Triple stimulation responsive core cross-linked polymeric micelle as well as preparation method and application thereof

A cross-linked polymer and stimuli-responsive technology, which is applied in drug delivery, drug combination, pharmaceutical formulation, etc., can solve the problems of few research reports, and achieve the effect of simple operation, mild reaction conditions, and good control release

Active Publication Date: 2019-02-12
SHAANXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have shown that single stimuli-responsive core-crosslinked polymer micelles often have certain limitations in application
[0005] So far, there are few reports on the design and synthesis of a nuclear cross-linked polymer micelle with multiple stimuli responses for the delivery of anticancer drugs

Method used

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  • Triple stimulation responsive core cross-linked polymeric micelle as well as preparation method and application thereof
  • Triple stimulation responsive core cross-linked polymeric micelle as well as preparation method and application thereof
  • Triple stimulation responsive core cross-linked polymeric micelle as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046]

[0047]

[0048] 1. Dissolve mPEG-Br (0.2g, 0.1mmol), NBM (1.55g, 7mmol), GMA (0.426g, 3mmol), PMDETA (0.0173g, 0.1mmol) in 4mL DMF, freeze-thaw and degas continuously 2 Add CuBr (0.0143g, 0.1mmol) once more, and then freeze-thaw and degas once more, and then react at 70°C for 24 hours under a nitrogen atmosphere. After the reaction, dilute with THF, pass through a neutral alumina column, and rotate to remove After most of the solvent, dialyze in deionized water for 3 days using a dialysis bag with a molecular weight cut-off of 8 kDa, and freeze-dry to obtain a white solid, which is the amphiphilic diblock polymer shown in formula I-1.

[0049] 2. The amphiphilic diblock polymer (0.4g, 0.86mmol) shown in formula I-1 and NaN 3 (0.25g, 3.87mmol), NH 4 Cl (0.21g, 3.87mmol) was dissolved in 20mL DMF, and reacted at 50°C for 24 hours under stirring. After the reaction, the insoluble salt was filtered off with a Buchner funnel. The bag was dialyzed in deionized water...

Embodiment 2

[0054]

[0055] 1. Dissolve mPEG-Br (0.4g, 0.2mmol), NBM (2.21g, 10mmol), GMA (1.42g, 10mmol), PMDETA (0.0346g, 0.2mmol) in 4mL DMF, freeze-thaw and degas continuously 2 Add CuBr (0.0286g, 0.2mmol) once more, and then freeze-thaw degassing once more, and then react at 70°C for 24 hours under a nitrogen atmosphere. After the reaction, dilute with THF, pass through a neutral alumina column, and rotate to remove After most of the solvent, use a dialysis bag with a molecular weight cut-off of 8KDa to dialyze in deionized water for 3 days, and freeze-dry to obtain a white solid, which is the amphiphilic diblock polymer shown in formula I-2.

[0056] 2. The amphiphilic diblock polymer (0.4g, 1.05mmol) shown in formula I-2 and NaN 3 (0.34g, 5.25mmol), NH 4 Cl (0.28g, 5.25mmol) was dissolved in 20mL DMF, and then reacted at 50°C for 24 hours under stirring. After the reaction, the insoluble salt was filtered off with a Buchner funnel. The bag was dialyzed in deionized water for 3...

Embodiment 3

[0061] Application of the triple stimulus-responsive nuclear cross-linked polymer micelles prepared in Example 1 as hydrophobic drug carriers

[0062] The azide-modified amphiphilic diblock polymer (30 mg, 0.06 mmol) shown in formula II-1, Nile red (1.5 mg, 0.005) and the cross-linking agent (17 mg, 0.04 mg) shown in formula III-1 mmol) was dissolved in 20mL THF, micelles were formed by dialysis, and then CuSO was added 4 ·5H 2 O (30mg, 0.12mmol) and sodium ascorbate (24mg, 0.12mmol), reacted at 25°C for 48 hours, and then dialyzed the unreacted cross-linking agent with an 8kDa dialysis bag to obtain triple stimulus responsiveness to light, oxidation and reduction. Core-crosslinked polymer drug-loaded micelles.

[0063] Fluorescence spectrometer detection (excitation wavelength is 560nm, micelle concentration is 0.2mg / mL) release curve of triple stimulus-responsive nuclear cross-linked polymer drug-loaded micelles under single stimulation and multiple stimulation, the result...

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Abstract

The invention discloses a triple stimulation responsive core cross-linked polymeric micelle as well as a preparation method and application thereof. The structural formula of the micelle is as shown in the description, wherein x is an integer of 30 to 70, y is an integer of 20 to 50 and the value of x1 is 20% to 50% of that of the x. According to the preparation method, an amphipathic diblock polymer is obtained through atom transfer radical polymerization (ATRP), and is modified by utilizing an azidation reaction; an azidation product can self-assemble to form a core-shell structure in water;and the light, oxidation and reduction triple stimulation responsive core cross-linked polymeric micelle is obtained through click chemistry under the action of a cross-linking agent with redox sensitiveness, anhydrous cupric sulfate and sodium ascorbate. The triple stimulation responsive core cross-linked polymeric micelle provided by the invention has favorable in-vitro stability, can be used for realizing a high-efficiency controlled release behavior of a hydrophobic drug under the double stimulation of light and oxidation or reduction, and has favorable application prospects in the aspects of the delivery and the controlled release of a hydrophobic anti-cancer drug.

Description

technical field [0001] The invention relates to a light-, oxidation- and reduction-responsive nuclear cross-linked polymer micelle, a preparation method and application thereof. Background technique [0002] With the rapid development of nanoscience and technology in recent years, more and more new nanomaterials have been used in drug delivery systems. At present, polymer-based nanocarriers mainly include prodrugs, vesicles, nano-cages, microgels, and polymer micelles. Due to its unique core-shell nanostructure, polymer micelles can improve the solubility of poorly soluble drugs and protect the drugs in the core from being degraded or enzymatically hydrolyzed when they are used as drug carriers. Due to the small size of drug-loaded polymer micelles, it can also increase the accumulation of drugs in cancer cells through enhanced cell permeability and EPR. It will cause the increase of vascular resistance and blood viscosity, and has little side effects on the normal body. ...

Claims

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Application Information

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IPC IPC(8): C08F8/48C08F8/30C08F293/00A61K47/34A61K9/107A61K9/00A61P35/00
CPCA61K9/0009A61K9/1075A61K47/34A61P35/00C08F8/30C08F8/48C08F293/005C08F2438/01
Inventor 雷忠利马肖杨红
Owner SHAANXI NORMAL UNIV
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