Multi-response type cross-linked polymer and drug-loading nano-micelles as well as preparation methods thereof

A technology of cross-linked polymers and drug-loaded nanometers, which is applied in the direction of pharmaceutical formulations, medical preparations containing active ingredients, and medical preparations containing active ingredients. Problems such as poor drug loading stability, to avoid poor cycle stability, overcome weak interaction, and improve drug loading stability

Active Publication Date: 2018-01-09
SOUTHWEST UNIVERSITY FOR NATIONALITIES
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Problems solved by technology

However, with the in-depth study of polymer nanomicelles, it is found that there are still some defects in its function in the process of drug delivery, which restricts its large-scale practical application
[0003] 1. Poor circulation stability in the body
Traditional polymer micelles are usually prepared from linear polymers. Although they have the advantages of simple methods and clear nanoparticle structures, they have poor stability during circulation in the body.
When the micelle enters the human body, it is easily affected by factors such as body fluid dilution, temperature, ion concentration, pH value, and biomolecules in the blood, causing the micelle structure to disintegrate, leading to early drug release and reduced tumor targeting efficiency. , cannot meet the requirement of long-term circulation stability in vivo (Ren T, Xia W, Dong H, Li Y. Sheddable micelles based on disulfide-linkedhybrid PEG-polypeptide copolymer for intracellular drug delivery. Polymer.2011,20(52):3580-3586 )
[0004] 2. Low drug loading stability
Although this technique is simple and can obtain greater drug loading efficiency, the interaction between the drug and the polymer in the drug-loaded micelles prepared by this technique is weak, and the loading stability of the drug is poor. It is often released early in the normal tissue in the body fluid circulation, causing greater toxic and side effects on normal tissue (Liu F, Kozlovskaya V, Medipelli S, et al. Temperature-sensitive polymersomes for controlled delivery of anticancerdrugs[J].Chemistry of Materials ,2015,27(23):7945-7956)
[0005] 3. Insufficient responsiveness in the cellular microenvironment
But still there are following shortcomings in its technical scheme: 1, under no external environmental stimulation, its drug release rate just can reach 26%, cause the circulation stability in the patient's body not good, release drug in advance will produce bigger effect on the normal tissue of patient. Large toxic and side effects; 2. Its drug loading rate is low, only 13.8%, which leads to low purity of the synthesized drug and affects the effect of treating cancer

Method used

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  • Multi-response type cross-linked polymer and drug-loading nano-micelles as well as preparation methods thereof
  • Multi-response type cross-linked polymer and drug-loading nano-micelles as well as preparation methods thereof
  • Multi-response type cross-linked polymer and drug-loading nano-micelles as well as preparation methods thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0057] Benzyl glutamate and triphosgene were dissolved in ethyl acetate at a mass ratio of 1:1 at 0.04 g / mL, then reacted in a reactor at 75 °C for 2 h, washed with water and sodium bicarbonate solution in sequence, and washed with Dry over magnesium sulfate, filter and then rotary evaporate to one-third of the original volume, crystallize in n-hexane, then freeze the product at -20°C for 24h, filter with suction, and dry at 25°C and a vacuum of 0.010MPa for 24h That's it.

[0058] Dissolve allylamine and the obtained benzyl glutamate cyclic anhydride in THF at a molar ratio of 1:40 to form a 0.25 g / mL solution, react at 25°C for 24 hours, and then use glacial ether for precipitation and suction filtration , and dried at 60°C for 24 hours to obtain polybenzyl glutamate;

[0059] Mix benzyl polyglutamate and N-isopropylacrylamide at a molar ratio of 1:1, dissolve in DMF to make a mixed solution of 0.01g / mL, add benzyl polyglutamate and N-isopropylacrylamide respectively 4% cr...

