CN104031207A - Self-assembling method of a galactose-containing thermo-sensitive copolymer - Google Patents

Abstract

The invention relates to a self-assembling method of a galactose-containing thermo-sensitive copolymer. The self-assembling method comprises the following steps: dissolving vinyl adipate galactose ester OVNG and diethylene glycol dimethacrylate DEGMA into a solvent, adding an evocating agent and a chain transfer agent, stirring and reacting for 10-15 hours under the protection of nitrogen to obtain a thermo-sensitive copolymer P(DEGMA-co-OVNG); preparing copolymer P (DEGMA-co-OVNG) water solutions with different concentrations, wherein the concentrations range from 0.2mg/ml to 2mg/ml, then, keeping the water solutions at the temperature of 25-50 DEG C to obtain the galactose-containing thermo-sensitive copolymer. By adopting the self-assembling method, through changing temperatures and concentrations, different forms of polymer micelles are formed, and the method has the characteristics of simple operation and obvious effect.

Description

A self-assembly method of thermosensitive copolymer containing galactose

technical field

The invention belongs to the field of preparation of temperature-sensitive materials, in particular to a self-assembly method of a temperature-sensitive copolymer containing galactose.

Background technique

Sugar plays a very important role in biological systems, which involves the recognition of a variety of biomolecules. By introducing sugar into the polymer, various sugar-containing polymers with different structures and functions can be artificially obtained. These sugar-containing copolymers have good hydrophilicity and biological specificity, and can be widely used in the field of biomedicine.

The reversible addition-fragmentation chain transfer radical polymerization (RAFT) method is the concept first proposed by Rizzardo in the report "Tailored polymers by free radical processes" at the 37th International Polymer Congress. Applying RAFT method to the synthesis of sugar-containing polymers can obtain high polymers with regular structure and small molecular weight dispersion width, which can improve the application performance of sugar-containing copolymers.

The self-assembly of nanomicelles is mainly formed by polymer polymers in solution, responding to changes in environmental factors, thereby changing their own morphology and forming aggregates. In response to temperature, the polymer can be interconverted between the relaxed linear aggregate state and the aggregated spherical micelles. High polymers with temperature-sensitive specificity can obtain an LCST close to the temperature of the human body by adjusting their LCST, and this type of material can be applied to the field of biomedical materials.

Contents of the invention

The technical problem to be solved by the present invention is to provide a self-assembly method of a galactose-containing temperature-sensitive copolymer. The invention adopts the RAFT method to synthesize a sugar-containing high polymer. The obtained polymer has a narrow molecular weight distribution and a relatively controllable reaction. The advantages.

A self-assembly method of a galactose-containing temperature-sensitive copolymer of the present invention comprises:

(1) Dissolve vinyl adipate OVNG and diethylene glycol dimethacrylate DEGMA in a solvent, add initiator and chain transfer agent at 60-80°C, and stir under nitrogen protection React for 10-15 hours to obtain a thermosensitive copolymer P(DEGMA-co-OVNG); wherein the molar ratio of OVNG to DEGMA is 1:5-1:15, and the molar ratio of chain transfer agent to initiator is 25:1-15 :1, the molar ratio of chain transfer agent to OVNG, DEGMA and is 1:120～1:80, and the mass ratio of monomer to solvent is 1:1～1:3;

(2) Prepare different concentrations of copolymer P (DEGMA-co-OVNG) aqueous solutions, the concentration range is 0.2-2mg/ml, and detect the P (DEGMA-co-OVNG) aqueous solution in UV to obtain the maximum absorption peak; then place 25-50°C to obtain a galactose thermosensitive copolymer.

The solvent in the step (1) is N,N-dimethylformamide DMF.

The initiator in the step (1) is VAZO-88.

The chain transfer agent in the step (1) is S-dodecyl-S'-(α,α'-dimethyl-α"-acetic acid)-trithiocarbonate.

The concentration gradient of the P(DEGMA-co-OVNG) aqueous solution in the step (2) is 0.2-0.4 mg/mL.

In the step (2), the maximum absorption wavelength is at 220-310 nm.

The preparation method of vinyl galactosyl adipate OVNG:

Dissolve divinyl adipate and galactose in the solvent anhydrous pyridine, add alkaline protease (Bacillus subtilis protease), and stir for 4-5 days at 40-50°C to obtain vinyl adipate half Lactose ester OVNG; the molar ratio of divinyl adipate to galactose is 1:1-4:1, the mass ratio of alkaline protease to galactose is 1:2-1:4; various related solutes The mass ratio of the sum of the mass of divinyl acid ester, galactose and alkaline protease to the solvent pyridine is 1:10-1:5.

Beneficial effect

(1) The present invention adopts the RAFT method to synthesize sugar-containing polymers, and the obtained polymers have the advantages of narrow molecular weight distribution and relatively controllable reactions;

(2) The sugar-containing copolymer synthesized by the temperature-sensitive material DEGMA in the present invention has low biological toxicity, good biocompatibility, and high sensitivity to temperature;

(3) The present invention uses water as a solvent during self-assembly, which has the advantages of safety, non-toxicity, environmental protection and cleaning;

(4) In the present invention, sugar-containing polymers with different LCSTs can be obtained by adjusting the feeding ratio of monomers, so as to obtain LCSTs close to human body temperature, and the obtained self-assembled micelles can be used as drug-loading materials.

