CN110483740A - A kind of polymer, pH sensibility nano vesicle and preparation method and application - Google Patents
A kind of polymer, pH sensibility nano vesicle and preparation method and application Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/30—Low-molecular-weight compounds
- C08G18/38—Low-molecular-weight compounds having heteroatoms other than oxygen
- C08G18/3819—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen
- C08G18/3842—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen containing heterocyclic rings having at least one nitrogen atom in the ring
- C08G18/3844—Low-molecular-weight compounds having heteroatoms other than oxygen having nitrogen containing heterocyclic rings having at least one nitrogen atom in the ring containing one nitrogen atom in the ring
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/64—Macromolecular compounds not provided for by groups C08G18/42 - C08G18/63
- C08G18/6484—Polysaccharides and derivatives thereof
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/83—Chemically modified polymers
- C08G18/84—Chemically modified polymers by aldehydes
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2375/00—Characterised by the use of polyureas or polyurethanes; Derivatives of such polymers
- C08J2375/04—Polyurethanes
Abstract
Present disclose provides a kind of polymer, pH sensibility nano vesicle and preparation method and application, polymer formulae are as follows:Wherein, m1+n1=9~19, m2+n2=9~19, p=5~10, R1ForR2It is selected from It is 100~160nm by the vesica partial size that the polymer is formed, the pH weak acidic medium for being 4.5~6.8 is largely expanded, partial size increases to 1.4~1.8 times, partial size increases multiple less than 1.1 times in neutral and alkaline medium, it is mutated less than 0.25, section pH value, and can be adjusted by adjusting the number of pyridine groups in side chain.The vesica that the disclosure provides can be realized to the weakly acidic sick cell targeted delivery of drugs of presentation.
Description
Technical field
The disclosure belongs to polymer chemistry and bio-pharmaceutical engineer technology domain, is related to a kind of polymer, pH sensibility is received
Rice vesica and preparation method and application.
Background technique
Here statement only provides background information related with the disclosure, without necessarily constituting the prior art.
Polymer vesicle, be it is a kind of by amphiphilic polymer by certain way be self-assembly of have aqueous cavity
Special self-assembly, with high stability, adjustable film character and can simultaneously encapsulating hydrophilic and hydrophobic combination ability.
Just because of these properties, before so that polymer vesicle is had a wide range of applications in drug delivery, gene therapy and organizational project
Scape.With the development of nanometer delivery system, since loaded drug, thorn can be discharged in specific target spot and specific time
The treatment for swashing response type nano carrier for cancer is more and more welcomed by the people.This kind of nano-carrier using diseased region as
Target spot discharges drug in response to local stimulation, substantially increases the concentration of local treatment drug, improve the effect for the treatment of.
It is well known that the pH of the special microenvironment and normal tissue of tumor tissues has very big difference, wherein in normal tissue
External pH is 7.4, internal pH 7.2, and pH is 7.4 during blood circulation；External pH is 6.5 inside tumor tissues
~7.2, early stage endosome pH are 6.0~6.5, and advanced stage endosome pH is 5.0~6.0, and the pH of lysosome is 4.5~5.0, this is just
The triggering factors that pH value is discharged as design medicine fixed point simultaneously realize that anti-tumor drug is released in tumour cell
It puts.
Patent CN105997879B disclose nano vesicle of a kind of pH and temperature doubling sensitivity and preparation method thereof and
Using, which is first successively gradually to synthesize the compounds such as β-asparagine acid benzyl ester, benzyloxycarbonyl group aspartic acid acid anhydrides,
Finally obtain polyethylene glycol (aspartic acid-diethyl ethylenediamine-co- histamine-co- diisopropyl ethylenediamine), ultrasound and
The nano vesicle of pH and temperature doubling sensitivity are formed under Dialysis.According to the disclosed invention people the study found that the nano vesicle
Do not have mutability, mutational range is uncontrollable, leads to carry medicine without specific aim.
Patent CN108078924A discloses a kind of polyethyleneglycol modified high drug load nano-micelle with responsiveness
Or the preparation method of vesica.This method is amphipathic by the way that polyethylene glycol is reacted generation with the Doxorubicin of modification with aconitate
Block copolymer, formed using anti-cancer drug doxorubicin as hydrophobic chain segment, using polyethylene glycol having as hydrophilic segment
The high drug load nano-micelle or vesica of responsiveness.This nano-micelle or vesica have using anticancer drug as hydrophobic segment
There is higher drugloading rate, while cis-aconitic matches acid labile, therefore nano-micelle obtained or vesica have responsiveness, are applicable in
In therapeutic field of tumor, chemotherapy efficiency can be improved, reduce the toxic side effect of anticancer drug normal tissue.But the disclosure is sent out
Bright people the study found that this method preparation micella or vesica under alkaline condition equally have sensibility, to weak acid sensibility compared with
It is low, it cannot achieve drug and sick cell precisely discharged.
The polymer that patent CN107099007B discloses a kind of Amphipathilic block polymer, light and pH double-response is compound
Type vesica and its preparation method and application, this method is obtained by ring-opening polymerisation and Transfer Radical Polymerization, amphipathic
Block polymer.It is embedding with polycaprolactone using the polymethylacrylic acid dimethylaminoethyl of azobenzene group modification as hydrophilic segment
Section is hydrophobic segment, by being self-assembly of vesica.But the disclosed invention people the study found that its hydrophobic segment by carbon carbon
Double-bond polymerization forms, and is difficult to degrade in vivo after releasing drug.
