associated complex or double salt with hydrophobic drug water miscible
Material.Cosolvent molecular structure is typically combined by an aromatic rings or aromatic rings system and anionic group, wherein aromatic rings
Part can interact with medicine, and anionic group then brings highly-water-soluble.Cosolvent is to the solubilized mechanism of medicine more
Complexity, obtains 4 points that are summarized as of common recognition: hydrophobic interaction, Aromatic-ring stacking interaction, hydrogen bond are formed and specificity interacts.
Application cosolvent is insoluble drug very effective solubilising means, often can make drug solubility that the increase of several orders of magnitude occurs.
But it is higher that it reaches concentration that effective solubilization needs, and due to blood diluting effect its can be bigger for internal aequum, quilt
Body may produce toxicity after absorbing, thus the application of cosolvent is confined to external medicament solubilization, mostly such as In Vitro Dissolution at present
Experiment substitutes organic solvent.The most how while making full use of cosolvent solubilization effect, it is to avoid it is absorbed by organisms, fall
Low issuable toxicity in vivo, becomes a major issue.This target is achieved, it will significantly expand the use of cosolvent
On the way so that it is become a kind of effectively instrument of practicality in pharmaceutics.
Hydrotropy polymer micelle is to combine the concept development of cosolvent on the basis of common micelle and come.Common micelle is due to can
With reasons such as increase drug solubility, raising medicine stability, increase targetings by the extensive concern of researcher, the most
Product is had to carry out clinical trial.Traditional micelle is by hydrophobic by amphipathic nature polyalcohol material (such as PEG-b-PLA, PEG-PE)
Active force assemble hydrophobic side in interior, water-wet side nano-core-shell structure outside, its bag medicine carrying thing mainly by micelle inner core with
Nonspecific hydrophobic interaction between medicine, therefore only has preferably bag and carries effect the medicine that a small amount of hydrophobicity is the strongest.
But major part medicine be often weak hydrophobic, cause most of micelle delivery system of current research report exist drug loading low and
The problem of poor stability.In consideration of it, there is researcher that cosolvent introduces the hydrophobic side of polymeric material, preparation bag carries corresponding medicine
The hydrotropy polymer micelle of thing, by the hydrotropy effect of medicine increases the compatibility of polymer hydrophobic end and medicine, thus reaches
To increasing drug loading and the purpose of stability, currently reported cosolvent has N-picoline nicotiamide (PNA), N, N-bis-
Methyl benzamide (DMBA), N, nicamide (DENA) and fluorenylmethyloxycarbonyl (α-Fmoc) etc..As the U.S. is general
Cross university Kim professor seminar by DENA be polymerized after connect PEG synthesized amphipathic hydrotropy polymeric material PEG-g-pDENA,
The encapsulating effect of paclitaxel (PTX) is substantially improved by its micelle being self-assembly of, and makes the dissolubility of PTX improve 6000 times,
Its solubilizing effect effect far above isocyatic free DENA or PEG-PLA.Carry the PEG-g-pDENA micelle medicine carrying amount of PTX
Reach 37.4% (high drug load of comparison PEG-PLA is 27.6%), can stably deposit at least 4 weeks that (comparison PEG-PLA is 24
Hour).Owing to DENA group has special solubilizing mechanism (Aromatic-ring stacking interaction and hydrogen bond action) to paclitaxel, therefore with it
He compares by cosolvent (DMBA or α-Fmoc), and DENA has abnormal good solubilizing effect to paclitaxel.The more important thing is, help
Solvent copolymerization forms polymer, will not be absorbed by organisms for human body, it is to avoid monomer cosolvent be administered may cause to body
Toxic and side effects.It addition, the stability of micelle and in vivo release behavior also can be by regulating and controlling the molecular size range of cosolvent polymer
Change.But, it is not enough that this hydrotropy polymer micelle there is also it: owing between carrier material molecule, polymerization forms micelle
Hydrophobic forces is the most weak, and the hydrophobicity of especially DENA, much smaller than the hydrophobic side (such as PLA) of conventional micellar material, causes material
Critical micelle concentration (CMC) is the highest, the micelle therefore formed under hemodilution it may happen that medicine separates out or prominent releases.This
One problem hinders the further development of hydrotropy polymer micelle.