Description of drawings

Figure 1: GPC test chart of P(DEGMA-co-OVNG);

Figure 2: UV spectrum of P(DEGMA-co-OVNG).

Detailed ways

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Example 1

(1) Dissolve DEGMA and OVNG at a molar ratio of 8:1 in 2 mL of N,N-dimethylformamide (DMF), and add the initiator azodicyclohexylcarbonitrile VAZO- 883.05mg and chain transfer agent S-dodecyl-S'-(α, α'-dimethyl-α″-acetic acid)-trithiocarbonate 9.09mg, stirred and reacted for 14h under nitrogen protection to obtain P (DEGMA-co-OVNG).

(2) Prepare the obtained sugar-containing thermosensitive copolymer into aqueous solutions with different concentrations, the concentration range is 0.2-2 mg/mL, and the concentration gradient is 0.2 mg/mL.

(3) Test the maximum absorption wavelength of the solution obtained above in an ultraviolet-visible spectrophotometer.

(4) Put the above solution in a temperature-variable ultraviolet-visible spectrophotometer, and measure its LCST value, which is about 32°C.

(5) Put the above 1 mg/mL polymer solution in a water bath at 32° C. for self-assembly to obtain temperature-sensitive sugar-containing copolymer micelles.

Example 2

(1) Dissolve DEGMA and OVNG in a molar ratio of 3:1 in 2 mL of N,N-dimethylformamide (DMF), and add the initiator azobiscyclohexylcarbonitrile VAZO- 880.27mg and chain transfer agent S-dodecyl-S'-(α, α'-dimethyl-α″-acetic acid)-trithiocarbonate 8.081mg, stirred and reacted for 14h under nitrogen protection to obtain P (DEGMA-co-OVNG).

(2) Prepare the obtained sugar-containing thermosensitive copolymer into aqueous solutions with different concentrations, the concentration range is 0.2-2 mg/mL, and the concentration gradient is 0.2 mg/mL.

(3) Test the maximum absorption wavelength of the solution obtained above in an ultraviolet-visible spectrophotometer.

(4) Put the above solution in a temperature-variable ultraviolet-visible spectrophotometer, and measure its LCST value, which is about 36°C.

(5) Put the above 1 mg/mL polymer solution in a water bath at 36° C. to allow self-assembly to obtain temperature-sensitive sugar-containing copolymer micelles.

Example 3

(1) Dissolve DEGMA and OVNG at a molar ratio of 6:1 in 2 mL of N,N-dimethylformamide (DMF), and add the initiator azobicyclohexylcarbonitrile VAZO- 883.05mg and chain transfer agent S-dodecyl-S'-(α, α'-dimethyl-α″-acetic acid)-trithiocarbonate 9.09mg, stirred and reacted for 14h under nitrogen protection to obtain P (DEGMA-co-OVNG).

(2) Prepare the obtained sugar-containing thermosensitive copolymer into aqueous solutions with different concentrations, the concentration range is 0.2-2 mg/mL, and the concentration gradient is 0.2 mg/mL.

(3) Test the maximum absorption wavelength of the solution obtained above in an ultraviolet-visible spectrophotometer.

(4) Put the above solution in a temperature-variable ultraviolet-visible spectrophotometer, and measure its LCST value, which is about 33°C.

(5) Put the above 1 mg/mL polymer solution in a water bath at 33° C. to allow self-assembly to obtain thermosensitive sugar-containing copolymer micelles.

Claims (5)

1. containing a self-assembling method for the temperature sensitive multipolymer of semi-lactosi, comprising:

(1) vinyl hexanodioic acid gala sugar ester OVNG and diethylene glycol dimethacrylate DEGMA are dissolved in solvent, under 60-80 DEG C of condition, add initiator and chain-transfer agent, under nitrogen protection, stirring reaction 10-15h, obtains temperature sensitive copolymer p (DEGMA-co-OVNG); Wherein the mol ratio of OVNG and DEGMA is 1:5～1:15, and the mol ratio of chain-transfer agent and initiator is 25:1～15:1, chain-transfer agent and OVNG, DEGMA and mol ratio be 1:120～1:80, the mass ratio of OVNG, DEGMA summation and solvent is 1:1～1:3;

(2) copolymer p (DEGMA-co-OVNG) aqueous solution of preparation different concns, concentration range is 0.2-2mg/ml, is then placed in 25-50 DEG C, obtains the temperature sensitive multipolymer of semi-lactosi.

2. a kind of self-assembling method containing the temperature sensitive multipolymer of semi-lactosi according to claim 1, is characterized in that: in described step (1), solvent is DMF DMF.

3. a kind of self-assembling method containing the temperature sensitive multipolymer of semi-lactosi according to claim 1, is characterized in that: in described step (1), initiator is VAZO-88.

4. a kind of self-assembling method containing the temperature sensitive multipolymer of semi-lactosi according to claim 1, it is characterized in that: chain-transfer agent is S-dodecyl-S'-(α, α '-dimethyl-α " acetic acid)-trithiocarbonate in described step (1).

5. a kind of self-assembling method containing the temperature sensitive multipolymer of semi-lactosi according to claim 1, is characterized in that: in described step (2), the concentration gradient of P (DEGMA-co-OVNG) aqueous solution is 0.2-0.4mg/mL.