On the whole, the disclosed invention people has found, it is wide that existing pH sensibility nano vesicle has a mutational range, to Jie
Matter pH susceptibility is not sensitive enough, and the disadvantage that mutational range is not easy to control.It is steeped especially as drug holding theca, the pH of lesion region
It is worth generally different from the pH value of normal body fluid (or blood), but difference is smaller, therefore it is smaller to prepare high pH sensibility, sudden change region
And the drug holding theca bubble that can accurately control catastrophe point realizes that targeted delivery of drugs aspect has great application value.
Summary of the invention
In order to solve the deficiencies in the prior art, purpose of this disclosure is to provide a kind of polymer, pH sensibility nano vesicle
And preparation method and application, in the pH sensibility nano vesicle which forms, side chain contains multiple pH sensitive groups, weak
It can be largely expanded (partial size increases to 1.4~1.8 times) in sour (pH=4.5~6.8) medium, and be situated between in neutral or alkalinity
It expands smaller in matter or does not expand (partial size increases multiple less than 1.1 times), show high pH sensibility.Mutational range is 0.25
Within a pH value, and section can be mutated to control it by adjusting the number of pyridine groups in side chain.Meanwhile the vesica can be with
Packaging medicine, drug release rate is very fast in weak acidic medium, can be higher than 85% by release amount of medicine in 30~150 hours,
And drug release is slower in neutral or alkaline medium, 150 hours release amount of medicine are less than 15%, therefore drug holding theca bubble is to disease
Become and weakly acidic sick cell realization targeted delivery of drugs is presented.The vesica periphery is Phosphorylcholine group simultaneously, similar cell wall
Structure of phospholipid, not only biocompatibility is high, but also easily accessible or pass through cell wall.
To achieve the goals above, the technical solution of the disclosure are as follows:
In a first aspect, structural formula is as follows present disclose provides a kind of polymer:
Wherein, m1+n1=9~19, m2+n2=9~19, p=5~10,
R1For
R2It is selected from
On the other hand, present disclose provides a kind of preparation method of above-mentioned polymer, single-ended dihydroxy-pyridine compounds
PyDH and diisocyanate carry out the polyurethane that polymerization reaction preparation both ends are isocyanate group, polyurethane molecular both ends it is different
Cyanic acid base carries out addition reaction with the amino of two chitosan oligosaccharides respectively and obtains polymer precursor, the primary amine groups in polymer precursor with
After holding the aldehyde radical of aldehyde-base Phosphorylcholine to carry out aldimine condensation reaction to obtain the final product；
The structural formula of the single-ended dihydroxy-pyridine compound PyDH is
The structural formula of the end aldehyde-base Phosphorylcholine is
The third aspect, present disclose provides a kind of pH sensibility nano vesicles, are assembled and are formed by above-mentioned polymer.
Fourth aspect, present disclose provides a kind of preparation methods of pH sensibility nano vesicle, and above-mentioned polymer is dissolved in
Polymer solution is obtained in organic solvent, and polymer and water are mixed with lotion, lotion is added into water and is prepared into water-
The double lotions of oil-water, remove organic solvent, pH sensibility nano vesicle are obtained after freeze-drying.
5th aspect, a kind of above-mentioned pH sensibility nano vesicle is as the application in pharmaceutical carrier.
6th aspect, a kind of targeted drug, including active medicine and targeting vector, the targeting vector are above-mentioned pH sensitive
Property nano vesicle.
Above-mentioned polymer is dissolved in organic solvent and obtains polymer by the 7th aspect, a kind of preparation method of targeted drug
Polymer and the water containing active medicine are mixed with lotion, lotion are added and is prepared into water-oil-water pair into water by solution
Lotion removes organic solvent, obtains targeted drug after freeze-drying.
The vesica of the disclosure includes positive and negative two kinds using Phosphorylcholine (PC) modified chitosan oligosaccharide as hydrophilic segment
Charge, has very strong and water binding ability, and material surface is not easy to adsorb and sink the biotic components such as collection protein, show good
Biocompatibility.The molecular backbone of the vesica is orderly aligned polyurethane segment, is influenced by hydrogen bond action, three-dimensional network
It is more stable.Contain multiple pyridine groups in side chain, freedom degree is larger, in acid medium pyridine groups matter more sensitive to medium
Sonization is changed into quaternary ammonium salt, and hydrogen bond action weakens, so that the repulsive force of molecule interchain enhances, macroscopic view is exactly to show as vesica
Expansion, auto-degradation rate are accelerated, and drug is made to be easier to discharge.It is hydrophobic that polyurethane orderly aligned simultaneously can enhance its segment
Property, the vesica partial size increase of formation, drugloading rate increases.
The disclosure has the beneficial effect that
1. the nano vesicle side chain that the disclosure provides contains pyridine groups, since it is located at side chain, freedom with higher
Degree, utilization rate is high, therefore the vesica has high pH sensibility, and especially to acid medium fast response time, extraneous pH's is small
Variation can bring dilation significantly to change, and have the characteristics that the speed of response is fast.
2. a large amount of Phosphorylcholine groups are contained in the nano vesicle periphery that the disclosure provides, so being not easy to adsorb and sink collection albumen
The biotic components such as matter and liposome will not generate damage to human body, have good biocompatibility.