Summary of the invention
It is an object of the invention to provide a kind of hydrotropy macromolecule carrier delivered for antitumor drug and preparation method and medicine carrying should
With, the method is on the basis of polyglutamic acyl glutamine (PGG), increases a cosolvent DENA molecule, defines tool
The macromolecule carrier heling solubilization.
It is a further object to provide the application in antitumor drug delivers of a kind of hydrotropy macromolecule carrier.I.e. passing through will
Medicine cosolvent introduces in polymer carrier materials, utilizes the interaction of cosolvent and medicine to prepare novel nano delivery system,
Improve the compatibility of carrier material and medicine, for the approach that the industrialization process offer of propelling China nanoscale medicine delivery system is new.
The concrete technical scheme realizing the object of the invention is:
A kind of hydrotropy macromolecule carrier (PGG-DENA) delivered for antitumor drug, it is as follows that feature is that this macromolecule carrier has
Shown structure:
Wherein: n is the degree of polymerization, the molecular weight of macromolecule carrier (PGG-DENA) is 30000～60000Da.
A kind of preparation method of above-mentioned macromolecule carrier (PGG-DENA), the method includes step in detail below:
1) 1,4-(chloromethyl) benzylated polyol is prepared
Will be to chloromethyl benzoic acid chlorides, NaBH4It is placed in round-bottomed flask, adds oxolane and the mixed solution of ethanol, under room temperature
Stir 1h, TLC and follow the tracks of reaction, treat that raw material point disappears, stopped reaction；Reactant liquor is evaporated, adds saturated sodium bicarbonate aqueous solution,
After be extracted with ethyl acetate, 1g is evaporated liquid correspondence 30ml saturated sodium bicarbonate aqueous solution and 20ml ethyl acetate, is evaporated organic layer
It is dried, obtains white solid Isosorbide-5-Nitrae-(chloromethyl) benzylated polyol；Wherein, the volume ratio of described oxolane and ethanol is 1:1；1g
10～15ml oxolanes corresponding to chloromethyl benzoic acid chlorides and the mixed solution of ethanol, to chloromethyl benzoic acid chlorides and NaBH4Rub
That ratio is 1:3；
2) N is prepared, N-diethyl-2-Hydroxylbenzamide
By 2-hydroxy niacin, N, N '-carbonyl dimidazoles is placed in round-bottomed flask, adds oxolane, stirs 60 DEG C and be heated to reflux
1h, adds diethylamine afterwards, and TLC follows the tracks of reaction, treats that raw material point disappears, stopped reaction；After being cooled to room temperature, reactant liquor is evaporated,
Adding ethyl acetate, 1g is evaporated liquid correspondence 5ml ethyl acetate, stirring to pulp, sucking filtration, is dried and to obtain white powder N, N-diethyl
-2-Hydroxylbenzamide；Wherein, the corresponding 10～15ml oxolanes of 1g 2-hydroxy niacin, 2-hydroxy niacin, N, N '-carbonyl diurethane
Imidazoles, the mol ratio of diethylamine are the corresponding 10～15ml ethyl acetate of 1:1:1.5,1g 2-hydroxy niacin；
3) 4-tertiary butyl dimethyl Si xylyl alcohol is prepared
By Isosorbide-5-Nitrae-(chloromethyl) benzylated polyol, DMAP, imidazoles in round-bottomed flask, add dichloromethane, stirring
To dissolving, adding tert-butyl chloro-silicane (TBDMSCl) afterwards, stir under room temperature, TLC follows the tracks of reaction, treats that raw material point disappears,
Stopped reaction, adds 1mol/L KHSO in reactant liquor4Aqueous solution, after with dichloromethane extract, 1g1,4-(chloromethyl) benzene first
Base alcohol correspondence 15ml 1mol/L KHSO4Aqueous solution and 10ml dichloromethane, be evaporated organic facies and obtain 4-tertiary butyl dimethyl Si first
Base benzylalcohol；Wherein, the corresponding 10～15ml dichloromethane of 1g Isosorbide-5-Nitrae-(chloromethyl) benzylated polyol, Isosorbide-5-Nitrae-(chloromethyl) benzylated polyol,
