CN103992483B - A kind of drug delivering material with the triple sensitivity of sugar, temperature and pH and preparation method thereof - Google Patents
A kind of drug delivering material with the triple sensitivity of sugar, temperature and pH and preparation method thereof Download PDFInfo
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- CN103992483B CN103992483B CN201410198923.2A CN201410198923A CN103992483B CN 103992483 B CN103992483 B CN 103992483B CN 201410198923 A CN201410198923 A CN 201410198923A CN 103992483 B CN103992483 B CN 103992483B
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Abstract
The invention belongs to macromolecular material and biomedical engineering field, be specifically related to a kind of drug delivering material with the triple sensitivity of sugar, temperature and pH and preparation method thereof.Preparation method is divided into two parts, Part I to include, and ATRP initiator A BIB trigger monomer PpBDEMA obtains polymer.Part II includes that ATRP initiator 21-β-CD trigger monomer DMAEMA obtains polymer.PolymerContaining adamantane structure, polymerContaining beta-schardinger dextrin-structure, both can be self-assembled into supermolecule.The present invention through being self-assembled into as Nano medication delivery vehicles, at blood sugar concentration eminence amphipathic nature polyalcohol from hydrophobicity to hydrophilic conversion, thus discharges the drug molecule of carrying in aqueous.
Description
Technical field
The invention belongs to macromolecular material and biomedical engineering field, be specifically related to one and there is sugar, temperature and pH tri-
Drug delivering material of weight sensitivity and preparation method thereof.
Background technology
Smart polymer application in terms of biotechnology in recent years is increasingly wider, such as medicine transmission, and biosensor,
Diagnostic techniques, organizational project aspect.Diabetes are a kind of metabolic diseases being characterized with hyperglycemia.Hyperglycemia then makes due to pancreas
Island element hyposecretion and biological agent is impaired causes, can cause various tissue, particularly eye, kidney, heart, blood vessel, nerve
Chronic lesion, dysfunction, reducing blood glucose is the main method treating diabetes at present, and traditional injection and drug administration need
Wanting doctor and patient strictly to control the consumption of medicine, long-time use also can make patient produce drug resistance and cause diabetes Liver and kidney
Damage.So, find a kind of sugar response medicine carrier particularly important for the treatment of diabetes.Phenylboric acid and derivant tool thereof
There are sugar response, this sugar Response System can realize the controllable release of medicine.Phenyl boronic acid derivative exists two kinds in aqueous
State, electronegative tetrahedral structure can form stable borate ester structure with glucose complexation, and it is dissolved in water,
And the phenylboric acid of neutrality trihedral structure and glucose form the circulus of instability.By changing Portugal in pH, and solution
The concentration of grape sugar realizes the purpose of phenylboric acid system sustained-release administration.This method can be convenient and safe high in blood sugar concentration intelligently
Site of disease selectivity release medicine, reach the purpose efficiently treated.
At present, most sugars responsive polymer drug delivering material is all to introduce sugar response by the amino of aminobenzene boric acid
Type functional group, in polymer architecture, completes the conveying of intelligent medicine, but cannot solve under physiological pH, physiological temperature conditions
Controllable release.
Summary of the invention
It is an object of the invention to the dissaving polymer of synthesis, thematic structure is novel, has sugar, pH and temperature three simultaneously
Weight response.Supermolecule polymer provided by the present invention can carry out sugar response, response under human body environment's (37 DEG C, pH=7.4)
Good biocompatibility front and back, high blood glucose concentration realizes the intelligent release of medicine under stimulating.
A kind of drug delivering material with the triple sensitivity of sugar, temperature and pH that the present invention proposes, described medicine carries
The structural formula of material is:
Wherein, m be 48-80, n be 4-8.
The one that the present invention proposes has the preparation method of the drug delivering material of the triple sensitivity of sugar, temperature and pH, tool
Body step is as follows: (lacking proportionate relationship between raw material, i.e. lack feasible scope)
(1) under nitrogen protection, by ABIB initiator, cuprous bromide, ATRP part PMDETA and PpBDEMA monomer with
Mol ratio 1:1.2:1.2:60-100 is dissolved in methyl phenyl ethers anisole, stirs 18-60 hour at 88-92 DEG C, concentrate remove after mantoquita
The mixed liquor of normal hexane and ether precipitates, obtains Ad-PpBDEMA polymer:
M is 48-80,
(2) under nitrogen protection, by 21Cl-β-CD initiator, Cu-lyt., ATRP part and DMAEMA monomer with mole
It is dissolved in dry DMF than 1:1.2:1.2:60-100, reacts 50-70 minute at 38-45 DEG C, just after concentration removing mantoquita
Hexane precipitates, dialyses 48 hours and remove DMF lyophilizing removing water, obtain star-type polymer 21-β-CD-DMAEMA；
N is 4-8,
3) the 21-β-CD-DMAEMA, the Ad-PpBDEMA that step (1) obtains that the step (2) that mol ratio is 5:1 is obtained
It is dissolved in THF, is stirred at room temperature 40-50 hour, obtain Supramolecular Assembling polymer, it is required drug delivering material.
