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Construction and application of vitamin E nano-carrier capable of reversing alcoholic liver disease

An alcoholic liver disease and nanocarrier technology, which can be applied to medical preparations without active ingredients, medical preparations containing active ingredients, metabolic diseases, etc., and can solve problems such as aggravation of oxidative stress

Active Publication Date: 2022-05-13
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although inhibition of CYP2E1 can limit the further exacerbation of oxidative stress, it is ineffective against the already generated ROS, so it needs to be combined with other ROS neutralizers / scavenger in the treatment

Method used

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  • Construction and application of vitamin E nano-carrier capable of reversing alcoholic liver disease
  • Construction and application of vitamin E nano-carrier capable of reversing alcoholic liver disease
  • Construction and application of vitamin E nano-carrier capable of reversing alcoholic liver disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 Preparation and characterization of vitamin E nanoemulsion modified with dodecylbenzenesulfonamide (p-DBSN)

[0047] Sulfonyl ligands are selected with high affinity and specificity for abundant potassium channels (sulfonylurea receptors) on the ER membrane and have been widely used in ligand-receptor-mediated ER targeting. research and application. Here, two sulfonyl ligands were used to prepare corresponding ER-targeted nanoformulations, p-dodecylbenzenesulfonamide (p-DBSN) and N-dodecyl-4-toluenesulfonamide ( N-DMSN).

[0048] Table 1: Recipe composition of p-DBSN modified vitamin E nanoemulsion

[0049]

[0050] First, CMZ-loaded, p-DBSN-modified endoplasmic reticulum-targeted vitamin E nanoemulsions (CMZ@ER-NEs) and their control nanoemulsions: NEs (non-targeting without CMZ), CMZ@NEs ( containing CMZ non-targeted) and ER-NEs (no CMZ targeted). The nanoemulsion under this preparation prescription presents typical emulsion morphology under a transmi...

Embodiment 2

[0054] Example 2 Preparation and Characterization of Physicochemical Properties of Vitamin E Nanoemulsion Modified by N-Dodecyl-4-Toluenesulfonamide (N-DMSN)

[0055] Table 3: Recipe composition of N-DMSN modified vitamin E nanoemulsion

[0056]

[0057] ER-targeted vitamin E nanoemulsions loaded with CMZ and N-DMSN (CMZ@ER-NEs) and their control nanoemulsion NEs, CMZ@NEs and ER-NEs were prepared by phacoemulsification. The nanoemulsion particle diameter under this preparation prescription is about 120-180nm, potential about 0 to-15mV (dynamic light scattering method detects), has certain cytotoxicity (see Image 6 ).

[0058] Using the fluorescent probe DiD as a model drug, non-targeting nanoemulsion DiD@NEs and N-DMSN modified endoplasmic reticulum-targeting nanoemulsion DiD@ER-NEs were prepared respectively, and the effects of the preparation on hepatocytes, macrophages and umbilical vein were investigated. In vitro uptake in endothelial cells. The results showed that...

Embodiment 3

[0060] Example 3 Investigation of p-DBSN-modified drug-loaded vitamin E nanoemulsion (CMZ@ER-NEs) in alleviating ethanol-induced hepatocyte stress in vitro

[0061] Stimulate hepatocytes (AML-12) with 100mM ethanol in vitro for 12h, add different emulsions (1mL culture solution corresponds to adding 10μL emulsion) and continue to culture for 24h, and then use western bolt method to investigate the key protein CYP2E1 of oxidative stress and endoplasmic reticulum stress Expression of the response protein XBP-1s (see Figure 9 ), or examine the expression of inflammatory transcription factors NF-κB (p65) and AP-1 (c-JUN) by immunofluorescence staining (see Figure 10 ). The results showed that ethanol stimulation could significantly upregulate the expressions of CYP2E1, XBP-1s and inflammatory transcription factors, while vitamin E nanoemulsions, especially drug-loaded CMZ@NEs and CMZ@ER-NEs could significantly inhibit these stress-related proteins under ethanol stimulation Hig...

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Abstract

The invention provides construction and application of a vitamin E nano-carrier capable of reversing alcoholic liver diseases. The nano preparation is loaded with chloromethylthiazole CMZ and vitamin E, the nano system is modified by small molecules or polypeptide with endoplasmic reticulum tropism to realize endoplasmic reticulum targeting of a carrier, CMZ is delivered to the endoplasmic reticulum of liver cells for site specific inhibition of CYP2E1 to limit generation of reactive oxygen species (ROS), and vitamin E neutralizes existing ROS, so that the CMZ / vitamin E nano preparation is prepared. Therefore, oxidative stress injury of the liver under alcohol stimulation is relieved, and alcoholic liver diseases are reversed. The nano-carrier disclosed by the invention can be a drug loading system such as nano-emulsion, liposome or lipid nanoparticles, the CMZ can be replaced by other CYP2E1 inhibitors, and the vitamin E can be replaced by other antioxidant components. The nano preparation is used by intravenous injection or oral administration, and can play a role in protecting the liver in related diseases caused by abnormal CYP2E1 expression.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to the construction and application of a vitamin E nanocarrier capable of reversing alcoholic liver disease. Hepatoprotective effects in fatty liver, non-alcoholic fatty liver, diabetes and drug poisoning and other diseases or pathological conditions. Background technique [0002] Drinking is an important part of culture and table manners, and an important medium of material and spiritual civilization. However, excessive alcohol consumption is an addictive behavior. In recent years, the global per capita alcohol consumption has increased rapidly [Nat Rev Dis Primers 4,16(2018)] [Gastroenterology 150,1786-1797(2016)], alcohol abuse-related morbidity and The mortality rate is rising year by year, bringing a heavy social and economic burden [W.H.O.Global status report on alcohol and health 2018]. [0003] The ingested ethanol can be quickly absorbed by the stomach (30%) and small intestine (70%...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K47/24A61K47/14A61K47/42A61K47/20A61K45/06A61K31/355A61K31/425A61P1/16A61P3/10
CPCA61K9/1075A61K47/24A61K47/14A61K47/42A61K47/20A61K45/06A61K31/355A61K31/425A61P1/16A61P3/10A61K2300/00
Inventor 游剑施莹莹李青坡
Owner ZHEJIANG UNIV
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