3. containing longer polyurethane segment in the nano vesicle main chain that the disclosure provides, and hard section contains multiple amino
Carbamate group can form fine and close hydrogen bond, to improve the stability of three-dimensional network.On the other hand, catabolite is
Alkaline matter can neutralize the acidic materials that degradation generates, avoid the generation of acid inflammation, will not be to having as pharmaceutical carrier
Body generates harm.
4. disclosure preparation method is simple, principle abundance, practical, easy to spread
5. the nano vesicle that the disclosure provides can be used as pharmaceutical carrier, realizes and the weakly acidic sick cell of presentation is oriented
Administration.
Detailed description of the invention
The Figure of description for constituting a part of this disclosure is used to provide further understanding of the disclosure, and the disclosure is shown
Meaning property embodiment and its explanation do not constitute the improper restriction to the disclosure for explaining the disclosure.
Fig. 1 be the embodiment of the present disclosure in prepare PyDH nuclear magnetic resonance spectroscopy (1H NMR) figure；
Fig. 2 be the embodiment of the present disclosure 1 in polymer A1 nuclear magnetic resonance spectroscopy (1H NMR) figure；
Fig. 3 be the embodiment of the present disclosure 1 in polymer B 1 nuclear magnetic resonance spectroscopy (1H NMR) figure；
The G5 of Fig. 4 is the G1 of the preparation of the embodiment of the present disclosure 1, prepared by embodiment 4 G4, the preparation of embodiment 5 are at different pH
Grain size curve
Fig. 5 is the curve of release amount of medicine of the G1-Y of the preparation of the embodiment of the present disclosure 1 at different pH.
Specific embodiment
It is noted that described further below be all exemplary, it is intended to provide further instruction to the disclosure.Unless another
It indicates, all technical and scientific terms used herein has usual with disclosure person of an ordinary skill in the technical field
The identical meanings of understanding.
It should be noted that term used herein above is merely to describe specific embodiment, and be not intended to restricted root
According to the illustrative embodiments of the disclosure.As used herein, unless the context clearly indicates otherwise, otherwise singular
Also it is intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet
Include " when, indicate existing characteristics, step, operation, device, component and/or their combination.
In view of existing vesica pH sensibility is lower, sudden change region is larger, is difficult to realize the deficiency of targeted delivery of drugs, the disclosure is mentioned
A kind of polymer, pH sensibility nano vesicle and preparation method and application are gone out.
A kind of exemplary embodiment of the disclosure, provides a kind of polymer, and structural formula is as follows:
Wherein, m1+n1=9~19, m2+n2=9~19, p=5~10,
R1For
R2It is selected from
The another embodiment of the disclosure provides a kind of preparation method of above-mentioned polymer, single-ended dihydroxy-pyridine
Compound PyDH and diisocyanate carry out the polyurethane that polymerization reaction preparation both ends are isocyanate group, a polyurethane molecular two
The isocyanate group at end obtains polymer precursor with the progress addition reaction of the amino of two chitosan oligosaccharides respectively, primary in polymer precursor
Amido carries out after aldimine condensation reacts with the aldehyde radical of end aldehyde-base Phosphorylcholine to obtain the final product；
The structural formula of the single-ended dihydroxy-pyridine compound PyDH is
The structural formula of the end aldehyde-base Phosphorylcholine is
In one or more embodiments of the embodiment, the diisocyanate is the aliphatic two with orderly segment
Isocyanates, such as hexamethylene diisocyanate -1,4-butanediol-hexamethylene diisocyanate, two isocyanide of tetramethylene
Acid esters -1,4- butanediol-tetramethylene diisocyanate, L-lysine diisocyanate -1,4- butanediol-L-lysine two are different
Cyanate etc..
In one or more embodiments of the embodiment, single-ended dihydroxy-pyridine compound PyDH and diisocyanate
Molar ratio is 1:1.1~1:1.2.
In one or more embodiments of the embodiment, preparing the solvent in polyurethane reaction system is N, N- dimethyl
Formamide (DMF).
It in one or more embodiments of the embodiment, prepares in polyurethane reaction system, single-ended dihydroxy-pyridine
It closes object PyDH and the total concentration of diisocyanate in the solution is 0.5~1.5g/mL.
In one or more embodiments of the embodiment, the reaction temperature for preparing polyurethane is 70~85 DEG C.
In one or more embodiments of the embodiment, the catalyst in polyurethane reaction system is prepared as the catalysis of tin class
Agent, such as dibutyl tin dilaurate, stannous octoate etc..
It in one or more embodiments of the embodiment, prepares in polyurethane reaction system, the additional amount of catalyst is
The 0.5~1% of single-ended dihydroxy-pyridine compound PyDH and diisocyanate gross mass.
In one or more embodiments of the embodiment, single-ended dihydroxy-pyridine compound PyDH and diisocyanate
Reaction end passes through di-n-butylamine method measurement-NCO content.It is about 3~4h that reaction, which reaches the time of terminal,.
In one or more embodiments of the embodiment, the number-average molecular weight of the chitosan oligosaccharide is 1600~4000, is taken off
Acetyl degree is greater than 90%, and further preferred deacetylation is greater than 92%.
In one or more embodiments of the embodiment, chitosan oligosaccharide solution is added into the material after polymerization reaction and carries out
Addition reaction.
In the series embodiment, the concentration of chitosan oligosaccharide solution is 1.0~1.5g/mL.
In one or more embodiments of the embodiment, the dosage of chitosan oligosaccharide is diisocyanate and single-ended dihydroxy pyrrole
4~6 times of the difference of acridine compound PyDH mole.When chitosan oligosaccharide is significantly excessive, only one ammonia on each chitosan oligosaccharide molecule
Base is reacted with-NCO, avoids being crosslinked, to be more easier to form vesica.