DMAP, imidazoles, the mol ratio of tert-butyl chloro-silicane are 1:0.7:1.4:1.7；1g1,4-(chloromethyl)
The corresponding 10～15ml 1mol/L KHSO of benzylated polyol4Aqueous solution；
4) N is prepared, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide
By 4-tertiary butyl dimethyl Si xylyl alcohol, N, N-diethyl-2-Hydroxylbenzamide, K2CO3In round-bottomed flask,
Adding anhydrous propanone, stirring is to dissolving, and 60 DEG C are heated to reflux, and TLC follows the tracks of reaction, treat that raw material point disappears, stopped reaction；To
Reactant liquor adds saturated NaHCO3Aqueous solution, after add ethyl acetate extraction, organic facies is evaporated to obtain N, N-diethyl-2-(uncle 4-
Butyl diformazan silica methylbenzyloxy) Benzoylamide；Wherein, 1g 4-tertiary butyl dimethyl Si xylyl alcohol corresponding 10～15ml
Acetone；4-tertiary butyl dimethyl Si xylyl alcohol, N, N-diethyl-2-Hydroxylbenzamide, K2CO3Mol ratio be
1:1.3:3；The corresponding 30～40m saturated NaHCO of 1g N, N-diethyl-2-Hydroxylbenzamide3Aqueous solution；1g N, N-diethyl-2-
The corresponding 10～15ml ethyl acetate of hydroxybenzamide；
5) N is prepared, N-diethyl-2-(4-methylol benzyloxy) Benzoylamide
N, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide is placed in round-bottomed flask, adds four
Hydrogen furan, the HCl/water solution regulation pH to 2～3 of dropping 2mol/L, stir 1 hour under room temperature, TLC follows the tracks of reaction, treats former
Shots disappears, stopped reaction；In reactant liquor, add dichloromethane extraction, be evaporated organic facies and obtain N, N-diethyl-2-(4-hydroxyl first
Base benzyloxy) Benzoylamide；Wherein, 1g N, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide pair
Answer 10～15ml oxolanes；1gN, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide is corresponding
20～30ml dichloromethane；
6) macromolecule carrier (PGG-DENA) of different modifying ratio is prepared
Polyglutamic acyl glutamine (PGG) is dissolved in DMF (DMF), in system, adds 1-ethyl-(3-
Dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC-HCl), DMAP (DMAP) stirring to dissolve, add respectively
Entering the N of different proportion, N-diethyl-2-(4-methylol benzyloxy) Benzoylamide, agitating solution is to golden yellow clear, room
Temperature reaction, TLC follows the tracks of reaction, treats that raw material point N, N-diethyl-2-(4-methylol benzyloxy) Benzoylamide disappears, and stops anti-
Should；Saturated NaHCO is dripped in system3, regulating pH to 8～9, dialysis, lyophilizing obtain the macromolecule of different modifying ratio and carry
Body (PGG-DENA)；N, N-diethyl-2-(4-methylol benzyloxy) Benzoylamide and polyglutamic acyl glutamine (PGG)
Mol ratio is 0.1～2:1；1-ethyl-(3-dimethylaminopropyl) carbon of 1g polyglutamic acyl glutamine PGG correspondence 0.86g
The DMAP (DMAP) of acyl diimmonium salt hydrochlorate (EDC-HCl) and 0.13mg.
A kind of above-mentioned macromolecule carrier carries the application of hydrophobic anticancer drug at bag, comprises the following steps:
By the macromolecule carrier PGG-DENA of different modifying ratio in centrifuge tube, being separately added into 0.5% sodium cholate solution, 1g is high
Molecular vehicle correspondence 200ml0.5% sodium cholate solution, concussion makes dissolving；After hydrophobic anticancer drug is dissolved in dichloromethane and third
In the mixed solution of ketone, wherein the volume ratio of dichloromethane and acetone is 1:1,1g hydrophobic anticancer drug correspondence 100ml dichloro
Methane and the mixed solution of acetone, concussion makes dissolving；Hydrophobic anticancer drug solution is dropwise instilled in macromolecule carrier solution,
Rear cell ultrasonication 1.5min, dialysis, lyophilizing must wrap carry hydrophobic anticancer drug polymer nanoparticle, particle diameter is
60～80nm, particle diameter distribution PDI is 0.1～0.5.
