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Multiple-target-point treating micelle for regulating and controlling microenvironment of Alzheimer disease (AD) and preparation method of multiple-target-point treating micelle

A multi-target, micellar technology, applied in the direction of non-active ingredients medical preparations, pharmaceutical formulas, nervous system diseases, etc., can solve the problem of lack of AD microenvironment adjustment, achieve stable blood circulation, simple and feasible preparation process , increase the effect of accumulation

Active Publication Date: 2020-01-07
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While delivering therapeutic drugs to target cells, the drug delivery system can play a synergistic effect with the drug by normalizing various biochemical molecules in the microenvironment, and enhance the overall therapeutic effect of the drug delivery system. However, the current AD nano Drug delivery strategies mainly focus on the delivery of single-target drugs to nerve cells, lacking the regulation of the AD microenvironment; therefore, it is necessary to develop a nano-drug delivery system that can target AD lesions and improve its microenvironment

Method used

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  • Multiple-target-point treating micelle for regulating and controlling microenvironment of Alzheimer disease (AD) and preparation method of multiple-target-point treating micelle
  • Multiple-target-point treating micelle for regulating and controlling microenvironment of Alzheimer disease (AD) and preparation method of multiple-target-point treating micelle
  • Multiple-target-point treating micelle for regulating and controlling microenvironment of Alzheimer disease (AD) and preparation method of multiple-target-point treating micelle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Ab peptide-modified polymer micellar nanoparticles loaded with insoluble AD treatment drug curcumin. Drug curcumin has been reported to have various mechanisms of action such as anti-inflammation and anti-oxidation, and is suitable for multi-target therapy of AD. Its polymer Synthetic methods such as figure 1 shown, including the following steps:

[0037] 1) Synthesis of Ab peptide-modified polyethylene glycol polylysine phenylboronate derivatives

[0038] (1) Weigh N 6 -Benzyloxycarbonyl-L-lysine 1g, triphosgene 0.3g, dissolved in 10mL tetrahydrofuran, under nitrogen protection, reacted at 50°C for 5 hours, precipitated with 50mL anhydrous n-hexane, and dried by suction to obtain lysine monomer;

[0039] (2) Weigh 210 mg of lysine monomer obtained in step (1), 100 mg of polyethylene glycol, dissolve in 3 mL of anhydrous N'N-dimethylformamide, and react at 55 ° C for 24 hours under nitrogen protection , use 30mL of anhydrous ether to precipitate, and filter and dry ...

Embodiment 2

[0048] Example 2 Ab peptide-modified polymer micelle nanoparticle preparation loaded with near-infrared probes

[0049] 1) Synthesis of Ab peptide-modified polyethylene glycol polylysine phenylboronate derivatives

[0050] (1) Weigh N 6 -Benzyloxycarbonyl-L-lysine 1g, triphosgene 0.45g, dissolved in 10mL tetrahydrofuran, under nitrogen protection, reacted at 55°C for 8 hours, precipitated with 80mL anhydrous n-hexane, and dried by suction to obtain lysine monomer;

[0051] (2) Weigh 240 mg of lysine monomer obtained in step (1), 100 mg of polyethylene glycol, dissolve in 3 mL of anhydrous N'N-dimethylformamide, and react at 60 ° C for 48 hours under nitrogen protection , use 30mL of anhydrous ether to precipitate, and filter and dry to obtain a white solid, dissolve 100mg of the white solid in a mixture of 1mL trifluoroacetic acid and 0.05mL hydrobromic acid (containing 30% acetic acid), react at room temperature for 6 hours, use pure water dialyzed and lyophilized;

[005...

Embodiment 3

[0059] Example 3 Ab peptide-modified polymer micelle nanoparticle formulation loaded with curcumin

[0060] 1) Synthesis of Ab peptide-modified polyethylene glycol polylysine phenylboronate derivatives

[0061] (1) Weigh N 6 -Benzyloxycarbonyl-L-lysine 1g, triphosgene 0.5g, dissolved in 10mL tetrahydrofuran, under nitrogen protection, reacted at 55°C for 10 hours, precipitated with 100mL anhydrous n-hexane, and dried by suction to obtain lysine monomer;

[0062] (2) Weigh 270 mg of lysine monomer obtained in step (1), 100 mg of polyethylene glycol, dissolve in 3 mL of anhydrous N'N-dimethylformamide, and react at 65 ° C for 72 hours under nitrogen protection , precipitated with 30 mL of anhydrous ether, and dried by suction to obtain a white solid. Dissolve 100 mg of the white solid in a mixture of 1 mL of trifluoroacetic acid and 0.03 mL of hydrobromic acid (containing 30% acetic acid), react at room temperature for 8 hours, dialyze with pure water and freeze-dry;

[0063...

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Abstract

The invention belongs to the field of drug preparations, and relates to a multiple-target-point treating micelle for regulating and controlling the microenvironment of Alzheimer disease (AD) and a preparation method of the multiple-target-point treating micelle. According to a preparation, a nano drug delivery system is prepared from an indissolvable drug, a synthetic polypeptide-modified polyethylene glycol polyamino acid polymer material, an injection solvent and the like, the RAGE-targeted polypeptide-modified polyethylene glycol polyamino acid polymer material is adopted, the indissolvabledrug is entrapped in the mode of being self-assembled in an aqueous-phase solution, the preparation method is simple, and particle size distribution of nanoparticles is even; through an RAGE-targetedreceptor, the micelle can cross abnormal blood-brain barriers and is accumulated on an AD lesion; bonding of ROS-sensitive phenylboronic acid ester functional groups serves as a block hydrophobization mode, the drug can be controllably released in the microenvironment of AD through the drug delivery system, meanwhile lesion ROS is cleared for effective normalization regulation of the microenvironment, and the curative effect on AD is exerted.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a multi-target therapeutic micelle for regulating the microenvironment of Alzheimer's disease and a preparation method thereof. Background technique [0002] Alzheimer's disease (AD) is a common neurodegenerative disease characterized by loss of central nervous cells and late brain atrophy. Clinically, it usually manifests as comprehensive dementia symptoms such as memory and cognitive dysfunction. However, after decades of pathological mechanism research, the pathogenesis of AD is still not clear. Clinical practice shows that at present, cholinergic drugs used in clinical practice can only compensate for the loss of neurotransmitters due to neuronal apoptosis, but cannot prevent the deterioration of the disease; in recent years, according to the "amyloid hypothesis" The developed antibody drugs have also failed in clinical research. Although the amyloid de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/64A61P25/28C08G69/48C08G69/40
CPCA61K47/6907A61K47/64A61K9/0019A61P25/28C08G69/48C08G69/40
Inventor 蒋晨卢逸飞
Owner FUDAN UNIV
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