阅读说明：本技术 一种MAA-co-DAA-co-PEGMA共聚物及其制备方法和应用 (MAA-co-DAA-co-PEGMA copolymer and preparation method and application thereof ) 是由 赵旭波 邱雨点 刘仲毅 于 2019-10-24 设计创作，主要内容包括：本发明属于药物载体技术领域,公开一种MAA-co-DAA-co-PEGMA共聚物及其制备方法和应用。结构式如下：。制备方法：分别将TBDMS-DAA、BACy溶解于DMF中,获得TBDMS-DAA溶液和BACy溶液；将TBAF溶解于THF中,获得TBAF溶液；在氮气氛围下,将MAA、TBDMS-DAA溶液、PEGMA、BACy溶液和SDS加入水中,混合,搅拌下加热至40~100℃,加入APS,反应5~10 h后,离心洗涤,冷冻干燥；将干燥产物加入到TBAF溶液中,搅拌,离心收集沉淀物,THF洗涤,水洗并冷冻干燥即得MAA-co-DAA-co-PEGMA共聚物。本发明MAA-co-DAA-co-PEGMA共聚物作为药物载体,载药量较高,能够解决药物自身的疏水性问题。(The invention belongs to the technical field of drug carriers, and discloses an MAA ‑co‑ DAA ‑co‑ PEGMA copolymer and a preparation method and application thereof. The structural formula is as follows: . The preparation method comprises the following steps: respectively dissolving TBDMS-DAA and BACy in DMF to obtain TBDMS-DAA solution and BACy solution; dissolving TBAF in THF to obtain a TBAF solution; adding MAA, TBDMS-DAA solution, PEGMA, BACy solution and SDS into water under nitrogen atmosphere, and mixingMixing, heating to 40 ~ 100 deg.C under stirring, adding APS, reacting for 5 ~ 10h, centrifuging, washing, freeze drying, adding the dried product into TBAF solution, stirring, centrifuging, collecting precipitate, washing with THF, washing with water, and freeze drying to obtain MAA ‑co‑ DAA ‑co‑ PEGMA copolymer. MAA of the invention ‑co‑ DAA ‑co‑ The PEGMA copolymer is used as a drug carrier, has high drug loading rate and can solve the problem of hydrophobicity of the drug.)

1. MAA-co-DAA-co-PEGMA copolymer characterized by the structural formula:

。

2. the MAA of claim 1-co-DAA-co-PEGMA copolymer is characterized in that a, b, c and d are positive integers, and a: b: c: d = (1 ~ 32): 1: 2.

3. A MAA as claimed in claim 1 or 2-co-DAA-co-A process for the preparation of PEGMA copolymers, characterized in that:

(1) respectively dissolving TBDMS-DAA and BACy in DMF to obtain TBDMS-DAA solution and BACy solution; dissolving TBAF in THF to obtain a TBAF solution;

(2) adding MAA, TBDMS-DAA solution, PEGMA, BACy solution and SDS into water under nitrogen atmosphere, mixing, heating to 40 ~ 100 deg.C under stirring, adding APS, reacting for 5 ~ 10h, centrifuging, washing, and freeze drying;

(3) adding the product obtained in the step (2) into TBAF solution, stirring, centrifugally collecting precipitate, washing with THF, washing with water and freeze-drying to obtain MAA-co-DAA-co-PEGMA copolymer.

4. The MAA of claim 3-co-DAA-co-The PEGMA copolymer is prepared by PEGMA with weight average molecular weight of 300 ~ 2000.