Described dialysis, lyophilizing refer to: selective retention molecular weight be 10000～100000 bag filter will filter after reactant liquor put
Dialysis 48～60h postlyophilizations in deionized water.
Described hydrophobic anticancer drug is paclitaxel, Docetaxel, SN38 or KOS-953.
The present invention, with the cosolvent DENA that polyglutamic acyl glutamine (PGG) is framework material covalent coupling PTX, utilizes DENA
Hydrotropy effect to PTX, the hydrotropy polymer nanoparticle PGG-DENA/PTX prepared, both avoided monomer cosolvent DENA
The toxic and side effects that body may be produced after direct administration, it is possible to solve hydrotropy polymer micelle PEG-g-pDENA dilution stability
The problem of difference.
The polymer nanoparticle (PGG-DENA/PTX) of the present invention its nanoparticle structure under acidic cancer environment is destroyed, anti-swollen
Tumor medicine discharges from nanoparticle, makes sustained drug accumulate at tumor tissues, has and widely should in terms for the treatment of pulmonary carcinoma, breast carcinoma
With.
The successful implementation of the present invention will provide a kind of effective for a series of personalized carrier material being applicable to different pharmaceutical of research and development
Approach, contributes to promoting the development of China's pharmaceutic adjuvant research field.
Accompanying drawing explanation
Fig. 1 is macromolecule carrier of the present invention1H NMR(D2O) figure；
Fig. 2 is the grain-size graph that the present invention carries paclitaxel polymer nanoparticle；
Fig. 3 is the transmission electron microscope picture that the present invention carries paclitaxel polymer nanoparticle.
Detailed description of the invention
In order to be better understood from the present invention, it is further elucidated with the present invention by embodiment below, but present disclosure not only office
It is limited to example below.
Embodiment 1
Preparation 1,4-(chloromethyl) benzylated polyol
By 1.134g to chloromethyl benzoic acid chlorides, 907.9mgNaBH4It is placed in 250mL round-bottomed flask, adds 100mL tetrahydrochysene furan
Mutter/ethanol (v/v=1:1), stir 5h, TLC under room temperature and follow the tracks of reaction, treat that raw material point disappears, stopped reaction.Reactant liquor is steamed
Dry, add 30ml saturated sodium bicarbonate aqueous solution, rear with the extraction of 20ml ethyl acetate, it is evaporated organic layer and is dried, obtain white solid
Body 1,4-(chloromethyl) benzylated polyol.
Embodiment 2
Preparation N, N-diethyl-2-Hydroxylbenzamide
1g 2-hydroxy niacin, 1.17gN, N '-carbonyl dimidazoles are placed in 100mL round-bottomed flask, addition, 30mL tetrahydrochysene furan
Muttering, 60 DEG C are heated to reflux, and add 0.79g (10.88mmmol) diethylamine afterwards, and backflow 48h, TLC follow the tracks of reaction, treat raw material
Point disappears, stopped reaction.Being evaporated by reactant liquor after being cooled to room temperature, add 30ml ethyl acetate stirring to pulp, sucking filtration obtains white
Powder, is dried to obtain white powder N, N-diethyl-2-Hydroxylbenzamide.
Embodiment 3
Preparation 4-tertiary butyl dimethyl Si xylyl alcohol
Weigh 157mg 1,4-(chloromethyl) benzylated polyol, 85mg DMAP, 95mg imidazoles, in 50ml round bottom
In flask, adding 15mL dichloromethane, stirring, to dissolving, adds 256mg tert-butyl chloro-silicane (TBDMSCl) afterwards.
Stir 1h, TLC under room temperature and follow the tracks of reaction, treat that raw material point disappears, stopped reaction. in reactant liquor, add 30ml1mol/L KHSO4
Aqueous solution, rear with the extraction of 40ml dichloromethane, it is evaporated organic facies and obtains 4-tertiary butyl dimethyl Si xylyl alcohol.
