CN103992483A - A drug delivery material with sugar, temperature and pH triple sensitivities and a preparing method thereof - Google Patents

Abstract

The invention belongs to the fields of polymer materials and biomedical engineering, and particularly relates to a drug delivery material with sugar, temperature and pH triple sensitivities, and a preparing method thereof. The preparing method mainly includes a first step of triggering polymerization of a monomer PpBDEMA by adopting ABIB as an ATRP initiator to obtain a polymer I; and a second step of triggering polymerization of a monomer DMAEMA by adopting 21-beta-CD as an ATRP initiator to obtain a polymer II. The polymer I has an adamantane structure and the polymer II has a beta-cyclodextrin structure, and the polymer I and the polymer II can be subjected to self-assembly to obtain a supermolecule. According to the drug delivery material, through self-assembly in an aqueous solution, a nanometer drug delivery carrier is obtained, and an amphiphilic polymer converts from hydrophobicity to hydrophilicity at the high concentration of blood sugar, thus releasing a carried drug molecule.

Description

A kind of drug delivering material with sugar, temperature and the triple susceptibility of pH and preparation method thereof

Technical field

The invention belongs to macromolecular material and biomedical engineering field, be specifically related to a kind of drug delivering material with sugar, temperature and the triple susceptibility of pH and preparation method thereof.

Background technology

The application of intelligent polymkeric substance aspect biotechnology is in recent years more and more wider, as drug delivery, and biosensor, diagnostic techniques, organizational project aspect.Diabetes are a kind of metabolic diseases taking hyperglycemia as feature.Hyperglycemia makes due to defect of insulin secretion and biological action is impaired causes, can cause various tissues, particularly chronic lesion, the dysfunction of eye, kidney, heart, blood vessel, nerve, reducing blood sugar is the main method for the treatment of at present diabetes, traditional injection and drug administration need doctor and patient strictly to control the consumption of medicine, and long-time use also can make patient produce resistance and cause Diabetic liver injury of the kidney.So, find a kind of sugared response medicine carrier particularly important for the treatment of diabetes.Phenylo boric acid and derivative thereof have sugar response, and this sugared Response System can realize the controllable release of medicine.In the aqueous solution, there is two states in phenylo boric acid derivative, electronegative tetrahedral structure can form stable borate ester structure with glucose complexing, it is water-soluble, and the phenylo boric acid of neutral trihedron structure and glucose form unsettled ring texture.By changing pH, and the concentration of glucose in solutions realizes the object of phenylo boric acid system sustained-release administration.This method can convenient and safely discharge medicine in the high site of disease selectivity of blood sugar concentration intelligently, reaches the object of efficient treatment.

At present, most sugars responsive polymer drug delivering material is all to introduce sugared response type functional group in polymer architecture by the amino of amino-benzene boric acid, completes intelligent drug conveying, but cannot solve in physiological pH, the controllable release under physiological temp condition.

Summary of the invention

The object of the invention is to synthetic hyperbranched polymer, thematic structure novelty has sugar simultaneously, the triple responsivenesss of pH and temperature.Supermolecule polymer provided by the present invention can carry out sugar response under human body environment (37 DEG C, pH=7.4), good biocompatibility before and after response, and hyperglycemia concentration realizes the intelligent release of medicine under stimulating.

A kind of drug delivering material with sugar, temperature and the triple susceptibility of pH that the present invention proposes, the structural formula of described drug delivering material is:

Wherein, m is 48-80, and n is 4-8.