5. The MAA of claim 3-co-DAA-co-A process for the preparation of PEGMA copolymers, characterized in that:

in the step (1), the concentration of the TBDMS-DAA solution is 90 ~ 270 mg/mL, the concentration of the BACy solution is 50 ~ 170 mg/mL, and the concentration of the TBAF solution is 0.1 ~ 0.4.4 mol/L;

in the step (2), the molar ratio of MAA, BACy, PEGMA and TBDMS-DAA is (1 ~ 32): 1: 2, the total input amount of APS is (1 ~ 3)/1000 of the total mass of MAA, PEGMA and TBDMS-DAA, and the consumption of water is 10 ~ 15 times of the total volume of TBDMS-DAA solution and BACy solution, and the concentration of SDS in the mixed solution in the step (2) is 1.5 ~ 2.0.0 g/L;

in the step (3), the amount of TBAF used is 3 ~ 10 times the amount of TBDMS-DAA charged in the step (2) on a molar basis.

6. A MAA as claimed in claim 1 or 2-co-DAA-co-The use of PEGMA copolymers as drug carriers.

Technical Field

The invention belongs to the technical field of drug carriers, and particularly relates to MAA-co-DAA-co-PEGMA copolymer and a preparation method and application thereof.

Background

Cancer has long been a significant disease threatening human life, and a study reported by the U.S. cable television news network (CNN) has shown that: the number of cancer patients in the world is still continuously increasing, and nearly 1810 ten thousand cancer diagnosis cases exist in 2018 alone, wherein 992 ten thousand people die of cancer, and the cancer death rate is more than half. According to the report released by the world health organization international cancer research institution on 9/12 days, by the end of this century, cancer will become the first killer worldwide and is the biggest obstacle to improving the life expectancy of people. Better treatment of cancer is achieved not only based on the high efficacy of anticancer drugs, but also the need for synergy of the antitumor drug delivery system and the high efficacy of drug release. Due to the high permeability and retention effect of tumor tissues, the nanoparticles are preferentially enriched at the tumor focus part, the passive targeted therapy of the tumor is realized to a certain extent, and the research heat of researchers on a targeted drug delivery system is stimulated.

The Hu subject group utilizes mesoporous silica nano material coated with polystyrene latex to load Bortezomib (BTZ) to prepare nanoparticles with the particle size of about 140 nm and the drug loading of 1.87 wt.%. Compared with free BTZ, the toxicity of H1299 non-small cell lung cancer cells of the drug-loaded nanoparticles is improved by 2.3 times, and in-vivo treatment experiments also show that the tumor inhibition effect of the drug-loaded nanoparticles is improved by about 1.5 times, but the cumulative release amount of the drug-loaded nanoparticles in phosphate buffer solution for 8 hours is about 68%, which shows that the drug-loaded nanoparticles are likely to have the problem of drug leakage under physiological conditions. The drug-loaded nanoparticles prepared by the authors by adopting a single emulsion technology have the drug-loaded efficiency of about 53%, the actual drug-loaded amount of BTZ is 5.1 wt%, and the particle size is 195 nm, the nanoparticles show obvious toxicity to S2-013 human pancreatic cancer cells, the half-inhibitory concentration is about 7.5 mM, and in vitro release data show that the PLGA nanoparticles can only release 25% of BTZ in 24 h.

In the past, BTZ nano-drugs have the defects of low drug loading, easy drug leakage in physiological environment, slow drug release in tumor cells, no targeting capability and the like.

Disclosure of Invention

The invention aims to provide an MAA-co-DAA-co-PEGMA copolymer and a preparation method and application thereof.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

MAA-co-DAA-co-PEGMA copolymer having the following structural formula:

。

preferably, a, b, c, d are positive integers and a: b: c: d = (1 ~ 32): 1: 2.

The MAA-co-DAA-co-Preparation method of PEGMA copolymer:

(1) respectively dissolving TBDMS-DAA and BACy in DMF to obtain TBDMS-DAA solution and BACy solution; dissolving TBAF in THF to obtain a TBAF solution;

(2) adding MAA, TBDMS-DAA solution, PEGMA, BACy solution and SDS into water under nitrogen atmosphere, mixing, heating to 40 ~ 100 deg.C under stirring, adding APS, reacting for 5 ~ 10h, centrifuging, washing, and freeze drying;

(3) adding the product obtained in the step (2) into TBAF solution, stirring, centrifugally collecting precipitate, washing with THF, washing with water and freeze-drying to obtain MAA-co-DAA-co-PEGMA copolymer.