In one or more embodiments of the embodiment, the reaction end of addition reaction is infrared detection-NCO absorption peak
(~2270cm-1) disappear.I.e. the time of addition reaction is 2~3.5h.
In one or more embodiments of the embodiment, the method for purification of polymer precursor are as follows: after addition reaction
Material dilution, is settled using water, then the solid after precipitating is dried.
In one or more embodiments of the embodiment, in the mole and polymer precursor of end aldehyde-base Phosphorylcholine
Primary amine groups mole it is equal.
In one or more embodiments of the embodiment, the reaction temperature of aldimine condensation reaction is 20~30 DEG C, reaction
Time is 2~3h.
In one or more embodiments of the embodiment, aldimine condensation reacting rear material is often settled using ethyl alcohol,
By solid washing, the drying after sedimentation.
The third of the disclosure assembles shape embodiment there is provided a kind of pH sensibility nano vesicle, by above-mentioned polymer
At.
In one or more embodiments of the embodiment, partial size is 100~160nm.
In one or more embodiments of the embodiment, in acid medium, the partial size of pH sensibility nano vesicle increases
1.4~1.8 times are added to, in neutral or alkaline medium, the partial size of pH sensibility nano vesicle increases to less than 1.1 times or do not increase
Add.
Embodiment there is provided a kind of preparation methods of pH sensibility nano vesicle for the 4th kind of the disclosure, will be above-mentioned poly-
Conjunction object, which is dissolved in organic solvent, obtains polymer solution, and polymer and water are mixed with lotion, lotion is added and is made into water
The standby double lotions of Cheng Shui-oil-water, remove organic solvent, pH sensibility nano vesicle are obtained after freeze-drying.
In one or more embodiments of the embodiment, the organic solvent is chloroform.
In one or more embodiments of the embodiment, the concentration of polymer solution is 0.005~0.015g/mL.
In one or more embodiments of the embodiment, the volume ratio of polymer solution and water is 4:0.5~1.5.
In one or more embodiments of the embodiment, polymer is mixed with water, ultrasonic treatment is prepared into lotion.
In one or more embodiments of the embodiment, during preparing the double lotions of water-oil-water, the body of lotion and water
Product is than being 1:0.5~1.
In one or more embodiments of the embodiment, lotion is added into water, and ultrasonic treatment is prepared into water-oil-water
Double lotions.
Diisocyanate (hexamethylene diisocyanate -1,4- the butanediol-six with orderly segment that the disclosure uses
Methylene diisocyanate, tetramethylene diisocyanate -1,4- butanediol-tetramethylene diisocyanate, two isocyanide of L-lysine
Acid esters -1,4- butanediol-L-lysine diisocyanate) preparation of the method according to disclosed in patent CN108976387A.
Single-ended dihydroxy-pyridine compound PyDH's the preparation method comprises the following steps: under dry argon gas in the disclosure, by 4-vinylpyridine
It is dissolved in DMF with 3- sulfydryl -1,2-PD, under the action of catalyst, after being stirred at room temperature for 24 hours, 12 times (~5 DEG C) of ice ether heavy
Drop filters, and room temperature in vacuo is dry to constant weight, obtains single-ended dihydroxy-pyridine compound A, yield 92~98%.Preferably, 4- ethylene
Pyridine and 3- sulfydryl -1,2- propylene glycol molar ratio are 1:1；4-vinylpyridine and 3- sulfydryl -1,2- propylene glycol are in diformazan Asia
Total concentration in sulfone is 0.3~0.6g/mL；Catalyst is n,N-diisopropylethylamine, and dosage is 4-vinylpyridine molal quantity
2.5%.Reaction equation is as follows:
The preparation of aldehyde-base Phosphorylcholine method according to disclosed in patent CN102070780A described in the disclosure, the acetaldehyde
The structural formula of base acetylcholine are as follows:
Embodiment there is provided a kind of above-mentioned pH sensibility nano vesicles as answering in pharmaceutical carrier for the 5th kind of the disclosure
With.
Embodiment there is provided a kind of targeted drug, including active medicine and targeting vector, the targets for the 6th kind of the disclosure
It is above-mentioned pH sensibility nano vesicle to carrier.
In one or more embodiments of the embodiment, the active medicine is anti-inflammatory drug or antineoplastic.
In one or more embodiments of the embodiment, the partial size of targeted drug is 120~190nm.
Embodiment there is provided a kind of preparation methods of targeted drug for the 7th kind of the disclosure, and above-mentioned polymer is dissolved in
Obtain polymer solution in organic solvent, polymer and the water containing active medicine be mixed with lotion, by lotion be added to
It is prepared into the double lotions of water-oil-water in water, removes organic solvent, obtains targeted drug after freeze-drying.
In one or more embodiments of the embodiment, the organic solvent is chloroform.
In one or more embodiments of the embodiment, the concentration of polymer solution is 0.005~0.015g/mL.
In one or more embodiments of the embodiment, the volume ratio of polymer solution and the water containing active medicine is
4:0.5~1.5.
In one or more embodiments of the embodiment, the active medicine is anti-inflammatory drug or antineoplastic.
In one or more embodiments of the embodiment, during preparing the double lotions of water-oil-water, the body of lotion and water
Product is than being 1:0.5~1.
