阅读说明：本技术 一种两亲性聚酯及其制备方法和用途 (Amphiphilic polyester and preparation method and application thereof ) 是由 李智慧 单鹏飞 李大爱 柳海圩 卢颖文 李钟玉 于 2021-08-13 设计创作，主要内容包括：本发明公开了一种两亲性聚酯及其制备方法和用途。本发明以酒石酸、1,3-二溴丙烷、1,6-己二酸为原料,以二甲基亚砜或N,N-二甲基甲酰胺为原料,在四甲基胍催化下分三步反应；第一步,分别合成疏水链段A和亲水链段B,其中疏水链段A和亲水链段B的末端官能团是不同的；第二步,将疏水链段A和亲水链段B混合,反应24小时；本发明的转化率达90％以上。此外,最终制得的两亲性聚酯能够在水溶液中组装成纳米胶束,可以装载药物尤其是疏水药物；同时该聚合物具有极好的生物相容性以及生物可降解性,所用原料天然无毒。本发明的优点是：操作简单,原料易得,常温制备。(The invention discloses an amphiphilic polyester and a preparation method and application thereof. Tartaric acid, 1, 3-dibromopropane and 1, 6-adipic acid are used as raw materials, dimethyl sulfoxide or N, N-dimethylformamide is used as a raw material, and three-step reaction is carried out under the catalysis of tetramethylguanidine; step one, respectively synthesizing a hydrophobic chain segment A and a hydrophilic chain segment B, wherein the terminal functional groups of the hydrophobic chain segment A and the hydrophilic chain segment B are different; secondly, mixing the hydrophobic chain segment A and the hydrophilic chain segment B, and reacting for 24 hours; the conversion rate of the invention reaches more than 90%. In addition, the finally prepared amphiphilic polyester can be assembled into a nano micelle in an aqueous solution, and can be loaded with drugs, particularly hydrophobic drugs; meanwhile, the polymer has excellent biocompatibility and biodegradability, and the used raw materials are natural and non-toxic. The invention has the advantages that: simple operation, easily obtained raw materials and normal temperature preparation.)

1. An amphiphilic polyester characterized by:

the chemical structure is as follows:

wherein the molecular weight of the polymer of the hydrophobic segment is between 1000-12000; the polymer molecular weight of the hydrophilic segment is between 1000-12000.

2. An amphiphilic polyester according to claim 1, wherein:

the catalyst is prepared by the following reaction of the following components in parts by mole:

1, 6-adipic acid: 100 portions of

1, 3-dibromopropane: 205 to 220 portions

Solvent: 160 to 200 portions of

Catalyst: 420 to 480 portions

Tartaric acid: 80 parts of the raw materials.

3. An amphiphilic polyester according to claim 2, wherein:

the catalyst is tetramethylguanidine.

4. An amphiphilic polyester according to claim 2, wherein:

the solvent is any one of dimethyl sulfoxide and N, N-dimethylformamide.

5. The process for the preparation of an amphiphilic polyester according to claim 1, characterized in that:

the method comprises the following steps:

synthesis of hydrophobic segment a: dissolving 100 parts by mole of 1, 6-adipic acid and 120 parts by mole of 105-dibromopropane in 80-100 parts by mole of a solvent, and slowly dropping 200 parts by mole of a catalyst for reaction for 24 hours;

step two: synthesis of a hydrophilic chain segment B: dissolving 100 parts by mole of 1, 3-dibromopropane and 140 parts by mole of tartaric acid in 80-100 parts by mole of a solvent, and slowly dropping 220-280 parts by mole of a catalyst for reaction for 24 hours;

step three: and (3) synthesis of amphiphilic polyester: slowly dripping the solution obtained in the first step into the solution obtained in the second step, reacting for 12 hours, then pouring the reaction liquid into water, dialyzing for 24 hours in a dialysis bag, and freeze-drying.

6. The process for the preparation of an amphiphilic polyester according to claim 5, characterized in that:

the catalyst is tetramethylguanidine.

7. The process for the preparation of an amphiphilic polyester according to claim 5, characterized in that:

the solvent is any one of dimethyl sulfoxide and N, N-dimethylformamide.

8. The process for the preparation of an amphiphilic polyester according to claim 5, characterized in that:

the reaction temperature of the first step, the second step and the third step is room temperature.

9. Use of an amphiphilic polyester according to any one of claims 1 to 4, characterized in that:

can be used as drug carrier.

