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Copolymer composite micelles based on dynamic imine bond and preparation method thereof

A technology of composite micelles and imine bonds, which is applied in the field of preparation of copolymer composite micelles, can solve the problems of difficult research and development of new micelles, limited response sensitivity, instability, etc., and achieve good biocompatibility Good effect with biodegradability and biocompatibility

Active Publication Date: 2021-01-08
LIAONING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although copolymer composite micelles can avoid the disassociation of common core-shell micelles due to changes in environmental conditions, there are still certain limitations in response sensitivity.
Although supramolecular copolymer micelles have higher sensitivity than conventional covalent bond micelles, they have certain limitations in stability
Supramolecular copolymer composite micelles are composite micelles based on hydrogen bonding. Although they can overcome the shortcomings of supramolecular copolymer micelles and copolymer composite micelles in terms of stability and sensitivity, self-assembly based on hydrogen bonding is There is still some instability in the process of preparation and transportation
Therefore, although supramolecular copolymer composite micelles show unique properties and attractive application prospects, the research and development of new micelles with more stability and sensitivity is still a difficult problem in this field.

Method used

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  • Copolymer composite micelles based on dynamic imine bond and preparation method thereof
  • Copolymer composite micelles based on dynamic imine bond and preparation method thereof
  • Copolymer composite micelles based on dynamic imine bond and preparation method thereof

Examples

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Embodiment 1

[0054] Embodiment 1 Preparation of copolymer complex micelles (4:6) based on dynamic imine bonds

[0055] (1) Synthesis of terminal polymers

[0056] 1. Synthesis of aldehyde-terminated polyethylene glycol monomethyl ether (MPEG-CHO)

[0057] Weigh 10g (2mmol) MPEG and place it in a 250mL reaction flask, dissolve it with 100mL dichloromethane, then add 3g (20mmol) p-CBA, 4.1g (20mmol) DCC and 0.6g (5.0mmol) DMAP, and stir magnetically at 25°C Reaction 24h. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated by rotary evaporation, and the obtained solid was dissolved in 80 mL of isopropanol, and then left overnight at 4°C. After filtering, the resulting solid was washed with isopropanol and diethyl ether in turn, and vacuum-dried to obtain MPEG-CHO with a yield of 78%, which was set aside for later use. The detection and analysis results are as figure 1 shown.

[0058] figure 1 is MPEG-CHO 1 H NMR spectrum. figure 1 The...

Embodiment 2

[0098] Embodiment 2 Preparation of copolymer complex micelles (5:5) based on dynamic imine bonds

[0099] Weigh 12.75mg (0.00125mmol) of MPEG-b-PCL and 12.25mg (0.00125mmol) of PNVCL-b-PCL and dissolve in 5mL of tetrahydrofuran, stir at room temperature for 24h, then slowly drop 1.0mL of the above solution into ultrapure water, Until the aqueous solution turns into a light blue milky white solution, then set the volume to 10mL, dialyze for 48h to remove tetrahydrofuran, and obtain MPEG-b-PCL and PNVCL-b-PCL with a concentration of 0.5mg / mL and a molar ratio of 5:5. Copolymer Complex Micellar Solution. The detection and analysis results are as Figure 14 ~ Figure 15 shown.

[0100] Figure 14 It is a transmission electron micrograph of a copolymer composite micelle (5:5). From Figure 14 It can be seen that the micelles are uniformly distributed spherically.

[0101] Figure 15 is the particle size distribution diagram of the copolymer composite micelles (5:5). From F...

Embodiment 3

[0102] Embodiment 3 Preparation of copolymer composite micelles (6:4) based on dynamic imine bonds

[0103] Weigh 15.20mg (0.0015mmol) of MPEG-b-PCL and 9.80mg (0.0010mmol) of PNVCL-b-PCL and dissolve in 5mL of tetrahydrofuran, stir at room temperature for 24h, then slowly drop 1.0mL of the above solution into ultrapure water, Until the aqueous solution turns into a light blue milky white solution, then set the volume to 10mL, dialyze for 48h to remove tetrahydrofuran, and obtain MPEG-b-PCL and PNVCL-b-PCL with a concentration of 0.5mg / mL and a molar ratio of 6:4. Copolymer Complex Micellar Solution. The detection and analysis results are as Figure 16 ~ Figure 17 shown.

[0104] Figure 16 It is a transmission electron micrograph of a copolymer composite micelle (6:4). From Figure 16 It can be seen that the micelles are uniformly distributed spherically.

[0105] Figure 17 is the particle size distribution diagram of the copolymer composite micelles (6:4). From Fi...

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Abstract

The invention relates to copolymer composite micelles based on dynamic imine linkages and a preparation method thereof. A methoxypolyethylene glycol-b-polycaprolactone block copolymer and poly(N-vinylcaprolactam)-b-polycaprolactone block copolymer based on dynamic imine linkages are synthesized through Schiff base reaction; copolymer composite micelles having a PCL (polycaprolactone) core and a MPEG (methoxypolyethylene glycol) and PNVCL (poly(N-vinylcaprolactam)) mixed shell is prepared by using the copolymers above as construction units. The copolymer composite micelles synthesized herein have the advantages that when the ambient temperature is higher than low critical dissolution temperature of a temperature-sensitive chain segment, the temperature responsive shell collapses on a hydrophobic core to form a hydrophobic area, the other hydrophilic chain segment supports the collapsed shell to form a channel so as to avoid micelle decomposition, and covered guest molecules are not released in blood and normal tissue; in case of a weak acidity environment having the pH close to 5.0, the block copolymer structure based on imine linkages is destroyed and is pH responsive, and the covered guest molecules are released.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of a dynamic imine bond-based copolymer composite micelle. Background technique [0002] Amphiphilic block copolymers can self-assemble in aqueous solution to form core-shell micelles with a size between 10-100 nm, which can improve the solubility and stability of insoluble drugs, and have broad application prospects in the fields of drug controlled release. However, the micelles of this core-shell structure are easily affected by external conditions such as solvent and temperature, and its structure is easily destroyed, which limits its application. Therefore, the research and development of new micelles with higher sensitivity and stability has attracted more and more attention. [0003] Copolymer composite micelle is to introduce block copolymers with different properties or responses (such as temperature, pH, etc.) into the same mi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/107A61K47/34C08G81/00C08G81/02
CPCA61K9/1075A61K47/34C08G81/00C08G81/027
Inventor 吴秋华王绍森辛宇豪张国林刘学矣杰宋溪明
Owner LIAONING UNIVERSITY
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