In one or more embodiments of the embodiment, organic solvent is removed, after being dialysed, then freezing is carried out and does
It is dry.Free active medicine is removed.
In the series embodiment, dialysed 2 days using the bag filter of 10KDa, it is primary that every 12h changes deionized water.
In order to enable those skilled in the art can clearly understand the technical solution of the disclosure, below with reference to tool
The technical solution of the disclosure is described in detail in the embodiment and comparative example of body.
The preparation of PyDH:
Under dry argon gas, 21.03g 4-vinylpyridine and 21.63g 3- sulfydryl -1,2-PD are dissolved in 100mL
0.65g n,N-diisopropylethylamine is added in DMF, and after being stirred at room temperature for 24 hours, 12 times of (~5 DEG C) of ice ether sedimentations are filtered, room temperature
It is dried under vacuum to constant weight, obtains single-ended dihydroxy-pyridine compound PyDH (41.35g, yield 96.9%),1H NMR is as shown in Figure 1.
Embodiment 1:
(1) preparation of polymer A1
10.4g compound PyDH, 25.59g hexamethylene diisocyanate -1,4- butanediol-hexa-methylene diisocyanate
Ester and 0.2g dibutyl tin dilaurate are dissolved in 50mL N, in N '-dimethyl formamide (DMF), oil bath heating to 80 DEG C of constant temperature
React 3.5h.22 DEG C are subsequently cooled to, the DMF solution of chitosan oligosaccharide (number-average molecular weight 1610, deacetylation 90%) is added
(80.5g chitosan oligosaccharide+100mLDMF) maintains temperature the reaction was continued 2.5h.After reaction, DMF solution is added into reaction flask
It is diluted to 0.25g/mL, is then filtered repeatedly twice with the deionized water sedimentation of octuple volume, 50 DEG C are dried under vacuum to constant weight,
Polymer A1 is obtained,1H NMR is as shown in Figure 2.
(2) preparation of polymer B 1
It takes 6.82g polymer A1 to be dissolved in 50mL anhydrous chloroform, 3.6g aldehyde-base Phosphorylcholine, 20 DEG C of isothermal reactions is added
2h.It is settled, is filtered with the ethyl alcohol of hexaploid product after reaction, three times, normal-temperature vacuum is dry to constant weight for ethanol washing.Obtain polymer
B1,1H NMR is as shown in Figure 3.
(3) preparation of nano vesicle G1
1 chloroformic solution of 80mL polymer B (0.01g/mL) is taken to mix with 20mL deionized water, with ultrasonic disperse at uniform cream
Liquid；Lotion is slowly added in 50mL deionized water, while ultrasonic disperse, chloroform is removed by vacuum distillation, is freeze-dried
To vesica, it is denoted as G1.
(4) preparation of medicament-carried nano vesica G1-Y
Take 1 chloroformic solution of 80mL polymer B (0.01g/mL) and 20mL dissolved with the deionized water of 10-hydroxycamptothecine
(10mg/mL) mixing, lotion is slowly added in 50mL deionized water by ultrasonic disperse at homogeneous latex emulsion, while ultrasonic disperse；It is logical
Cross vacuum distillation and remove chloroform, then the bag filter of 10KDa dialyse in deionized water two days, every 12h change once go from
Sub- water, then be freeze-dried and obtain medicament-carried nano vesica.It is denoted as G1-Y, carrying medicine encapsulation rate is 85%.
Embodiment 2:
(1) preparation of polymer A2
10.4g compound PyDH, 22.5g tetramethylene diisocyanate -1,4- butanediol-hexamethylene diisocyanate
50mL N is dissolved in 0.18g dibutyl tin dilaurate, and in N '-dimethyl formamide (DMF), oil bath heating is anti-to 75 DEG C of constant temperature
Answer 3h.25 DEG C are subsequently cooled to, the DMF solution (80.5g of chitosan oligosaccharide (number-average molecular weight 1610, deacetylation 90%) is added
Chitosan oligosaccharide+100mLDMF), maintain temperature the reaction was continued 2.5h.After reaction, DMF solution is added into reaction flask to be diluted to
Then 0.25g/mL is filtered, 50 DEG C are dried under vacuum to constant weight, are gathered repeatedly twice with the deionized water sedimentation of octuple volume
Close object A2.
(2) preparation of polymer B 2
It takes 6.51g polymer A2 to be dissolved in 50mL anhydrous chloroform, 3.6g aldehyde-base Phosphorylcholine, 20 DEG C of isothermal reactions is added
2h.It is settled, is filtered with the ethyl alcohol of hexaploid product after reaction, three times, normal-temperature vacuum is dry to constant weight for ethanol washing.Obtain polymer
B2。
(3) preparation of nano vesicle G2
2 chloroformic solution of 80mL polymer B (0.01g/mL) is taken to mix with 20mL deionized water, with ultrasonic disperse at uniform cream
Liquid；Lotion is slowly added in 80mL deionized water, while ultrasonic disperse, chloroform is removed by vacuum distillation, is freeze-dried
To vesica, it is denoted as G2.
Embodiment 3:
(1) preparation of polymer A3
10.4g compound PyDH, 32.56g L-lysine diisocyanate -1,4- butanediol-L-lysine diisocyanate
Ester and 0.24g stannous octoate are dissolved in 50mL N, in N '-dimethyl formamide (DMF), oil bath heating to 80 DEG C of isothermal reaction 3h.
