阅读说明：本技术 一种聚二硫缩醛及其制备方法和应用 (Poly-dithioacetal and preparation method and application thereof ) 是由 袁友永 宗庆瑜 王可伟 肖炫 姜茂麟 李佶锶 于 2020-06-17 设计创作，主要内容包括：本发明公开了一种聚二硫缩醛及其制备方法和应用。本发明的聚二硫缩醛具有良好的生物相容性和可降解性,可在水相中自组装形成纳米颗粒并用作疏水性抗癌药物的运输载体,在肿瘤细胞内溶酶体酸性和高谷胱甘肽含量的环境中可以快速释放出颗粒内核中的疏水性抗癌药物,放大肿瘤细胞内的氧化应激水平,从而有效逆转耐药,具有巨大的临床应用潜能。(The invention discloses a polydithioacetal, a preparation method and application thereof. The polydithioacetal disclosed by the invention has good biocompatibility and degradability, can be self-assembled in a water phase to form nanoparticles and used as a transport carrier of a hydrophobic anticancer drug, can quickly release the hydrophobic anticancer drug in particle cores in the environment with lysosome acidity and high glutathione content in tumor cells, and can amplify the oxidative stress level in the tumor cells, so that the drug resistance is effectively reversed, and the polydithioacetal has huge clinical application potential.)

1. A polydithioacetal characterized by: the structural formula is as follows:

wherein m is a natural number of 110 to 117, and n is a natural number of 10 to 16.

2. The process for producing polydithioacetal according to claim 1, wherein: the method comprises the following steps:

1) carrying out a reaction of cinnamaldehyde and trimethyl orthoformate to obtain cinnamaldehyde methyl acetal;

2) carrying out a reaction of cinnamaldehyde methyl acetal and 2-hydroxyethyl disulfide to obtain a cinnamaldehyde disulfide monomer;

3) and carrying out polymerization reaction on the cinnamaldehyde disulfide monomer and hexamethylene diisocyanate, and terminating the reaction by methoxy polyethylene glycol to obtain the polydithio acetal.

3. The method of claim 2, wherein: the method comprises the following steps:

1) dispersing cinnamaldehyde, trimethyl orthoformate and an acidic catalyst in a solvent for reaction, and separating and purifying a product to obtain cinnamaldehyde methyl acetal;

2) dispersing cinnamaldehyde methyl acetal, 2-hydroxyethyl disulfide and an acidic catalyst in a solvent for reaction, and then separating and purifying a product to obtain a cinnamaldehyde disulfide monomer;

3) dispersing a cinnamaldehyde disulfide monomer, hexamethylene diisocyanate and a catalyst in a solvent, carrying out polymerization reaction, adding methoxy polyethylene glycol to terminate the reaction, and separating and purifying the product to obtain the polydithio acetal.

4. The production method according to claim 2 or 3, characterized in that: the mol ratio of the cinnamaldehyde to the trimethyl orthoformate in the step 1) is 1: (2-4).

5. The production method according to claim 3, characterized in that: the acid catalyst in the steps 1) and 2) is at least one of p-toluenesulfonic acid monohydrate, concentrated sulfuric acid and ferric sulfate.

6. The production method according to claim 2 or 3, characterized in that: the mol ratio of the cinnamaldehyde methyl acetal to the 2-hydroxyethyl disulfide in the step 2) is 1: (2-4).

7. The production method according to claim 2 or 3, characterized in that: the mol ratio of the cinnamaldehyde disulfide monomer to the hexamethylene diisocyanate in the step 3) is 1: (0.9-1.1).

8. The production method according to claim 2 or 3, characterized in that: the number average molecular weight of the methoxypolyethylene glycol in the step 3) is 4000-6000 g/mol.

9. The production method according to claim 3, characterized in that: the catalyst in the step 3) is at least one of an organic tin catalyst, dimethylcyclohexylamine and an organic bismuth catalyst.

10. Use of polydithioacetals as claimed in claim 1 for the preparation of drug-loaded nanoparticles.

Technical Field

The invention relates to polydithioacetal and a preparation method and application thereof, belonging to the technical field of polymer materials.

Background

During chemotherapy, cancer cells evolve continuously to generate multidrug resistance (MDR), which can severely limit the efficacy of tumor therapy and affect the survival and quality of life of patients. In methods of reversing multidrug resistance, modulating Reactive Oxygen Species (ROS) levels is a more effective method of killing multidrug resistant cancer cells with diverse mechanisms. Active oxygen in cancer cells plays an important role in regulating and inducing apoptosis, and is closely related to proliferation, survival and drug resistance of cancer cells. Compared with non-drug resistant cancer cells and normal cells, the active oxygen level and the antioxidant enzyme activity of the drug resistant cancer cells are obviously increased, so that the multi-drug resistant cancer cells are more easily affected by the change of the active oxygen level. A large number of studies have shown that compounds that modulate the level of reactive oxygen species in cells can sensitize multidrug resistant cancer cells to chemotherapeutic drugs.

The nano-drug carrier is a nano-level drug carrier delivery system, and the drug is encapsulated in the particles or adsorbed on the surfaces of the particles so as to adjust the drug release speed, increase the permeability of a biological membrane, change the distribution of the drug in the body, improve the bioavailability of the drug and the like. The nano drug-loading technology is one of the important development directions of nano biotechnology and modern pharmaceutical technology, and has wide application prospect in the research of the application aspect of the medical field.

Therefore, the development of a material for conveying the anticancer drugs, the improvement of the concentration of the anticancer drugs in drug-resistant cells, the realization of the rapid release of the anticancer drugs in cells, and the amplification of the oxidative stress level in tumor cells, thereby effectively reversing the drug resistance, has great significance.

