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A kind of enzymatic cationic liposome and its application

A cationized, liposome technology, applied in the directions of liposome delivery, medical preparations with inactive ingredients, and medical preparations containing active ingredients, etc. The anti-cancer effect and other issues of the prime factor to achieve the effect of promoting enrichment and penetration

Active Publication Date: 2021-10-29
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PEGylated long-circulating liposomal doxorubicin Doxil is approved by the FDA for the treatment of tumors such as Kaposi's sarcoma and multiple myeloma, but it relies on the EPR effect to enrich and penetrate poorly in solid tumors, and has no performance better anticancer efficacy than free doxorubicin (DOX) formulations (Barenholz Y. -The first FDA-approved nano-drug: Lessons learned[J].Journal of Controlled Release,2012,160(2):117-134.)

Method used

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  • A kind of enzymatic cationic liposome and its application
  • A kind of enzymatic cationic liposome and its application
  • A kind of enzymatic cationic liposome and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Preparation of DOPE-GSH and contrast DOPE-EGG

[0039] Preparation of DOPE-GSH:

[0040] 1) Add Boc-protected lysine (Boc-Lys, 0.35 g, 1 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide salt in dichloromethane (DCM, 10 mL) salt (EDC, 0.39g, 2mmol) and N-hydroxysuccinimide (NHS, 0.23g, 2mmol), reacted at room temperature for 4h, then added dioleoylphosphatidylethanolamine (DOPE, 0.75g, 1mmol), at room temperature Under reaction 12h.

[0041] 2) Add trifluoroacetic acid (TFA, 10 mL) and react at room temperature for 4 h. After concentrated by rotary evaporation, dialyzed in methanol (molecular weight cut-off: 500Da) for 24h, and dried by rotary evaporation, a lysine-modified DOPE product (DOPE-Lys, about 0.65g, yield 74.5%) was obtained.

[0042] 3) Add Boc-γ-Glu(otbu)-Cys(Trt)-Gly(pro-GSH, 0.71g, 1mmol), EDC (0.39g, 2mmol) and NHS (0.23g, 2mmol) in DCM (10mL) , reacted at room temperature for 4h, then added DOPE-Lys (0.38g, 0.5mmol), and reacted at room...

Embodiment 2

[0088] Example 2: Preparation and Characterization of GCSDL Liposomes and Control CCDL Liposomes

[0089] Adopt ammonium sulfate gradient method to prepare GCSDL liposome, the preparation process is as follows:

[0090] 1) In a 250mL flask, mix HSPC (hydrogenated soybean lecithin) (23.6mg, 0.03mmol), CHOL (cholesterol) (7.7mg, 0.02mmol) and DOPE-GSH (glutathione) in a molar ratio of 3:2:3 Peptide-modified dioleoylphosphatidylethanolamine) (43.0mg, 0.03mmol) was dissolved in chloroform (10mL) and rotovaped under reduced pressure to form a lipid film.

[0091] 2) Add ammonium sulfate solution (0.3M, 20mL), and after hydration under ultrasonic, extrude the solution on a polycarbonate filter membrane (100nm) to obtain a blank liposome solution. ) at 5000r / min, centrifuge for 60min to remove excess ammonium sulfate solution.

[0092] 3) Mix the concentrated liposomes with DOX (doxorubicin) (mass ratio: 16:2) in 4.6 mL of histidine buffer (10 mM, pH 6.5) containing 10% (w / w) sucro...

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Abstract

The invention relates to an enzymatic cationic liposome and an enzymatic cationic drug-carrying liposome. After the liposome enters the blood circulation through intravenous injection, γ-glutamyl transfer reaction can occur under the catalysis of γ-glutamyl transpeptidase highly expressed in tumor vascular endothelial cells and tumor cells to generate cationic primary amine, and complete The surface potential changes from negative potential to positive potential, forming cationic liposomes. Subsequently, cationized liposomes trigger cell membrane caveolae and vesicle-mediated endocytosis to complete transvascular endothelial cells and tumor cell transport, thereby enhancing the tumor enrichment of liposomes and achieving deep penetration drug delivery. The liposome has excellent antitumor effect on solid tumors such as liver cancer and pancreatic cancer, and solves the problems of low enrichment and poor penetration of traditional nanomedicine in solid tumors, and is of great significance in the field of nanomedicine treatment of solid tumors.

Description

(1) Technical field [0001] The invention relates to the technical field of anti-tumor nano-medicines, in particular to an enzymatic cationic liposome capable of tumor enrichment and deep delivery through endocytosis and translocation and its application. (2) Background technology [0002] Anti-tumor nano-drugs are considered to utilize tumor permeability and retention effect (Enhanced Permeability and Retention, EPR effect) to achieve tumor-targeted accumulation and reduce drug side effects. However, solid tumors are often accompanied by complex biological barriers, such as dense extracellular matrix, increased tissue hydraulic pressure, lack of vascular distribution, and dense arrangement of vascular endothelial cells. These biological barriers greatly reduce the tumor EPR effect, hinder the enrichment and penetration of nano-drugs, and make it difficult for nano-drugs to effectively exert anti-tumor effects. The study found (Wilhelm S, Tavares A J, Dai Q, etal.Analysis of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/127A61K47/24A61K47/28A61K31/704A61P35/00
CPCA61K9/127A61K47/24A61K47/28A61K31/704A61P35/00
Inventor 王国伟黄品同吴碧寒李群英
Owner ZHEJIANG UNIV
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