Embodiment 2

[0062] Benzyl glutamate and triphosgene were dissolved in ethyl acetate at a mass ratio of 2:1 at 0.05 g / mL, then reacted in a reactor at 50 °C for 8 h, washed with water and sodium bicarbonate solution in sequence, and washed with Dry over magnesium sulfate, filter and then rotary evaporate to one-third of the original volume, crystallize in n-hexane, then freeze the product at -20°C for 24h, filter with suction, and dry at 25°C and vacuum 0.012MPa for 24h That's it.

[0063] Allylamine and benzyl glutamic acid anhydride were mixed and dissolved in dichloromethane at a molar ratio of 1:50 to form a 0.52 g / mL solution, reacted in a reactor at 10°C for 36 h, and then cooled with ice Diethyl ether was precipitated, suction filtered, and dried at 60°C for 24 hours to obtain polybenzyl glutamate.

[0064] Mix polybenzyl glutamate and N-isopropylacrylamide at a molar ratio of 1:50, dissolve in DMF to make a mixed solution of 0.02g / mL, add polybenzyl glutamate and N-isopropylacryla...

Embodiment 3

[0067] Benzyl glutamate and triphosgene were dissolved in ethyl acetate at a mass ratio of 3:1 at 0.05 g / mL, then reacted in a reactor at 85°C for 3 h, washed with water and sodium bicarbonate solution in sequence, and washed with Dry over magnesium sulfate, filter and rotary evaporate to one-third of the original volume, crystallize in n-hexane, then freeze the product at -20°C for 24h, filter with suction, and dry at 25°C under a vacuum of 0.014MPa for 16h That's it.

[0068] Allylamine and glutamic acid anhydride were mixed and dissolved in DMSO at a molar ratio of 1:60 to form a 0.30 g / mL solution, reacted at 50°C for 48 hours, and then precipitated with glacial ether, suction filtered, and dissolved at 60 Dry at ℃ for 24h to obtain polybenzyl glutamate.

[0069] Mix benzyl polyglutamate and N-isopropylacrylamide at a molar ratio of 1:20, dissolve in DMSO to form a mixed solution of 0.05g / mL, add benzyl polyglutamate and N-isopropylacrylamide respectively 5% cross-linkin...

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Abstract

The invention relates to a multi-response type cross-linked polymer and drug-loading nano-micelles as well as preparation methods thereof. Specifically, the multi-response type cross-linked polymer drug-loading nano-micelles are prepared by taking N,N'-di(acrylyl)cystamine as a cross-linking agent, utilizing the multi-response type cross-linked polymer formed by crossly linking a benzyl ester typepolyamino acid derivative group and a temperature sensitive group, dissolving the multi-response type cross-linked polymer and connecting with an anti-tumor drug through a hydrazone bond, then dropwise adding the solution into de-ionized water to form micelles, and carrying out dialysis, freezing and drying. The multi-response type cross-linked polymer and the drug-loading nano-micelles, providedby the invention, have the characteristics of stable structure, good drug loading stability, high drug loading rate and high tumor cell microenvironment response efficiency.

Description

technical field [0001] The invention belongs to the technical field of drug carriers and their preparation, in particular to multi-responsive cross-linked polymers, drug-loaded nano-micelles and their preparation methods, in particular to cross-linked polymerization with reduction responsiveness, pH responsiveness and temperature sensitivity Drugs, drug-loaded nanomicelles and their preparation methods as tumor cell microenvironment targeting functions. Background technique [0002] Polymer nanomicelle is a nanoparticle with a hydrophobic core and a hydrophilic shell formed by the self-assembly of amphiphilic polymers in aqueous solution, and the particle size is generally 10-200nm. Among them, the hydrophobic inner core can effectively pack drug molecules, while the hydrophilic shell can make the micelles stably dispersed in aqueous solution. Because polymer nanomicelle has good water solubility and high permeability and retention effect (EPR) on tumor tissue, it has good ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08F283/04C08F220/54A61K9/107A61K47/64A61K47/54A61K47/69A61K47/58A61K31/704A61P35/00
Inventor 周庆翰屈婧
Owner SOUTHWEST UNIVERSITY FOR NATIONALITIES
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