23 DEG C are subsequently cooled to, DMF solution (the 96.6g chitosan oligosaccharide of chitosan oligosaccharide (number-average molecular weight 1610, deacetylation 90%) is added
+ 100mLDMF), maintain temperature the reaction was continued 3h.After reaction, DMF solution is added into reaction flask and is diluted to 0.25g/mL,
Then it is filtered, 50 DEG C are dried under vacuum to constant weight, obtain polymer A3 repeatedly twice with the deionized water sedimentation of octuple volume.
(2) preparation of polymer B 3
It takes 7.52g polymer A3 to be dissolved in 50mL anhydrous chloroform, 3.6g aldehyde-base Phosphorylcholine, 25 DEG C of isothermal reactions is added
2h.It is settled, is filtered with the ethyl alcohol of hexaploid product after reaction, three times, normal-temperature vacuum is dry to constant weight for ethanol washing.Obtain polymer
B3。
(3) preparation of nano vesicle G3
3 chloroformic solution of 80mL polymer B (0.01g/mL) is taken to mix with 20mL deionized water, with ultrasonic disperse at uniform cream
Liquid；Lotion is slowly added in 50mL deionized water, while ultrasonic disperse, chloroform is removed by vacuum distillation, is freeze-dried
To vesica, it is denoted as G3.
Embodiment 4:
(1) preparation of polymer A4
14.56g compound PyDH, 34.12g hexamethylene diisocyanate -1,4- butanediol-hexa-methylene diisocyanate
Ester and 0.28g stannous octoate are dissolved in 50mL N, in N '-dimethyl formamide (DMF), oil bath heating to 80 DEG C of isothermal reactions
3.5h.22 DEG C are subsequently cooled to, the DMF solution (64.4g of chitosan oligosaccharide (number-average molecular weight 1610, deacetylation 90%) is added
Chitosan oligosaccharide+100mLDMF), maintain temperature the reaction was continued 2.5h.After reaction, DMF solution is added into reaction flask to be diluted to
Then 0.25g/mL is filtered, 50 DEG C are dried under vacuum to constant weight, are gathered repeatedly twice with the deionized water sedimentation of octuple volume
Close object A4.
(2) preparation of polymer B 4
It takes 8.09g polymer A4 to be dissolved in 50mL anhydrous chloroform, 3.6g aldehyde-base Phosphorylcholine, 25 DEG C of isothermal reactions is added
2.5h.It is settled, is filtered with the ethyl alcohol of hexaploid product after reaction, three times, normal-temperature vacuum is dry to constant weight for ethanol washing.It is polymerize
Object B4.
(3) preparation of nano vesicle G4
4 chloroformic solution of 80mL polymer B (0.01g/mL) is taken to mix with 20mL deionized water, with ultrasonic disperse at uniform cream
Liquid；Lotion is slowly added in 50mL deionized water, while ultrasonic disperse, chloroform is removed by vacuum distillation, is freeze-dried
To vesica, it is denoted as G4.
Embodiment 5:
(1) preparation of polymer A5
20.8g compound PyDH, 46.92g hexamethylene diisocyanate -1,4- butanediol-hexa-methylene diisocyanate
Ester and 0.2g dibutyl tin dilaurate are dissolved in 100mL N, in N '-dimethyl formamide (DMF), oil bath heating to 80 DEG C of constant temperature
React 3.5h.25 DEG C are subsequently cooled to, the DMF solution of chitosan oligosaccharide (number-average molecular weight 1610, deacetylation 90%) is added
(80.5g chitosan oligosaccharide+100mLDMF) maintains temperature the reaction was continued 2.5h.After reaction, DMF solution is added into reaction flask
It is diluted to 0.25g/mL, is then filtered repeatedly twice with the deionized water sedimentation of octuple volume, 50 DEG C are dried under vacuum to constant weight,
Obtain polymer A5.
(2) preparation of polymer B 5
It takes 9.99g polymer A5 to be dissolved in 50mL anhydrous chloroform, 3.6g aldehyde-base Phosphorylcholine, 20 DEG C of isothermal reactions is added
2h.It is settled, is filtered with the ethyl alcohol of hexaploid product after reaction, three times, normal-temperature vacuum is dry to constant weight for ethanol washing.Obtain polymer
B5。
(3) preparation of nano vesicle G5
5 chloroformic solution of 80mL polymer B (0.01g/mL) is taken to mix with 20mL deionized water, with ultrasonic disperse at uniform cream
Liquid；Lotion is slowly added in 60mL deionized water, while ultrasonic disperse, chloroform is removed by vacuum distillation, is freeze-dried
To vesica, it is denoted as G5.
Embodiment 6:
(1) preparation of polymer A6
10.4g compound PyDH, 25.59g hexamethylene diisocyanate -1,4- butanediol-hexa-methylene diisocyanate
Ester and 0.2g stannous octoate are dissolved in 50mL N, in N '-dimethyl formamide (DMF), oil bath heating to 80 DEG C of isothermal reaction 3.5h.
