Heart and brain dual targeting lipidosome as well as preparation method and applications of heart and brain dual targeting lipidosome

A technology targeting liposomes and liposomes, applied in the field of medicine, can solve problems such as side effects and low efficiency, and achieve the effect of individualized treatment

Active Publication Date: 2018-10-16
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although myocardial targeted therapy has been explored for many years, there are still some challenges of side effects and inefficiency

Method used

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  • Heart and brain dual targeting lipidosome as well as preparation method and applications of heart and brain dual targeting lipidosome
  • Heart and brain dual targeting lipidosome as well as preparation method and applications of heart and brain dual targeting lipidosome
  • Heart and brain dual targeting lipidosome as well as preparation method and applications of heart and brain dual targeting lipidosome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1 Synthesis of Brain Targeting Molecule Diisoamylphosphoethanolamine-Polyethylene Glycol-1000-p-P-Carboxyphenyl-α-D-Acetyl Mannosamine (DSPE-PEG-1000-Ac4MAN)

[0070]

[0071] Formula I (wherein the polyethylene glycol part is PEG-1000)

[0072] Azide-polyethylene glycol-carboxy 1000 (1.3 g) was dissolved in tetrahydrofuran (20 mL), then Pd / c (0.066 g) and acetic acid (1 mL) were added, and hydrogen gas was introduced at room temperature to react overnight. After the crude product was filtered, it was rotary evaporated to dryness, then dissolved in dichloromethane (20 mL), triethylamine (TEA, 0.65 mL) and Ac 4 MAN (1.5g) was reacted overnight at room temperature. Go through the column to get PEG1000-Ac 4 MAN (1.18 g), 62% yield. Dissolve PEG 1000-Ac4MAN (1.18g) in dichloromethane, add NHS (0.2g) and EDCI (0.45g) in sequence, react overnight at room temperature, and pass through the column to obtain succinimide polyethylene glycol acetyl mannoside (1.0 g),...

Embodiment 2

[0074] Example 2 Brain targeting molecule diisoamylphosphoethanolamine-polyethylene glycol-600-p-p-carboxyphenyl-α-D-acetylmannosamine (DSPE-PEG-600-Ac 4 MAN) synthesis

[0075]

[0076] Formula I (wherein the polyethylene glycol part is PEG-600)

[0077] Azide-polyethylene glycol-carboxy 600 (1.3 g) was dissolved in tetrahydrofuran (20 mL), then Pd / c (0.078 g) and acetic acid (1 mL) were added, hydrogen gas was introduced at room temperature, and the reaction was carried out overnight. After the crude product was filtered, it was rotary evaporated to dryness, then dissolved in dichloromethane (20 mL), added triethylamine (TEA, 0.79 mL) and Ac4MAN (1.7 g), and reacted overnight at room temperature. After passing through the column, PEG600-Ac4MAN (1.08 g) was obtained with a yield of 62%. Dissolve PEG 600-Ac4MAN (0.95g) in dichloromethane (20mL), add NHS (0.3g) and EDCI (0.51g) in sequence, react overnight at room temperature, and pass through the column to obtain succinim...

Embodiment 3

[0079] Example 3 Brain targeting molecule diisoamylphosphoethanolamine-polyethylene glycol-2000-p-p-carboxyphenyl-α-D-acetylmannosamine (DSPE-PEG-2000-Ac 4 MAN) synthesis

[0080]

[0081] Formula I (wherein the polyethylene glycol part is PEG-2000)

[0082] Azide-polyethylene glycol-carboxy 2000 (1.3 g) was dissolved in tetrahydrofuran (20 mL), then Pd / c (0.052 g) and acetic acid (1 mL) were added, and hydrogen gas was introduced at room temperature to react overnight. After the crude product was filtered, it was rotary evaporated to dryness, then dissolved in dichloromethane (20 mL), added triethylamine (TEA, 0.54 mL) and Ac4MAN (1.34 g), and reacted overnight at room temperature. Through the column, PEG2000-Ac4MAN (1.15 g) was obtained with a yield of 63%. Dissolve PEG 2000-Ac4MAN (0.95g) in dichloromethane (20mL), add NHS (0.09g) and EDCI (0.19g) in turn, react overnight at room temperature, and pass through the column to obtain succinimide polyethylene glycol Acetyl...

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Abstract

The invention discloses a heart and brain dual targeting lipidosome as well as a preparation method and applications of the heart and brain dual targeting lipidosome. The heart and brain dual targeting lipidosome is obtained by coupling an Anti-cTnI protein antibody or a fragment of the Anti-cTnI protein antibody on the surface of a lipidosome modified by an acetylated glycoester-polyethylene glycol-phosphatidyl ethanolamine conjugate as shown in the formula I. According to the technical scheme, by modifying the mannose molecule derivative and the Anti-cTnI protein antibody on the surface of the lipidosome, the lipidosome has the dual targeting effects including brain targeting and heart targeting, and the treatment for the heart and the brain can be realized. The in-vitro cell experiment,the affinity experiment and the in-vivo distribution experiment prove that the lipidosome can treat myocardial diseases, and also can span the blood brain barrier for treating diseases caused by cardiogenic diseases. In addition, by changing the length of the PEG (Linker) on the surface of the lipidosome, the spatial positions of the sugar molecule derivative and the antibody can be changed, thusthe distribution of medicines in the heart and the brain tissue can be changed, the distribution change of the medicines in the heart and the brain can be regulated, and the individualized treatmentis realized.

Description

technical field [0001] The invention relates to a liposome used as a drug carrier and its preparation method and application, in particular to a liposome which has dual targeting effects on the brain and the heart and can realize simultaneous treatment of the heart and brain and its preparation method. The invention belongs to the technical field of medicine. Background technique [0002] Cardiovascular and cerebrovascular diseases (Aspen syndrome, heart and brain insufficiency, etc.) seriously threaten human health, with high mortality and morbidity. Cardiovascular and cerebrovascular diseases are accompanied by insufficient blood supply to the heart and brain. Due to myocardial ischemia, the heart is in a state of lack of energy, which can cause arrhythmias and angina. When this occurs, it can also result in acute myocardial infarction, often resulting in cardiogenic shock. At the same time, the blood supply to the brain is also reduced by abnormal cardiac function due ...

Claims

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Application Information

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IPC IPC(8): A61K47/54A61K47/68A61K47/60A61K47/69A61K33/36A61P9/00A61P9/10A61P25/00A61P35/00C08G65/332C08G65/335
CPCA61K33/36A61K47/549A61K47/60A61K47/68A61K47/6913A61P9/00A61P9/10A61P25/00A61P35/00C08G65/3328C08G65/3356
Inventor 杨宝峰彭海生刘肖莹李明慧廉明明唐淑坤刘云翠柴彦群
Owner HARBIN MEDICAL UNIVERSITY
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