The one that the present invention proposes has sugar, the preparation method of the drug delivering material of temperature and the triple susceptibility of pH, and concrete steps are as follows: (between raw material, lack proportionlity, lack feasible scope)

(1) under nitrogen protection; ABIB initiator, cuprous bromide, ATRP part PMDETA and PpBDEMA monomer are dissolved in methyl-phenoxide with mol ratio 1:1.2:1.2:60-100; at 88-92 DEG C, stir 18-60 hour; concentrated in the mixed solution of normal hexane and ether, precipitate after removing mantoquita, obtain Ad-PpBDEMA polymkeric substance:

M is 48-80,

(2) under nitrogen protection, 21Cl-β-CD initiator, cuprous chloride, ATRP part and DMAEMA monomer are dissolved in dry DMF with mol ratio 1:1.2:1.2:60-100, at 38-45 DEG C, react 50-70 minute, concentrated in normal hexane, precipitate after removing mantoquita, dialyse and within 48 hours, remove DMF freeze-drying except anhydrating, obtain star-type polymer 21-β-CD-DMAEMA;

N is 4-8,

3) 21-β-CD-DMAEMA that the step that is 5:1 by mol ratio (2) obtains, the Ad-PpBDEMA that step (1) obtains is dissolved in THF, at room temperature stirs 40-50 hour, obtains Supramolecular Assembling polymkeric substance , be required drug delivering material.

The present invention has following beneficial effect:

1) sugared response polymer drug delivering material provided by the present invention has sugar response functional group, and its special hydrophobic segment structure can provide self-assembly power in water, forms nano particle.

2) the small molecules phenylo boric acid sugar ester after sugared response polymer drug delivering material itself provided by the present invention and sugar response and the polymkeric substance that becomes double-hydrophilic all have good biocompatibility.After polymkeric substance provided by the invention and sugar response, phenylo boric acid comes off and sugar forms small molecules complex compound from polymkeric substance, and the metabolism of phenylo boric acid in just can satellite excretes thus, has good biocompatibility.

3) the present invention has sugar, temperature, and the triple responsivenesss of pH, can better must be used for drug release, chemical sensor and polymkeric substance and the field such as separate.

Brief description of the drawings

Fig. 1: the functionalized flat BDEMA of ATRP initiator 2-isobutyl bromide-1-diamantane ester trigger monomer P of diamantane generates the nuclear-magnetism figure of Ad-PpBDEMA;

Fig. 2: the functionalized ATRP initiator 21Cl-β-CD of beta-cyclodextrin causes DMAEMA monomer and generates 21-β-CD-DMAEMA.

Embodiment

Elaborate below by embodiment: the present embodiment is implemented under taking technical solution of the present invention as prerequisite, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to subordinate's embodiment.

Embodiment 1:

1) 0.03g (0.1mmol) ABIB initiator, 0.0208g (0.12mmol) ATRP part PMDETA and 2.73g (10mmol) PpBDEMA monomer are dissolved in 2.5ml methyl-phenoxide, the freezing circulation three times of bleeding, last when freezing to the logical nitrogen of system, add 1.12mg (0.1mmol) cuprous bromide, the logical nitrogen of deoxygenation is at 90 DEG C, stir 40 hours, concentrated in the mixed solution of normal hexane and ether, precipitate after removing mantoquita, obtain Ad-PpBDEMA polymkeric substance :

2) 0.2821g (2.835mmol) 21Cl-β-CD initiator, 0.4913g (2.835mmol) ATRP part and 4.4569g (28.35mmol) DMAEMA monomer are dissolved in the DMF that 16ml is dry, the freezing circulation three times of bleeding, last when freezing to the logical nitrogen of system, add 0.2821g (2.835mmol) cuprous bromide, the logical nitrogen of deoxygenation reacts 1 hour at 40 DEG C, concentrated removing after mantoquita precipitated with normal hexane, DMF is removed in dialysis, obtains star-type polymer 21-β-CD-DMAEMA.

3) by 0.114mmol21-β-CD-DMAEMA, 0.023mmolAd-PpBDEMA is dissolved in 30ml THF, at room temperature stirs 48 hours, and the dialysis membrane with 80000 is dialysed and within 72 hours, obtained Supramolecular Assembling polymkeric substance .