Preferably, PEGMA has a weight average molecular weight of 300 ~ 2000.

Preferably, in step (1), the concentration of the TBDMS-DAA solution is 90 ~ 270 mg/mL, the concentration of the BACy solution is 50 ~ 170 mg/mL, the concentration of the TBAF solution is 0.1 ~ 0.4 mol/L, in step (2), the molar ratio of MAA, BACy, PEGMA and TBDMS-DAA is (1 ~ 32) to 1: 2, the total amount of APS added is (1 ~ 3)/1000 of the total mass of MAA, PEGMA and TBDMS-DAA, and the amount of water used is 10 ~ 15 times the total volume of the TBDMS-DAA solution and the BACy solution, and in step (2), the concentration of SDS added to the mixed solution (i.e., the mixed solution of MAA, TBDMS-DAA solution, PEGMA, BACy solution and SDS added to water, and mixed solution) is 1.5 ~ 2.0.0 g/L, and in step (3), the amount of TBAF-DAA solution added to water used is 3 ~ 10 times the amount of TBAF solution (TBDMS-DAA) in step (3).

The MAA-co-DAA-co-The use of PEGMA copolymers as drug carriers.

In the invention: MAA is methacrylic acid, BACy is N, N' -bis (acryloyl) cystamine, PEGMA is polyethylene glycol methacrylate, TBDMS-DAA is tert-butyldimethylsilyl dopamine acrylamide, DMF is N, N-dimethylformamide, SDS is sodium dodecyl sulfate, APS is ammonium persulfate, TBAF is tetrabutylammonium fluoride, THF is tetrahydrofuran.

Has the advantages that: MAA of the invention-co-DAA-co-The PEGMA copolymer is used as a drug carrier, has higher drug loading rate and can solve the problem of hydrophobicity of the drug; the cross-linking agent selects BACy to ensure that the carrier has higher degradability; after the copolymer carrier loads the drug, the release rate is greater than that of a neutral medium in the presence of acid and 10 mM glutathione, so that the copolymer has wide application prospect in the aspect of serving as an ideal drug delivery system.

Drawings

FIG. 1: MAA obtained in example 1 of the invention-co-DAA-co-TEM images of PEGMA copolymers;

FIG. 2: MAA obtained in example 1 of the invention-co-DAA-co-DLS profile of PEGMA copolymer;

FIG. 3: MAA obtained in example 1 of the invention-co-DAA-co-An infrared spectrum of the PEGMA copolymer;

FIG. 4: MAA obtained in example 1 of the invention-co-DAA-co-XPS spectra of PEGMA copolymer: (a) full spectrum, (b) C1 spectrum, (C) O1 spectrum;

FIG. 5: MAA obtained in example 1 of the invention-co-DAA-co-PEGMA copolymer in PBStability test in S buffer (pH =7.4) and PBS + DMEM (1: 9, pH = 7.4);

FIG. 6: MAA-co-DAA-co-Drug release profile of PEGMA copolymer @ BTZ.

Detailed Description

The following examples are intended to illustrate the invention in further detail, but are not to be construed as limiting the invention in any way; in the examples described below, TBDMS-DAA is prepared by Lee S B, Gonza ́ lez-Cabenzas C, Kim K M, et al, protective-functionalized synthetic polymer as a dense doped dense substrate for a composite reaction [ J ]. Biomacromolecules, 2015, 16(8): 2265-2275, which differs from the preparation of TBDMS-DMA in that: replacing methacryloyl chloride with an equimolar amount of acryloyl chloride; BACy references S.jin, J.X.Wan, L.Z.Meng, X.X.Huang, J.Guo, L.Liu, C.C.Wang, Biodegradation and toxicity of protease/redox/pH stimulation-reactive PEGlated PMAA nanoparticles for targeting drive, ACS application. interface 7 (2015) 19843 and 19852; other materials used, unless otherwise specified, were purchased from conventional chemical companies and raw material suppliers.