Technical Field

The invention relates to the technical field of polymer synthesis, in particular to an amphiphilic polyester and a preparation method and application thereof.

Background

Drug Delivery Systems (DDSs) are of great interest to researchers because they can achieve targeted release of drugs at tumors in time, space, and dosage. Amphiphilic Block Polymer (ABP) is a widely researched drug delivery system, can be self-assembled in an aqueous solution to form a nano micelle with a core-shell structure, and a core can play a role in loading drugs, so that the stability and water solubility of the drugs are improved. At the same time, good biocompatibility and biodegradability are essential as a drug delivery system. The linear aliphatic polyester has good biocompatibility and biodegradability, so that the linear aliphatic polyester is widely applied to the fields of tissue engineering, biomedicine and the like. Therefore, the development of amphiphilic polyester compounds is of great significance.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide an amphiphilic polyester.

In order to achieve the purpose, the invention provides the following technical scheme:

an amphiphilic polyester, which is a mixture of at least one amphiphilic polyester,

the chemical structure is as follows:

wherein the molecular weight of the polymer of the hydrophobic segment is between 1000-12000; the polymer molecular weight of the hydrophilic segment is between 1000-12000.

As a further improvement of the present invention,

the catalyst is prepared by the following reaction of the following components in parts by mole:

1, 6-adipic acid: 100 portions of

1, 3-dibromopropane: 205 to 220 portions

Solvent: 160 to 200 portions of

Catalyst: 420 to 480 portions

Tartaric acid: 80 parts of the raw materials.

As a further improvement of the present invention,

the catalyst is tetramethylguanidine.

As a further improvement of the present invention,

the solvent is any one of dimethyl sulfoxide and N, N-dimethylformamide.

As another object of the present invention, there is provided a process for producing an amphiphilic polyester,

the method comprises the following steps:

synthesis of hydrophobic segment a: dissolving 100 parts by mole of 1, 6-adipic acid and 120 parts by mole of 105-dibromopropane in 80-100 parts by mole of a solvent, and slowly dropping 200 parts by mole of a catalyst for reaction for 24 hours;

step two: synthesis of a hydrophilic chain segment B: dissolving 100 parts by mole of 1, 3-dibromopropane and 140 parts by mole of tartaric acid in 80-100 parts by mole of a solvent, and slowly dropping 220-280 parts by mole of a catalyst for reaction for 24 hours;

step three: and (3) synthesis of amphiphilic polyester: slowly dripping the solution obtained in the first step into the solution obtained in the second step, reacting for 12 hours, then pouring the reaction liquid into water, dialyzing for 24 hours in a dialysis bag, and freeze-drying.

As a further improvement of the present invention,

the catalyst is tetramethylguanidine.

As a further improvement of the present invention,

the solvent is any one of dimethyl sulfoxide and N, N-dimethylformamide.

As a further improvement of the present invention,

the reaction temperature of the first step, the second step and the third step is room temperature.

The amphiphilic polyester prepared by the invention is used as a drug carrier.

The amphiphilic polyester prepared by the invention mainly comprises two parts, one is a hydrophobic chain segment, the part without hydroxyl is the hydrophobic chain segment, the other is a hydrophilic chain segment, and the part with hydroxyl is the hydrophilic chain segment; therefore, in the preparation process, the hydrophobic chain segment and the hydrophilic chain segment are separately synthesized, and then the two chain segments are polymerized to obtain the final amphiphilic polyester, so that the separate synthesis has the advantages that the hydrophobic chain segment and the hydrophilic chain segment cannot interfere with each other, and the stable amphiphilic polyester is finally obtained.

Wherein the reaction equation of the hydrophobic segment is as follows:

wherein the reaction equation of the hydrophilic segment is:

the reaction equation for mutual polymerization of the hydrophobic segment and the hydrophilic segment is as follows:

tartaric acid, 1, 3-dibromopropane and 1, 6-adipic acid are used as raw materials, dimethyl sulfoxide or N, N-dimethylformamide is used as a raw material, and three-step reaction is carried out under the catalysis of tetramethylguanidine; step one, respectively synthesizing a hydrophobic chain segment A and a hydrophilic chain segment B, wherein the terminal functional groups of the hydrophobic chain segment A and the hydrophilic chain segment B are different; secondly, mixing the hydrophobic chain segment A and the hydrophilic chain segment B, and reacting for 24 hours; the conversion rate of the invention reaches more than 90%. In addition, the finally prepared amphiphilic polyester can be assembled into a nano micelle in an aqueous solution, and can be loaded with drugs, particularly hydrophobic drugs; meanwhile, the polymer has excellent biocompatibility and biodegradability, and the used raw materials are natural and non-toxic. The invention has the advantages that: simple operation, easily obtained raw materials and normal temperature preparation.