Embodiment 2:

1) 0.03g (0.1mmol) ABIB initiator, 0.0208g (0.12mmol) ATRP part PMDETA and 2.18g (8mmol) PpBDEMA monomer are dissolved in 2.5ml methyl-phenoxide, the freezing circulation three times of bleeding, last when freezing to the logical nitrogen of system, add 1.12mg (0.1mmol) cuprous bromide, the logical nitrogen of deoxygenation is at 90 DEG C, stir 40 hours, concentrated in the mixed solution of normal hexane and ether, precipitate after removing mantoquita, obtain Ad-PpBDEMA polymkeric substance :

2) with embodiment 1 step 2);

3) with embodiment 1 step 3).

Embodiment 3

1) 0.03g (0.1mmol) ABIB initiator, 0.0208g (0.12mmol) ATRP part PMDETA and 1.36g (5mmol) PpBDEMA monomer are dissolved in 2.5ml methyl-phenoxide, the freezing circulation three times of bleeding, last when freezing to the logical nitrogen of system, add 1.12mg (0.1mmol) cuprous bromide, the logical nitrogen of deoxygenation is at 90 DEG C, stir 40 hours, concentrated in the mixed solution of normal hexane and ether, precipitate after removing mantoquita, obtain Ad-PpBDEMA polymkeric substance :

2) with embodiment 1 step 2);

3) with embodiment 1 step 3).

Embodiment 4

1) with embodiment 1 step 1);

2) 0.2821g (2.835mmol) 21Cl-β-CD initiator, 0.4913g (2.835mmol) ATRP part and 3.5655g (22.68mmol) DMAEMA monomer are dissolved in the DMF that 16ml is dry, the freezing circulation three times of bleeding, last when freezing to the logical nitrogen of system, add 0.2821g (2.835mmol) cuprous bromide, the logical nitrogen of deoxygenation reacts 1 hour at 40 DEG C, concentrated removing after mantoquita precipitated with normal hexane, DMF is removed in dialysis, obtains star-type polymer 21-β-CD-DMAEMA.

3) with embodiment 1 step 3).

Embodiment 5

1) with embodiment 1 step 1);

2) 0.2821g (2.835mmol) 21Cl-β-CD initiator, 0.4913g (2.835mmol) ATRP part and 2.6741g (17.01mmol) DMAEMA monomer are dissolved in the DMF that 16ml is dry, the freezing circulation three times of bleeding, last when freezing to the logical nitrogen of system, add 0.2821g (2.835mmol) cuprous bromide, the logical nitrogen of deoxygenation reacts 1 hour at 40 DEG C, concentrated removing after mantoquita precipitated with normal hexane, DMF is removed in dialysis, obtains star-type polymer 21-β-CD-DMAEMA;

3) with embodiment 1 step 3).

Claims (2)

1. there is a drug delivering material for sugar, temperature and the triple susceptibility of pH, it is characterized in that the structural formula of described drug delivering material is:

Wherein, m is 48-80, and n is 4-8.

2. as claimed in claim 1 have a sugar, and the preparation method of the drug delivering material of temperature and the triple susceptibility of pH, is characterized in that concrete steps are as follows:

(1) under nitrogen protection; ABIB initiator, cuprous bromide, ATRP part PMDETA and PpBDEMA monomer are dissolved in methyl-phenoxide with mol ratio 1:1.2:1.2:60-100; at 88-92 DEG C, stir 18-60 hour; concentrated in the mixed solution of normal hexane and ether, precipitate after removing mantoquita, obtain Ad-PpBDEMA polymkeric substance:

M is 48-80,

(2) under nitrogen protection; 21Cl-β-CD initiator, cuprous chloride, ATRP part and DMAEMA monomer are dissolved in dry DMF with mol ratio 1:21:21:60-100; at 38-45 DEG C, react 50-70 minute; concentrated in normal hexane, precipitate after removing mantoquita; dialyse and within 48 hours, remove DMF freeze-drying except anhydrating, obtain star-type polymer 21-β-CD-DMAEMA:

N is 4-8,

3) 21-β-CD-DMAEMA that the step that is 5:1 by mol ratio (2) obtains, the Ad-PpBDEMA that step (1) obtains is dissolved in THF, at room temperature stirs 40-50 hour, obtains Supramolecular Assembling polymkeric substance , be required drug delivering material.