Reduction-responsive targeting polymer micelles for mucus penetration and preparation methods thereof

A polymer micelle and mucus penetration technology, applied in the field of reduction-responsive targeted polymer micelle and its preparation, can solve the problem of hindering the interaction between nanoparticles and lesion cells, reducing the effect of nanoparticle endocytosis, and reducing intracellular drug Slow and controlled release and other issues, to achieve good reduction targeting responsiveness, good mucus penetration performance, and good stability

Inactive Publication Date: 2018-02-13
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although the modification of polyethylene glycol enables the nanoparticles to obtain the above properties, it hinders the interaction between the nanoparticles and the lesion cells and reduces the endocytosis effect of the nanoparticles, thereby reducing the sustained and controlled release of intracellular drugs and affecting the desired therapeutic effect

Method used

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  • Reduction-responsive targeting polymer micelles for mucus penetration and preparation methods thereof
  • Reduction-responsive targeting polymer micelles for mucus penetration and preparation methods thereof
  • Reduction-responsive targeting polymer micelles for mucus penetration and preparation methods thereof

Examples

Experimental program
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preparation example Construction

[0033] A method for preparing a reduction-responsive amphiphilic polymer conjugate, the steps are as follows:

[0034] Poly(lactic-co-glycolic acid) (PLGA), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine, 3,3'-disulfide Dipropionic acid is dissolved in N,N-dimethylformamide at a molar ratio of 1:(1.2~5):(0.6~2):(3~10), stirred and reacted at room temperature for 24~48h in the above solution Poly(lactic-co-glycolic acid) copolymer (PLGA):polyethylene glycol (PEG)=1:4 is dissolved in polyethylene glycol (PEG) by molar ratio, stirred at room temperature for 24-48 hours, post-treatment to obtain reduction-responsive amphiphilic Polymer combination.

[0035] The concentration of the PLGA dissolved in N,N-dimethylformamide is preferably 0.05-0.25 g / ml.

[0036] The specific steps of post-treatment are: dialyze the reaction solution in N,N-dimethylformamide for 12-24 hours, then dialyze in pure water for 24-48 hours, and freeze-dry to obtain the ...

Embodiment 1

[0044] Synthesis of reduction-responsive amphiphilic polymer conjugates.

[0045] Take polylactic acid-glycolic acid copolymer (PLGA, molecular weight is 10kDa) 1g, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 100mg, 4-dimethylaminopyridine 30mg, 85mg of 3,3'-dithiodipropionic acid was dissolved in 12ml of N,N-dimethylformamide, stirred at room temperature for 24 hours, and then 90mg of polyethylene glycol (PEG, molecular weight 1kDa) was added to the above solution , after stirring at room temperature for 24 hours, the reaction solution was dialyzed in N,N-dimethylformamide for 12 hours, then dialyzed in pure water for 24 hours, and then freeze-dried to obtain a reduction-responsive amphiphilic polymer conjugate.

[0046] Such as figure 1 As shown in the H NMR spectrum, the characteristic peaks of PLGA and PEG can be obtained, which proves that the amphiphilic polymer conjugate is synthesized successfully.

Embodiment 2

[0048] Synthesis of reduction-responsive amphiphilic polymer conjugates.

[0049] Take polylactic acid-glycolic acid copolymer (PLGA, molecular weight is 21kDa) 0.4g, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 70mg, 4-dimethylaminopyridine 23mg , 65mg of 3,3'-dithiodipropionic acid, dissolved in 10ml of N,N-dimethylformamide, stirred at room temperature for 28 hours, then added polyethylene glycol (PEG, molecular weight 2.5 kDa) 25 mg, stirred at room temperature for 28 hours, dialyzed the reaction liquid in N,N-dimethylformamide for 14 hours, dialyzed in pure water for 26 hours, and freeze-dried to obtain a reduction-responsive amphiphilic polymer conjugate.

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Abstract

The invention relates to a reduction-responsive targeting polymer micelle for mucus penetration and a preparation method thereof. Combining PLGA and PEG through reduction-responsive disulfide bonds to form an amphiphilic polymer conjugate, and post-assembly to form reduction-responsive micelles to achieve good mucus permeability, reduction-responsive bond breaking performance and targeting cell-mediated The performance of endocytosis, and the effective particle size is 70-110nm, and the particle size is more uniform; due to the coating of PEG, the surface of micelles is neutral, and the cytotoxicity is low, and it can penetrate into the bottom cell layer in the mucus layer and reach the bottom cells After injection of glutathione solution, the reduction-responsive disulfide bond breaks, the PEG protection is removed, and the coated targeted folic acid is exposed, which specifically binds to the folic acid receptor overexpressed on the cell membrane surface of the lesion cell, and is mediated by folic acid Receptor-mediated endocytosis improves the efficiency of nanocarriers entering cells, allowing more carriers to enter cells for slow and controlled release of drugs, achieving better therapeutic effects.

Description

technical field [0001] The invention relates to a reduction-responsive targeting polymer micelle for mucus penetration and a preparation method thereof, belonging to the technical field of preparation of drug carrier materials. Background technique [0002] Mucus provides the first line of defense for the exposed surfaces of the lungs, respiratory tract, stomach, eyes, nasopharynx, vagina, etc. Its high adhesion and viscoelasticity enable foreign pathogens, toxins, particles, etc. to be adhered to the mucus and Rapid removal is the normal mucus clearance mechanism. A large number of experiments by researchers have proved that mucus can also strongly fix and remove traditional nanoparticles, which has also become a major obstacle to local drug delivery and gene delivery on the mucosal surface. Using the adhesive properties of mucus, the researchers designed two types of adhesive nanoparticles. One is positively charged nanoparticles that can electrostatically adsorb with ne...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/107A61K47/34A61K47/10
Inventor 常津房蕾宫晓群王生杨文涛
Owner TIANJIN UNIV
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