Drawings

FIG. 1 is a nuclear magnetic spectrum of a hydrophobic segment polymer A of example 2;

FIG. 2 is a nuclear magnetic spectrum of a hydrophilic segment polymer B of example 2;

FIG. 3 is a nuclear magnetic spectrum of the amphiphilic polymer of example 2;

FIG. 4 shows the fluorescence absorption spectrum of the amphiphilic polymer of example 2 before and after wrapping Nile red;

FIG. 5 is fluorescence absorption spectra of amphiphilic polymer coated nile red of example 2 in PBS solution at pH5.0 for various times;

FIG. 6 is fluorescence absorption spectrum of amphiphilic polymer coated nile red of example 2 in PBS solution at pH7.4 for different time periods;

FIG. 7 is fluorescence absorption spectra of amphiphilic polymer coated nile red of example 2 in PBS solution at pH9.0 for various times;

FIG. 8 is an assembled electron micrograph of the amphiphilic polymer of example 2;

fig. 9 is a DLS plot of the amphiphilic polymer of example 2.

Detailed Description

The invention will be further described in detail with reference to the following examples, which are given in the accompanying drawings.

Example 1

Synthesizing an amphiphilic polymer;

the method comprises the following steps: synthesis of hydrophobic segment a: 0.68g of 1, 6-adipic acid and 1.01gde1, 3-dibromopropane are dissolved in 6ml of dimethyl sulfoxide, and then 1.08g of tetramethylguanidine is slowly dropped to react for 24 hours;

step two: synthesis of a hydrophilic chain segment B: 1.94g of 1, 3-dibromopropane and 1.50g of tartaric acid are dissolved in 10ml of dimethyl sulfoxide, and then 2.30g of tetramethylguanidine is slowly dropped to react for 24 hours;

step three: and (3) synthesis of amphiphilic polyester: slowly dripping the solution obtained in the step one into the solution obtained in the step two, reacting for 12 hours, pouring the reaction liquid into water, dialyzing for 24 hours in a dialysis bag, and then freeze-drying.

Example 2

Synthesis of amphiphilic polymer:

the method comprises the following steps: synthesis of hydrophobic segment a: 0.69g of 1, 6-adipic acid and 1.01g of 1, 3-dibromopropane are dissolved in 6ml of dimethyl sulfoxide, and then 1.10g of tetramethylguanidine is slowly dropped to react for 24 hours;

step two: synthesis of a hydrophilic chain segment B: 1.94g of 1, 3-dibromopropane and 1.50g of tartaric acid are dissolved in 10ml of dimethyl sulfoxide, and then 2.30g of tetramethylguanidine is slowly dropped to react for 24 hours;

step three: and (3) synthesis of amphiphilic polyester: slowly dripping the solution obtained in the step one into the solution obtained in the step two, reacting for 12 hours, pouring the reaction liquid into water, dialyzing for 24 hours in a dialysis bag, and then freeze-drying.

Example 3

Synthesis of amphiphilic polymers

The method comprises the following steps: synthesis of hydrophobic segment a: 0.70g of 1, 6-adipic acid and 1.01g of 1, 3-dibromopropane are dissolved in 6ml of dimethyl sulfoxide, and then 1.11g of tetramethylguanidine is slowly dropped to react for 24 hours;

step two: synthesis of a hydrophilic chain segment B: 1.94g of 1, 3-dibromopropane and 1.50g of tartaric acid are dissolved in 10ml of dimethyl sulfoxide, and then 2.30g of tetramethylguanidine is slowly dropped to react for 24 hours;

step three: and (3) synthesis of amphiphilic polyester: slowly dripping the solution obtained in the step one into the solution obtained in the step two, reacting for 12 hours, pouring the reaction liquid into water, dialyzing for 24 hours in a dialysis bag, and then freeze-drying.

And (3) detection:

1. the hydrophobic segment a, the hydrophilic segment B, and the final product obtained in example 2 were subjected to nuclear magnetic detection, and fig. 1, fig. 2, and fig. 3 were obtained, respectively.