Embodiment 4
Preparation N, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide
Weigh 271mg4-tertiary butyl dimethyl Si xylyl alcohol, 252.2mgN, N-diethyl-2-Hydroxylbenzamide,
414mgK2CO3In 50ml round-bottomed flask, adding 20mL anhydrous propanone, stirring is to dissolving, and 60 DEG C are heated to reflux 24h, TLC
Follow the tracks of reaction, treat that raw material point disappears, stopped reaction.The saturated NaHCO of 30mL is added in reactant liquor3Aqueous solution, after add 30ml second
Acetoacetic ester extracts, and organic facies is evaporated to obtain N, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide.
Embodiment 5
Weigh 1gN, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide in 50ml round-bottomed flask,
Add in 20mL oxolane, the HCl/water solution regulation pH to 2～3 of dropping 2mol/L, stirs 1h, TLC and follows the tracks of under room temperature
Reaction, treats that raw material point disappears, stopped reaction.In reactant liquor, add q. s. methylene chloride extraction, be evaporated organic facies and obtain N, N-bis-
Ethyl-2-(4-methylol benzyloxy) Benzoylamide.
Embodiment 6
The macromolecule carrier (PGG-DENA) of preparation different modifying ratio
Weigh 2.62g polyglutamic acyl glutamine (PGG) and be dissolved in 30mLN, in dinethylformamide (DMF), add in system
Enter 2.53g 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDC-HCl), 0.42g4-dimethylamino naphthyridine
(DMAP) stirring is to dissolving, and is separately added into the N of different proportion, N-diethyl-2-(4-methylol benzyloxy) Benzoylamide (with PGGA
Equivalent proportion is respectively 0.1,0.3,0.6,0.8,1), agitating solution is followed the tracks of to golden yellow clear, room temperature reaction, TLC
Reaction, treats that raw material point N, N-diethyl-2-(4-methylol benzyloxy) Benzoylamide disappears, stopped reaction.Drip in system
Saturated NaHCO, regulates pH to 8～9, and dialysis, lyophilizing obtain the macromolecule carrier PGG-DENA of different modifying ratio.
Embodiment 7
Prepare macromolecule and carry paclitaxel polymer nanoparticle (PGG-DENA/PTX)
Weigh the macromolecule carrier PGG-DENA of 100mg different modifying ratio (10%, 30%, 60%, 80%, 100%) in 50ml
In centrifuge tube, being separately added into 2ml 0.5% sodium cholate solution, concussion makes dissolving.Weigh 40mg paclitaxel respectively and be dissolved in 25ml bis-
In chloromethanes/acetone (v/v=3:1), concussion makes dissolving.Dropwise being instilled in macromolecular solution by paclitaxel solution, rear cell surpasses
Sound crushes 1.5min, and dialysis, lyophilizing obtain polymer nanoparticle PGG-DENA/PTX.Nanoparticle pattern is observed by transmission electron microscope,
With its drug loading of high effective liquid chromatography for measuring, result shows that the macromolecule carrier drug loading that modification ratio is 80% is up to 8%.
Embodiment 8
Configuration macromolecule carries paclitaxel polymer nanoparticle (PGG-DENA/PTX) 1mg/ml, stands 2 minutes after ultrasonic 5 minutes,
Measuring its size and particle diameter distribution with Malvern laser particle analyzer, Fig. 3 shows nano-particle footpath narrowly distributing, and size is about
60-80nm, PDI are between 0.1～0.5.
Claims (5)
1. the hydrotropy macromolecule carrier delivered for antitumor drug, it is characterised in that this macromolecule carrier has as follows
Structure:
Wherein: n is the degree of polymerization, the molecular weight of macromolecule carrier is 30000～60000Da.