The method have the advantages that
1) sugar response polymer drug delivering material provided by the present invention has sugared response functional group, its special dredging
Water segmented structure is provided that self assembly power in aqueous phase, forms nano-particle.
2) the little molecule benzene boron after sugar response polymer drug delivering material itself provided by the present invention and sugar respond
Acid sugar ester and become the polymer of double-hydrophilic and be respectively provided with good biocompatibility.The polymer that the present invention provides rings with sugar
Should come off from polymer and the sugar little molecular complex of formation by phenylboric acid afterwards, thus phenylboric acid just can be with internal metabolism
Excrete, there is good biocompatibility.
3) present invention has sugar, temperature, the triple response of pH, more preferable can must be used for drug release, chemical sensor and gather
The fields such as compound separation.
Accompanying drawing explanation
The ATRP initiator 2-isobutyl bromide-1-Buddha's warrior attendant alkyl ester flat BDEMA of trigger monomer P of Fig. 1: diamantane (obsolete) functionalization generates
The nuclear-magnetism figure of Ad-PpBDEMA；
The ATRP initiator 21Cl-β-CD of Fig. 2: beta-schardinger dextrin-functionalization causes DMAEMA monomer to generate 21-β-CD-
DMAEMA。
Detailed description of the invention
Elaborate below by embodiment: the present embodiment is implemented under premised on technical solution of the present invention,
Give detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to the embodiment of subordinate.
Embodiment 1:
1) by 0.03g (0.1mmol) ABIB initiator, 0.0208g (0.12mmol) ATRP part PMDETA and 2.73g
(10mmol) during PpBDEMA monomer is dissolved in 2.5ml methyl phenyl ethers anisole, freezing pumping cycle three times, leads to system during last freezing
Nitrogen, adds 1.12mg (0.1mmol) cuprous bromide, and deoxygenation leads to nitrogen at 90 DEG C, stir 40 hours, concentrate after removing mantoquita
The mixed liquor of normal hexane and ether precipitates, obtains Ad-PpBDEMA polymer:
2) by 0.2821g (2.835mmol) 21Cl-β-CD initiator, 0.4913g (2.835mmol) ATRP part and
4.4569g (28.35mmol) DMAEMA monomer is dissolved in the DMF that 16ml is dried, freezing pumping cycle three times, freezing for the last time
Time system led to nitrogen, add 0.2821g (2.835mmol) cuprous bromide, deoxygenation is led to nitrogen and is reacted 1 hour at 40 DEG C, dense
Contracting precipitates with normal hexane after removing mantoquita, and dialysis removes DMF, obtains star-type polymer21-β-CD-DMAEMA。
3) 0.114mmol21-β-CD-DMAEMA, 0.023mmolAd-PpBDEMA are dissolved in 30ml THF, at room temperature
Stirring 48 hours, the dialyzer with 80000 is dialysed and is obtained Supramolecular Assembling polymer in 72 hours。
Embodiment 2:
1) by 0.03g (0.1mmol) ABIB initiator, 0.0208g (0.12mmol) ATRP part PMDETA and 2.18g
(8mmol) during PpBDEMA monomer is dissolved in 2.5ml methyl phenyl ethers anisole, freezing pumping cycle three times, leads to nitrogen to system during last freezing
Gas, adds 1.12mg (0.1mmol) cuprous bromide, and deoxygenation leads to nitrogen at 90 DEG C, stir 40 hours, concentrates after removing mantoquita just
The mixed liquor of hexane and ether precipitates, obtains Ad-PpBDEMA polymer:
2) with embodiment 1 step 2)；
3) with embodiment 1 step 3).
