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Acetylation sugar ester-polyethylene glycol-phosphatidyl ethanolamine conjugate and preparation method and application thereof

A technology of phosphatidylethanolamine conjugates and distearoylphosphatidylethanolamine, applied in the field of medicine, can solve the problems that hinder the application and effect of solid tumor treatment, and the mechanism has not been fully understood

Active Publication Date: 2018-09-28
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there is evidence that ATO induces apoptosis, induces cell differentiation, promotes the generation of reactive oxygen species, and inhibits angiogenesis, the mechanism by which ATO kills glioma cells is not fully understood.
And ATO can only be used in very low concentrations because healthy cells are also killed when exposed to high concentrations of ATO
Therefore, in clinical trials, the dilemma between the effectiveness and toxicity of the amount derived from ATO has hindered the application and effect of the treatment of solid tumors, and ATO has not yet been formally used to treat solid tumors.

Method used

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  • Acetylation sugar ester-polyethylene glycol-phosphatidyl ethanolamine conjugate and preparation method and application thereof
  • Acetylation sugar ester-polyethylene glycol-phosphatidyl ethanolamine conjugate and preparation method and application thereof
  • Acetylation sugar ester-polyethylene glycol-phosphatidyl ethanolamine conjugate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1 Synthesis of targeting molecule diisoamylphosphoethanolamine-polyethylene glycol-1000-p-p-carboxyphenyl-α-D-acetylmannosamine (DSPE-PEG-1000-Ac4MAN)

[0069]

[0070] 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 4MAN (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), 78% yield. Dissolve succinimide polyethylene glycol acetyl mannoside (0.95g) ...

Embodiment 2

[0072] Example 2 Targeting molecule Diisoamylphosphoethanolamine-polyethylene glycol-600-p-p-carboxyphenyl-α-D-acetylmannosamine (DSPE-PEG-600-Ac 4 MAN) synthesis

[0073]

[0074] 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 PEG600-Ac4MAN (0.95g) in dichloromethane (20mL), add NHS (0.3g) and EDCI (0.51g) in turn, react at room temperature overnight, and pass through the column to obtain succinimide polyethylene glycol acetylene Mannoside (0.82 g), 80% yield. Add succinimid...

Embodiment 3

[0076] Example 3 Targeting molecule Diisoamylphosphoethanolamine-polyethylene glycol-2000-p-p-carboxyphenyl-α-D-acetylmannosamine (DSPE-PEG-2000-Ac 4 MAN) synthesis

[0077]

[0078] 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 Acetylmannoside (0.87g), 82% yield. Add TEA (0.15 mL) and DSPE (0.3 g) dissolved i...

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Abstract

The invention discloses acetylation sugar ester-polyethylene glycol-phosphatidyl ethanolamine conjugate and a preparation method and application thereof. The acetylation sugar ester-polyethylene glycol-phosphatidyl ethanolamine conjugate is named as distearoyl-phosphatidylethanolamine-polyethylene glycol-p-p-carboxy phenyl-gamma-acid-alpha-D-acetylmannosamine (DSPE-PEG-Ac4MAN), and the acetylationsugar ester-polyethylene glycol-phosphatidyl ethanolamine conjugate has the structure shown in the formula I. In addition, the invention further provides brain-targeted liposome comprising the acetylation sugar ester-polyethylene glycol-phosphatidyl ethanolamine conjugate. A pharmacodynamic test proves that the liposome can have the 'prodrug' effect in a body, through the effect of hydrolytic enzymes in the body, cell uptake and body interior activity of drugs are improved, and the good killing activity on C6 / U87 cells is achieved. A brain-targeted drug is prepared through drug-containing arsenic trioxide (arsenic trioxide), the purpose that the arsenic trioxide crosses the blood-brain barrier to treat glioma is achieved, and the survival time of mice is obviously prolonged. A new technical means is provided for treatment of brain glioma.

Description

technical field [0001] The invention relates to an acetylated sugar ester-polyethylene glycol-phosphatidylethanolamine conjugate and its preparation method and application, in particular to the application of the conjugate in the construction of arsenic trioxide liposomes. The invention belongs to the technical field of medicine. Background technique [0002] As the most important threat to human health, intracranial tumors remain a serious and unsolved clinical problem, among which glioma is the most common brain tumor in adults with high recurrence and mortality rates. Chemotherapy, radiation therapy, surgical resection, or their combination are the main options for the treatment of glioma. However, patients still suffer from a series of chemotherapy side effects and a high recurrence rate. Due to the aggressive nature of gliomas, brain tumor cells cannot be completely removed. Glioma cells hide in various regions of the brain, even in the contralateral hemisphere, whil...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/60A61K33/36A61P35/00
CPCA61K33/36A61K47/60A61K47/6911A61P35/00
Inventor 彭海生杜智敏廉明明王娜唐淑坤李明慧刘肖莹张文远
Owner HARBIN MEDICAL UNIVERSITY
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