2. the preparation method of macromolecule carrier described in a claim 1, it is characterised in that the method includes step in detail below:
1) 1,4-(chloromethyl) benzylated polyol is prepared
Will be to chloromethyl benzoic acid chlorides, NaBH4It is placed in round-bottomed flask, adds oxolane and the mixed solution of ethanol, under room temperature
Stir 1h, TLC and follow the tracks of reaction, treat that raw material point disappears, stopped reaction；Reactant liquor is evaporated, adds saturated sodium bicarbonate aqueous solution,
After be extracted with ethyl acetate, 1g is evaporated liquid correspondence 30ml saturated sodium bicarbonate aqueous solution and 20ml ethyl acetate, is evaporated organic layer
It is dried, obtains white solid Isosorbide-5-Nitrae-(chloromethyl) benzylated polyol；Wherein, the volume ratio of described oxolane and ethanol is 1:1；1g
10～15ml oxolanes corresponding to chloromethyl benzoic acid chlorides and the mixed solution of ethanol, to chloromethyl benzoic acid chlorides and NaBH4Rub
That ratio is 1:3；
2) N is prepared, N-diethyl-2-Hydroxylbenzamide
By 2-hydroxy niacin, N, N '-carbonyl dimidazoles is placed in round-bottomed flask, adds oxolane, stirs 60 DEG C and be heated to reflux
1h, adds diethylamine afterwards, and TLC follows the tracks of reaction, treats that raw material point disappears, stopped reaction；After being cooled to room temperature, reactant liquor is evaporated,
Adding ethyl acetate, 1g is evaporated liquid correspondence 5ml ethyl acetate, stirring to pulp, sucking filtration, is dried and to obtain white powder N, N-diethyl
-2-Hydroxylbenzamide；Wherein, the corresponding 10～15ml oxolanes of 1g 2-hydroxy niacin, 2-hydroxy niacin, N, N '-carbonyl diurethane
Imidazoles, the mol ratio of diethylamine are the corresponding 10～15ml ethyl acetate of 1:1:1.5,1g 2-hydroxy niacin；
3) 4-tertiary butyl dimethyl Si xylyl alcohol is prepared
By Isosorbide-5-Nitrae-(chloromethyl) benzylated polyol, DMAP, imidazoles in round-bottomed flask, add dichloromethane, stirring
To dissolving, adding tert-butyl chloro-silicane afterwards, stir under room temperature, TLC follows the tracks of reaction, treats that raw material point disappears, and stops anti-
Should, in reactant liquor, add 1mol/L KHSO4Aqueous solution, after with dichloromethane extract, 1g1,4-(chloromethyl) benzylated polyol pair
Answer 15ml 1mol/L KHSO4Aqueous solution and 10ml dichloromethane, be evaporated organic facies and obtain 4-tertiary butyl dimethyl Si xylyl alcohol；
Wherein, the corresponding 10～15ml dichloromethane of 1g Isosorbide-5-Nitrae-(chloromethyl) benzylated polyol, Isosorbide-5-Nitrae-(chloromethyl) benzylated polyol, 4-diformazan ammonia
Yl pyridines, imidazoles, the mol ratio of tert-butyl chloro-silicane are 1:0.7:1.4:1.7；1g1,4-(chloromethyl) benzylated polyol
Corresponding 10～15ml 1mol/L KHSO4Aqueous solution；
4) N is prepared, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide
By 4-tertiary butyl dimethyl Si xylyl alcohol, N, N-diethyl-2-Hydroxylbenzamide, K2CO3In round-bottomed flask,
Adding anhydrous propanone, stirring is to dissolving, and 60 DEG C are heated to reflux, and TLC follows the tracks of reaction, treat that raw material point disappears, stopped reaction；To
Reactant liquor adds saturated NaHCO3Aqueous solution, after add ethyl acetate extraction, organic facies is evaporated to obtain N, N-diethyl-2-(uncle 4-
Butyl diformazan silica methylbenzyloxy) Benzoylamide；Wherein, 1g 4-tertiary butyl dimethyl Si xylyl alcohol corresponding 10～15ml
Acetone；4-tertiary butyl dimethyl Si xylyl alcohol, N, N-diethyl-2-Hydroxylbenzamide, K2CO3Mol ratio be
1:1.3:3；The corresponding 30～40m saturated NaHCO of 1g N, N-diethyl-2-Hydroxylbenzamide3Aqueous solution；1g N, N-diethyl-2-
The corresponding 10～15ml ethyl acetate of hydroxybenzamide；
5) N is prepared, N-diethyl-2-(4-methylol benzyloxy) Benzoylamide
N, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide is placed in round-bottomed flask, adds four
Hydrogen furan, the HCl/water solution regulation pH to 2～3 of dropping 2mol/L, stir 1 hour under room temperature, TLC follows the tracks of reaction, treats former