Embodiment 3
1) by 0.03g (0.1mmol) ABIB initiator, 0.0208g (0.12mmol) ATRP part PMDETA and 1.36g
(5mmol) during PpBDEMA monomer is dissolved in 2.5ml methyl phenyl ethers anisole, freezing pumping cycle three times, leads to nitrogen to system during last freezing
Gas, adds 1.12mg (0.1mmol) cuprous bromide, and deoxygenation leads to nitrogen at 90 DEG C, stir 40 hours, concentrates after removing mantoquita just
The mixed liquor of hexane and ether precipitates, obtains Ad-PpBDEMA polymer:
2) with embodiment 1 step 2)；
3) with embodiment 1 step 3).
Embodiment 4
1) with embodiment 1 step 1)；
2) by 0.2821g (2.835mmol) 21Cl-β-CD initiator, 0.4913g (2.835mmol) ATRP part and
3.5655g (22.68mmol) DMAEMA monomer is dissolved in the DMF that 16ml is dried, freezing pumping cycle three times, freezing for the last time
Time system led to nitrogen, add 0.2821g (2.835mmol) cuprous bromide, deoxygenation is led to nitrogen and is reacted 1 hour at 40 DEG C, dense
Contracting precipitates with normal hexane after removing mantoquita, and dialysis removes DMF, obtains star-type polymer21-β-CD-DMAEMA。
3) with embodiment 1 step 3).
Embodiment 5
1) with embodiment 1 step 1)；
2) by 0.2821g (2.835mmol) 21Cl-β-CD initiator, 0.4913g (2.835mmol) ATRP part and
2.6741g (17.01mmol) DMAEMA monomer is dissolved in the DMF that 16ml is dried, freezing pumping cycle three times, freezing for the last time
Time system led to nitrogen, add 0.2821g (2.835mmol) cuprous bromide, deoxygenation is led to nitrogen and is reacted 1 hour at 40 DEG C, dense
Contracting precipitates with normal hexane after removing mantoquita, and dialysis removes DMF, obtains star-type polymer21-β-CD-DMAEMA；
3) with embodiment 1 step 3).
Claims (2)
1. a drug delivering material with the triple sensitivity of sugar, temperature and pH, it is characterised in that described drug delivering material
Structural formula be:
Wherein, m be 48-80, n be 4-8.
2. there is the preparation method of the drug delivering material of the triple sensitivity of a sugar, temperature and pH as claimed in claim 1,
It is characterized in that specifically comprising the following steps that
(1) under nitrogen protection, by ABIB initiator, cuprous bromide, ATRP part PMDETA and PpBDEMA monomer with mole
It is dissolved in methyl phenyl ethers anisole than 1:1.2:1.2:60-100, stirs 18-60 hour at 88-92 DEG C, just own after concentration removing mantoquita
The mixed liquor of alkane and ether precipitates, obtains Ad-PpBDEMA polymer:
M is 48-80,
(2) under nitrogen protection, by 21Cl-β-CD initiator, Cu-lyt., ATRP part and DMAEMA monomer with mol ratio 1:
21:21:60-100 is dissolved in dry DMF, reacts 50-70 minute at 38-45 DEG C, at normal hexane after concentration removing mantoquita
Middle precipitation, dialyses 48 hours and removes DMF, and lyophilizing removes water, obtains star-type polymer 21-β-CD-DMAEMA:
N is 4-8,
3) 21-β-CD-DMAEMA, the Ad-PpBDEMA that step (1) obtains that the step (2) that mol ratio is 5:1 obtains are dissolved in
THF, is stirred at room temperature 40-50 hour, obtains Supramolecular Assembling polymer, is described drug delivering material.
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| CN104262643A (en) * | 2014-10-21 | 2015-01-07 | 南京慧联生物科技有限公司 | Supramolecular hydrogel microsphere prepared by taking liquid drop as template and preparation method thereof |
| CN105527285B (en) * | 2015-12-21 | 2018-03-06 | 陕西师范大学 | One kind proves that adamantane and beta cyclodextrin assemble successful method |
| CN105622692B (en) * | 2016-01-28 | 2018-05-01 | 南开大学 | A kind of sugar response supermolecular gel with tetra- stranded structures of G- and preparation method thereof |
| CN105802106B (en) * | 2016-04-22 | 2018-02-09 | 同济大学 | A kind of preparation method of the supermolecule nano aggregation of temperature, UV and the triple responses of reducing agent |
| CN109529791B (en) * | 2018-12-20 | 2021-08-03 | 江苏大学 | Method for preparing high-density boric acid site adsorbent based on supramolecular interface assembly strategy |
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| CN102070756A (en) * | 2010-12-10 | 2011-05-25 | 北京化工大学 | Sugar-responsive medicament delivery material and preparation method thereof |
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