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Recombinant high density lipoprotein (HDL) medicament delivery system with functions of targeted and reverse cholesterol transport (RCT) on vascular wall and application thereof

A high-density lipoprotein and drug-loading system technology, applied in the field of fat-soluble cardiovascular drug carriers, can solve the problems of endangering human health, low bioavailability, and harm, and achieve high drug loading and high apolipoprotein binding rate , The effect of improving physiological function

Inactive Publication Date: 2014-05-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] As we all know, cardiovascular drugs, especially some traditional Chinese medicine ingredients, are mostly fat-soluble and have low bioavailability, which brings a lot of inconvenience to clinical application. Sustained-release particulate preparations of vascular drugs, such as liposomes, solid lipid nanoparticles, etc., but the common lipid materials used in these preparations are mostly derived from the oils used in enteral and parenteral nutrition emulsions, long-term use or Intravenous injection, potentially harmful
For example, glycerol monostearate is generally used as a food additive; the content of triglyceride and cholesterol in the blood is closely related to hyperlipidemia and atherosclerosis. Long-term intake of these exogenous fats will definitely endanger Human health, for patients with cardiovascular and cerebrovascular diseases, does more harm than good

Method used

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  • Recombinant high density lipoprotein (HDL) medicament delivery system with functions of targeted and reverse cholesterol transport (RCT) on vascular wall and application thereof
  • Recombinant high density lipoprotein (HDL) medicament delivery system with functions of targeted and reverse cholesterol transport (RCT) on vascular wall and application thereof
  • Recombinant high density lipoprotein (HDL) medicament delivery system with functions of targeted and reverse cholesterol transport (RCT) on vascular wall and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026]

[0027]

[0028] Preparation process: put the prescribed amount of medicine, lecithin, and cholesterol in a vial, add an appropriate amount of chloroform, dissolve it with ultrasound, transfer it into an eggplant-shaped bottle, place it in a rotary evaporator, remove the organic phase under reduced pressure, and dry it in vacuum 2h, add an appropriate amount of hydration medium dissolved with sodium cholate, ultrasonically disperse evenly into a translucent suspension, then use a probe to ultrasonically pulverize to make it transparent and opalescent liquid, pass through a 0.22 μm filter membrane, add apolipoprotein, After dissolving, place in a refrigerator at 4°C, stir magnetically at 300rpm for 3-6h, and dialyze overnight with 2L of Tris-HCl buffer containing NaCl and sodium EDTA to obtain rHDL.

[0029] Adopt transmission electron microscope to observe the form before and after incubation of rHDL and albumen in embodiment 1, see appendix figure 1 In B and D, ...

Embodiment 2

[0031]

[0032] The preparation process is the same as in Example 1. The average particle size of the prepared rHDL after incubation with the protein is 211.5 nm, the encapsulation rate is 89.12%, and the protein binding rate is 44.1%.

[0033] In vitro cell experiment: the mouse cell line RAW264.7 macrophage was used to stimulate the oxidized low-density lipoprotein to replicate the foam cell model, and discoid rHDL was added to the two types of cells to investigate the effect on very low-density lipoprotein (VLDL), Targeting of rHDL under the action of lecithin cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), the results showed that the phagocytosis of discoid rHDL in foam cells was 0.19 μg / 1000000 cells, macrophages The uptake of rHDL was 0.084μg / 1000000 cells, there was a significant difference between the two, and the phagocytosis was dependent on VLDL and CETP. After adding LCAT, the phagocytosis of foam cells increased to 0.505μg / 1000000 ...

Embodiment 3

[0036]

[0037] The preparation process is the same as in Example 1. The average particle size of the prepared rHDL after incubation with the protein is 173.4 nm, the encapsulation rate is 88.12%, and the protein binding rate is 61.3%.

[0038] In vitro cell test: as in Example 2, the uptake of disc-shaped rHDL foam cells was 0.21 μg / 1,000,000 cells, and the uptake of macrophages was 0.087 μg / 1,000,000 cells.

[0039] Cell cholesterol efflux experiment: Same as Example 2, rHDL mediates intracellular cholesterol efflux, and the content is reduced to 41.2% of the initial amount of intracellular cholesterol, indicating that the rHDL constructed with the same components as the natural HDL apolipoprotein is more than containing only apoA-I rHDL has a higher ability to mediate cholesterol efflux.

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Abstract

The invention belongs to the medical technical field, and relates to a new function of high density lipoproteins (HDLs) of different structures as a targeted carrier for a liposoluble cardiovascular medicament. The recombinant HDL can be taken as a cholesterol receptor for receiving excess extra-hepatic cellular cholesterol and transporting the cholesterol to liver for metabolism, thus achieving the purpose of treating cardiovascular or arteriosclerotic disease. In the invention, the HDLs or lipid components thereof are recombined into the carrier for the liposoluble medicament in vitro so as to achieve dual functions of medicament delivery to an atherosclerosis focal area on a vascular wall and reverse cholesterol transport (RCT), which provides a new effective way for treating cardiovascular disease.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the preparation of different structurally recombined high-density lipoproteins and its new function as a carrier of fat-soluble cardiovascular medicines, to achieve the functions of transporting medicines to target atherosclerotic lesions on blood vessel walls and reversely transporting cholesterol. Background technique [0002] Numerous studies have shown that the level of plasma high density lipoprotein (HDL) is negatively correlated with the occurrence and severity of atherosclerosis (As) and coronary heart disease. An important mechanism of HDL's resistance to As is that HDL participates in reverse cholesterol transport, moving excess cholesterol out of extrahepatic tissues and transporting it to the liver for transformation and clearance. In addition, HDL also has the functions of anti-lipid oxidation, inhibiting platelet aggregation and expression of adhesion molecules, af...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/42A61K47/24A61K47/28A61K47/14A61P9/10
Inventor 刘建平张文丽谷晓
Owner CHINA PHARM UNIV
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