Be subsequently cooled to 23 DEG C, be added chitosan oligosaccharide (number-average molecular weight 2420, deacetylation 93%) DMF solution (121g chitosan oligosaccharide+
100mLDMF), temperature the reaction was continued 2.5h is maintained.After reaction, DMF solution is added into reaction flask and is diluted to 0.25g/
Then mL is filtered, 50 DEG C are dried under vacuum to constant weight, obtain polymer repeatedly twice with the deionized water sedimentation of octuple volume
A6。
(2) preparation of polymer B 6
It takes 8.44g polymer A6 to be dissolved in 50mL anhydrous chloroform, 5.6g aldehyde-base Phosphorylcholine, 22 DEG C of isothermal reactions is added
2h.It is settled, is filtered with the ethyl alcohol of hexaploid product after reaction, three times, normal-temperature vacuum is dry to constant weight for ethanol washing.Obtain polymer
B6。
(3) preparation of nano vesicle G6
6 chloroformic solution of 80mL polymer B (0.01g/mL) is taken to mix with 20mL deionized water, with ultrasonic disperse at uniform cream
Liquid；Lotion is slowly added in 50mL deionized water, while ultrasonic disperse, chloroform is removed by vacuum distillation, is freeze-dried
To vesica, it is denoted as G6.
Embodiment 7:
(1) preparation of polymer A7
10.4g compound PyDH, 25.59g hexamethylene diisocyanate -1,4- butanediol-hexa-methylene diisocyanate
Ester and 0.23g dibutyl tin dilaurate are dissolved in 50mL N, in N '-dimethyl formamide (DMF), oil bath heating to 80 DEG C of constant temperature
React 3.5h.25 DEG C are subsequently cooled to, the DMF solution of chitosan oligosaccharide (number-average molecular weight 3220, deacetylation 95%) is added
(128.8g chitosan oligosaccharide+100mLDMF) maintains temperature the reaction was continued 2.5h.After reaction, DMF solution is added into reaction flask
It is diluted to 0.25g/mL, is then filtered repeatedly twice with the deionized water sedimentation of octuple volume, 50 DEG C are dried under vacuum to constant weight,
Obtain polymer A7.
(2) preparation of polymer B 7
It takes 10.04g polymer A7 to be dissolved in 50mL anhydrous chloroform, 8.11g aldehyde-base Phosphorylcholine is added, 25 DEG C of constant temperature are anti-
Answer 3h.It is settled, is filtered with the ethyl alcohol of hexaploid product after reaction, three times, normal-temperature vacuum is dry to constant weight for ethanol washing.It is polymerize
Object B7.
(3) preparation of nano vesicle G7
7 chloroformic solution of 80mL polymer B (0.01g/mL) is taken to mix with 20mL deionized water, with ultrasonic disperse at uniform cream
Liquid；Lotion is slowly added in 50mL deionized water, while ultrasonic disperse, chloroform is removed by vacuum distillation, is freeze-dried
To vesica, it is denoted as G7.
Analysis and explanation: following analysis method is used for all embodiments, unless otherwise stated.
Vesica particle size determination: it takes a certain amount of nano vesicle to be respectively placed in the phosphate buffer solution of pH=4.5~6.5 and soaks
3h is steeped, a certain amount of buffer solution is then taken to measure the partial size of nano vesicle by Nano Zeta Sizer current potential particle instrument.
Medicament slow release performance: it takes nano drug-carrying vesica to be placed in phosphate buffer solution and impregnates, take buffering at regular intervals
Solution surveys its UV absorption, and the amount of release Ceftibuten is calculated by absorbance-concentration absorption curve.
Measure the size of nano vesicle G1, G4, G5 partial size at different pH respectively to compare different feed ratios to nanocapsule
The influence of change of size is steeped, wherein G1, G4, G5 respectively represent nano vesicle prepared by different feed ratios, and measurement result is as schemed
4.The result shows that the nano vesicle of disclosure preparation has high pH sensibility, mutational range is can be controlled within 0.25 pH value.
As the number of pyridine groups on side chain increases, more sensitive to acid medium, catastrophe point is closer to neutral.
The nano drug-carrying vesica G1-Y for taking the quality such as 3 parts, is separately immersed in the solution of pH=5.1, pH=5.3, pH=5.5
In, the UV absorption of medium is surveyed at regular intervals, and release 10- is calculated by standard ultraviolet absorptivity-concentration absorption curve
The content of hydroxycamptothecin.Measurement result such as Fig. 5.The result shows that the nano drug-carrying vesica of the disclosure has pH sensibility, work as pH
When value is greater than mutational range, medicament slow release rate is more gentle, and release time is long, and burst size is also especially low, burst size after 150h
Still less than 15%.When pH value is less than mutational range, rate of release is most fast, and burst size can reach 90% or more in 40h.This says
The targeted release to faintly acid sick cell can be achieved in bright drug holding theca bubble.
The foregoing is merely preferred embodiment of the present disclosure, are not limited to the disclosure, for the skill of this field
For art personnel, the disclosure can have various modifications and variations.It is all within the spirit and principle of the disclosure, it is made any to repair
Change, equivalent replacement, improvement etc., should be included within the protection scope of the disclosure.