2. Wrapped nile red experiment:

(1) accurately weighing 200mg of the amphiphilic polymer synthesized in the example 2, and dissolving the amphiphilic polymer in 2ml of dimethyl sulfoxide to form a solution A;

(2) accurately weighing 200mg of the amphiphilic polymer synthesized in the embodiment 2 and 40mg of nile red, and dissolving the amphiphilic polymer and the nile red in 2ml of dimethyl sulfoxide to form a solution B;

(3) dripping the solution A and the solution B into 100ml of vigorously stirred pure water respectively, stirring for 3 hours, and then pouring into dialysis bags respectively for dialysis for 24 hours to obtain emulsion C and emulsion D respectively;

(4) respectively taking 4ml of emulsion C and emulsion D, and carrying out fluorescence absorption test to obtain the front and back fluorescence absorption spectra of the amphiphilic polymer coated Nile red (figure 4);

(5) adding 1ml of emulsion D into 4ml of buffer solution with pH value of 5.0, pH value of 7.4 and pH value of 9.0 to obtain emulsion E, emulsion F and emulsion G, and performing fluorescence absorption test at different time to obtain fluorescence absorption spectra of the amphiphilic polymer in buffer solutions with different pH values at different time (corresponding to FIG. 5, FIG. 6 and FIG. 7 respectively).

3. The polymer obtained in example 2 was examined by a scanning electron microscope, and fig. 8 was obtained.

4. The polymer obtained in example 2 was analyzed for particle size by a nanosize particle size analyzer (DLS) and a ZETA potential analyzer (DLS), and fig. 9 was obtained.

The amphiphilic polyester prepared by the invention mainly comprises two parts, one is a hydrophobic chain segment, and the other is a hydrophilic chain segment; therefore, in the preparation process, the hydrophobic chain segment and the hydrophilic chain segment are separately synthesized, and then the two chain segments are polymerized to obtain the final amphiphilic polyester, so that the separate synthesis has the advantages that the hydrophobic chain segment and the hydrophilic chain segment cannot interfere with each other, and the stable amphiphilic polyester is finally obtained.

Wherein the reaction equation of the hydrophobic segment is as follows:

wherein the reaction equation of the hydrophilic segment is:

the reaction equation for mutual polymerization of the hydrophobic segment and the hydrophilic segment is as follows:

as can be seen from fig. 1 to 3, the polymers contemplated in examples 1 to 3 were all synthesized.

And as can be seen from fig. 4, emulsion C does not contain nile red and does not fluoresce when directly exposed to an aqueous solution, and thus does not fluoresce in the fluorescence absorption spectrum, whereas emulsion D does fluoresce in the fluorescence absorption spectrum, thus illustrating that the polymer prepared in example 2 can carry hydrophobic drugs.

Fig. 5 to 7 show the release of the drug at different pH values, and the drug is released continuously with time, so that the fluorescence decreases.

FIG. 8 illustrates that the amphiphilic polymer can be assembled into nano-sized particles, and the morphology of the particles is reflected by an electron microscope and is spherical

The DLS diagram of fig. 9 reflects the size and size distribution of the assembled nanoparticles, and the particle sizes are mainly distributed around 100nm, so it is said that the particles with a size of 100nm can be enriched in solid tumors, thereby achieving the purpose of targeted delivery.

Tartaric acid, 1, 3-dibromopropane and 1, 6-adipic acid are used as raw materials, dimethyl sulfoxide or N, N-dimethylformamide is used as a raw material, and three-step reaction is carried out under the catalysis of tetramethylguanidine; step one, respectively synthesizing a hydrophobic chain segment A and a hydrophilic chain segment B, wherein the terminal functional groups of the hydrophobic chain segment A and the hydrophilic chain segment B are different; secondly, mixing the hydrophobic chain segment A and the hydrophilic chain segment B, and reacting for 24 hours; the conversion rate of the invention reaches more than 90%. In addition, the finally prepared amphiphilic polyester can be assembled into a nano micelle in an aqueous solution, and can be loaded with drugs, particularly hydrophobic drugs; meanwhile, the polymer has excellent biocompatibility and biodegradability, and the used raw materials are natural and non-toxic. The invention has the advantages that: simple operation, easily obtained raw materials and normal temperature preparation.

The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.