Shots disappears, stopped reaction；In reactant liquor, add dichloromethane extraction, be evaporated organic facies and obtain N, N-diethyl-2-(4-hydroxyl first
Base benzyloxy) Benzoylamide；Wherein, 1g N, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide pair
Answer 10～15ml oxolanes；1gN, N-diethyl-2-(4-tert-butyl group diformazan silica methylbenzyloxy) Benzoylamide is corresponding
20～30ml dichloromethane；
6) macromolecule carrier of different modifying ratio is prepared
Polyglutamic acyl glutamine is dissolved in DMF, in system, adds 1-ethyl-(3-dimethylamino third
Base) phosphinylidyne diimmonium salt hydrochlorate, DMAP stirring to dissolve, be separately added into the N of different proportion, N-diethyl-2-(4-
Methylol benzyloxy) Benzoylamide, agitating solution is to golden yellow clear, and room temperature reaction, TLC follows the tracks of reaction, treats raw material point
N, N-diethyl-2-(4-methylol benzyloxy) Benzoylamide disappears, stopped reaction；Saturated NaHCO is dripped in system3, adjust
Joint pH to 8～9, dialysis, lyophilizing obtain the macromolecule carrier PGG-DENA of different modifying ratio；N, N-diethyl-2-(4-hydroxyl
Methylbenzyloxy) mol ratio of Benzoylamide and polyglutamic acyl glutamine PGG is 0.1～2:1；1g polyglutamic acyl glutamine pair
Answer 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and the DMAP of 0.13mg of 0.86g.
3. macromolecule carrier described in a claim 1 bag carry hydrophobic anticancer drug application, it is characterised in that include with
Lower step:
By the macromolecule carrier of different modifying ratio in centrifuge tube, it is separately added into 0.5% sodium cholate solution, 1g macromolecule carrier pair
200ml0.5% sodium cholate solution, concussion is answered to make dissolving；After that hydrophobic anticancer drug is dissolved in the mixing of dichloromethane and acetone is molten
In liquid, wherein the volume ratio of dichloromethane and acetone is 1:1,1g hydrophobic anticancer drug correspondence 100ml dichloromethane and acetone
Mixed solution, concussion make dissolving；Dropwise being instilled by hydrophobic anticancer drug solution in macromolecule carrier solution, rear cell surpasses
Sound crushes 1.5min, and dialysis, lyophilizing must wrap the polymer nanoparticle carrying hydrophobic anticancer drug, and particle diameter is 60～80nm, particle diameter
Distribution PDI is 0.1～0.5.
Preparation method the most according to claim 2, it is characterised in that described dialysis, lyophilizing refer to: selective retention molecular weight
Be 10000～100000 bag filter will filter after reactant liquor be placed in deionized water dialysis 48～60h postlyophilizations.
Application the most according to claim 3, it is characterised in that described hydrophobic anticancer drug is paclitaxel, Taxotere
Alcohol, SN38 or KOS-953.
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| CN107383362A (en) * | 2017-06-30 | 2017-11-24 | 华东师范大学 | Hydrotropy polymer carrier and preparation method and application for insoluble drug delivering |
| CN111135145A (en) * | 2020-03-05 | 2020-05-12 | 福建齐衡科技有限公司 | Preparation process of polyethylene glycol micelle with high drug loading |
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| US20150283253A1 (en) * | 2014-04-07 | 2015-10-08 | Nitto Denko Corporation | Novel polymer-based hydrotropes for hydrophobic drug delivery |
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2016
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| US20150283253A1 (en) * | 2014-04-07 | 2015-10-08 | Nitto Denko Corporation | Novel polymer-based hydrotropes for hydrophobic drug delivery |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107383362A (en) * | 2017-06-30 | 2017-11-24 | 华东师范大学 | Hydrotropy polymer carrier and preparation method and application for insoluble drug delivering |
| CN111135145A (en) * | 2020-03-05 | 2020-05-12 | 福建齐衡科技有限公司 | Preparation process of polyethylene glycol micelle with high drug loading |
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