Claims (10)
1. a kind of polymer, characterized in that structural formula is as follows:
Wherein, m1+n1=9~19, m2+n2=9~19, p=5~10,
R1For
R2It is selected from
2. a kind of preparation method of polymer described in claim 1, characterized in that single-ended dihydroxy-pyridine compound PyDH with
Diisocyanate carries out the polyurethane that polymerization reaction preparation both ends are isocyanate group, the isocyanate group at a polyurethane molecular both ends
Addition reaction is carried out with the amino of two chitosan oligosaccharides respectively and obtains polymer precursor, primary amine groups and end acetaldehyde in polymer precursor
After the aldehyde radical progress aldimine condensation reaction of base Phosphorylcholine to obtain the final product；
The structural formula of the single-ended dihydroxy-pyridine compound PyDH is
The structural formula of the end aldehyde-base Phosphorylcholine is
3. the preparation method of polymer as claimed in claim 2, characterized in that the diisocyanate is with orderly segment
Aliphatic diisocyanate；Preferably, the diisocyanate is that hexamethylene diisocyanate -1,4-butanediol-six is sub-
Methyl diisocyanate, tetramethylene diisocyanate -1,4- butanediol-tetramethylene diisocyanate or L-lysine two are different
Cyanate -1,4- butanediol-L-lysine diisocyanate；
Or, the molar ratio of single-ended dihydroxy-pyridine compound PyDH and diisocyanate is 1:1.1~1:1.2；
Or, preparing the solvent in polyurethane reaction system is n,N-Dimethylformamide；
Or, prepare in polyurethane reaction system, single-ended dihydroxy-pyridine compound PyDH and diisocyanate in the solution total
Concentration is 0.5~1.5g/mL；
Or, the reaction temperature for preparing polyurethane is 70~85 DEG C；
Or, preparing the catalyst in polyurethane reaction system is tin catalyst；Preferably, tin catalyst is tin dilaurate two
Butyl tin or stannous octoate；
Or, preparing in polyurethane reaction system, the additional amount of catalyst is single-ended dihydroxy-pyridine compound PyDH and two isocyanides
The 0.5~1% of acid esters gross mass；
Or, chitosan oligosaccharide solution is added into the material after polymerization reaction carries out addition reaction；Preferably, the concentration of chitosan oligosaccharide solution
For 1.0~1.5g/mL；
Or, the dosage of chitosan oligosaccharide is 4~6 times of the difference of diisocyanate and single-ended dihydroxy-pyridine compound PyDH mole；
Or, the method for purification of polymer precursor are as follows: dilute the material after addition reaction, settled using water, then will be sunk
Solid behind shallow lake is dried；
Or, the mole of end aldehyde-base Phosphorylcholine is equal with the mole of the primary amine groups in polymer precursor；
Or, the reaction temperature of aldimine condensation reaction is 20~30 DEG C, the reaction time is 2~3h；
Or, aldimine condensation reacting rear material is often settled using ethyl alcohol, by solid washing, the drying after sedimentation.
4. a kind of pH sensibility nano vesicle, characterized in that assembled and formed by polymer described in claim 1；
Preferably, partial size is 100~160nm；
Preferably, in acid medium, the partial size of pH sensibility nano vesicle increases to 1.4~1.8 times, is situated between in neutral or alkalinity
In matter, the partial size of pH sensibility nano vesicle increases to less than 1.1 times or does not increase.
5. a kind of preparation method of pH sensibility nano vesicle, characterized in that be dissolved in polymer described in claim 1 organic
Polymer solution is obtained in solvent, and polymer and water are mixed with lotion, lotion is added and is prepared into water-oil-water into water
Double lotions remove organic solvent, and pH sensibility nano vesicle is obtained after freeze-drying.
6. the preparation method of pH sensibility nano vesicle as claimed in claim 5, characterized in that the organic solvent is chlorine
It is imitative；
Or, the concentration of polymer solution is 0.005~0.015g/mL；
Or, the volume ratio of polymer solution and water is 4:0.5~1.5；
Or, polymer is mixed with water, ultrasonic treatment is prepared into lotion；
Or, the volume ratio of lotion and water is 1:0.5~1 during preparing the double lotions of water-oil-water；
Or, lotion is added into water, ultrasonic treatment is prepared into the double lotions of water-oil-water.
7. the pH that a kind of pH sensibility nano vesicle as claimed in claim 4 or preparation method described in claim 5 or 6 obtain
Sensibility nano vesicle is as the application in pharmaceutical carrier.
8. a kind of targeted drug, characterized in that including active medicine and targeting vector, the targeting vector is claim 4 institute
The pH sensibility nano vesicle that the pH sensibility nano vesicle stated or preparation method described in claim 5 or 6 obtain；
Preferably, the active medicine is anti-inflammatory drug or antineoplastic；
Preferably, the partial size of targeted drug is 120~190nm.
9. a kind of preparation method of targeted drug, characterized in that polymer described in claim 1 is dissolved in organic solvent and is obtained
Polymer solution is obtained, polymer and the water containing active medicine are mixed with lotion, lotion is added into water and is prepared into water-
The double lotions of oil-water, remove organic solvent, obtain targeted drug after freeze-drying.
10. the preparation method of targeted drug as claimed in claim 9, characterized in that the organic solvent is chloroform；
Or, the concentration of polymer solution is 0.005~0.015g/mL；
Or, the volume ratio of polymer solution and the water containing active medicine is 4:0.5~1.5；
Or, the active medicine is anti-inflammatory drug or antineoplastic；
Or, the volume ratio of lotion and water is 1:0.5~1 during preparing the double lotions of water-oil-water；
Or, removal organic solvent, after being dialysed, then is freeze-dried；
Preferably, it is dialysed 2 days using the bag filter of 10KDa, it is primary that every 12h changes deionized water.
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| CN113350286A (en) * | 2021-05-22 | 2021-09-07 | 南开大学 | Functional synergistic zwitterion lipid for 'water bridge' mediated hyper-response and preparation method and application thereof |
| CN113350286B (en) * | 2021-05-22 | 2022-07-26 | 南开大学 | Functional synergistic zwitterionic lipid of 'water bridge' mediated super response, preparation method and application thereof |
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