Disclosure of Invention

The invention aims to provide polydithioacetal, a preparation method and application thereof.

The technical scheme adopted by the invention is as follows:

a polydithioacetal having the formula:

wherein m is a natural number of 110 to 117, and n is a natural number of 10 to 16.

The preparation method of the polydithioacetal comprises the following steps:

1) carrying out a reaction of cinnamaldehyde and trimethyl orthoformate to obtain cinnamaldehyde methyl acetal;

2) carrying out a reaction of cinnamaldehyde methyl acetal and 2-hydroxyethyl disulfide to obtain a cinnamaldehyde disulfide monomer;

3) and carrying out polymerization reaction on the cinnamaldehyde disulfide monomer and hexamethylene diisocyanate, and terminating the reaction by methoxy polyethylene glycol to obtain the polydithio acetal.

Preferably, the method for producing polydithioacetal includes the steps of:

1) dispersing cinnamaldehyde, trimethyl orthoformate and an acidic catalyst in a solvent for reaction, and separating and purifying a product to obtain cinnamaldehyde methyl acetal;

2) dispersing cinnamaldehyde methyl acetal, 2-hydroxyethyl disulfide and an acidic catalyst in a solvent for reaction, and then separating and purifying a product to obtain a cinnamaldehyde disulfide monomer;

3) dispersing a cinnamaldehyde disulfide monomer, hexamethylene diisocyanate and a catalyst in a solvent, carrying out polymerization reaction, adding methoxy polyethylene glycol to terminate the reaction, and separating and purifying the product to obtain the polydithio acetal.

Preferably, the molar ratio of the cinnamaldehyde to the trimethyl orthoformate in the step 1) is 1: (2-4).

Preferably, the acidic catalyst in step 1) and step 2) is at least one of p-toluenesulfonic acid monohydrate, concentrated sulfuric acid and ferric sulfate.

Preferably, the addition amount of the acid catalyst in the step 1) is 3 to 5 percent of the mass of the cinnamaldehyde.

Preferably, the solvent in step 1) is at least one of methanol, dichloromethane and tetrahydrofuran.

Preferably, the reaction in the step 1) is carried out in a heating reflux state, and the reaction time is 3-5 h.

Preferably, the molar ratio of the cinnamaldehyde methyl acetal to the 2-hydroxyethyl disulfide in the step 2) is 1: (2-4).

Preferably, the addition amount of the acidic catalyst in the step 2) is 0.5 to 1 percent of the mass of the cinnamaldehyde methyl acetal.

Preferably, the solvent in step 2) is at least one of benzene, toluene and 1, 4-dioxane.

Preferably, the reaction in the step 2) is carried out in a heating reflux state, and the reaction time is 36-48 h.

Preferably, the molar ratio of the cinnamaldehyde disulfide monomer to the hexamethylene diisocyanate in the step 3) is 1: (0.9-1.1).

Preferably, the number average molecular weight of the methoxypolyethylene glycol in the step 3) is 4000-6000 g/mol.

Preferably, the adding amount of the methoxy polyethylene glycol in the step 3) is 0.02-0.05% of the mass of the hexamethylene diisocyanate.

Preferably, the catalyst in step 3) is at least one of an organotin catalyst, dimethylcyclohexylamine and an organobismuth catalyst.

Preferably, the addition amount of the tin catalyst in the step 3) is 5-10% of the mass of the hexamethylene diisocyanate.

Preferably, the solvent in step 3) is at least one of tetrahydrofuran, dichloromethane and acetonitrile.

The invention has the beneficial effects that: the polydithioacetal disclosed by the invention has good biocompatibility and degradability, can be self-assembled in a water phase to form nanoparticles and used as a transport carrier of a hydrophobic anticancer drug, can quickly release the hydrophobic anticancer drug in particle cores in the environment with lysosome acidity and high glutathione content in tumor cells, and can amplify the oxidative stress level in the tumor cells, so that the drug resistance is effectively reversed, and the polydithioacetal has huge clinical application potential.

Drawings

FIG. 1 is a scheme showing the synthesis of polydithioacetals of the present invention.

FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of cinnamaldehyde methyl acetal.

FIG. 3 is a NMR spectrum of cinnamaldehyde disulfide monomer.

FIG. 4 shows the NMR spectrum of polydithioacetal.

Figure 5 is a graph of the particle size distribution of drug-loaded nanoparticle CD-NP in aqueous solution.

FIG. 6 is a graph showing the variation of the particle size of drug-loaded nanoparticle CD-NP under different conditions.

Figure 7 is a graph of in vitro drug release profiles of drug-loaded nanoparticle CD-NP under different conditions.

FIG. 8 is a graph of the flow cytometry detection of the uptake of drug-loaded nanoparticles CD-NP by tumor cells.

FIG. 9 is a graph of the uptake of drug-loaded nanoparticles CD-NP by tumor cells observed by laser confocal imaging.

FIG. 10 is a graph showing the amplification of intracellular oxidative stress of polydithioacetal.

FIG. 11 is a graph showing the effect of drug-loaded nanoparticle CD-NP on killing of MCF-7 and MCF-7/ADR cells.

Figure 12 is a graph of in vivo distribution assays of drug-loaded nanoparticle CD-NPs.

Figure 13 is a graph of in vivo treatment trials of drug-loaded nanoparticle CD-NP.

FIG. 14 is a graph showing the change in body weight of mice in each experimental group in an in vivo treatment experiment.

Detailed Description

The invention will be further explained and illustrated with reference to specific examples.