A brain-targeted nanoliposome loaded with positively charged polymer/mir-195 complex and its preparation method and application

A technology of mir-195 and nano-liposomes, which is applied in the field of brain-targeted nano-liposomes and its preparation, can solve the problems of poor stability of nucleic acid therapeutic drugs and hinder drug development, etc., to inhibit Aβ aggregation and facilitate entrapment and delivery , to avoid the effect of destruction

Active Publication Date: 2021-09-24
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the poor stability of nucleic acid therapeutic drugs and the inability to penetrate the blood-brain barrier (Blood-Brain Barriers, BBB) are the key problems hindering their drug development

Method used

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  • A brain-targeted nanoliposome loaded with positively charged polymer/mir-195 complex and its preparation method and application
  • A brain-targeted nanoliposome loaded with positively charged polymer/mir-195 complex and its preparation method and application
  • A brain-targeted nanoliposome loaded with positively charged polymer/mir-195 complex and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] This example provides a preparation method of the brain-targeting molecule mannose-modified PEGylated phospholipid DSPE-PEG2000-MAN:

[0087] Dissolve 10 g of D-mannose in 100 mL of acetic anhydride and 100 mL of pyridine, and react overnight at room temperature. It was extracted with ethyl acetate and water, and the organic phase was dried and spin-dried to obtain acetylated D-mannose with a yield of 93.88%.

[0088] Dissolve 21g of acetylated D-mannose in 100mL of dichloromethane, add 22.85g of p-nitrophenol and 16mL of boron trifluoride ether solution, and react overnight at room temperature. Extract with ethyl acetate and sodium hydroxide solution, dry the organic phase and spin dry. The p-nitroacetylated D-mannose was obtained by recrystallization with a yield of 70.12%.

[0089] Dissolve 2.43g of p-nitroacetylated D-mannose in 100mL of methanol, add 1.35g of sodium methoxide to react overnight at room temperature, continue to add 3mL of trifluoroacetic acid to t...

Embodiment 2

[0096] This example provides a preparation method of the brain targeting molecule TAT peptide modified PEGylated phospholipid DSPE-PEG600-TAT:

[0097] 1. Preparation of DSPE-PEG600-N 3 :

[0098] 25g PEG600 (41.7mmol, 1eq) was dissolved in 150mL DCM (dichloromethane) and 14mLTEA (triethylamine, 166.7mmol, 4eq), and stirred to dissolve PEG600. Ice bath, when the temperature of the system drops to 0°C, slowly add 19g of TsCl (4-methylsulfonyl chloride, 166.7mmol, 4eq) dropwise with a constant pressure dropping funnel, and stir overnight after the dropwise addition is complete. The reaction was monitored by TLC. The next day, add 50mL of 2M HCl to the system, stir for 15min, extract with dichloromethane and water, dry the organic phase by spin-drying, pass through a 200-300 mesh silica gel column, the mobile phase is PE (petroleum ether) and EA (ethyl acetate) according to The mixed solution prepared at a volume ratio of 5:1 gave Compound 1, 27.45 g of a colorless oily liquid...

Embodiment 3

[0115] This example provides the preparation of a brain-targeting nanoliposome PEI / miR-195+MAN+TAT-LIP (DPMT195) double-modified with PEI / miR-195 complex glycosyl and cell-penetrating peptide method:

[0116] 1. Preparation of PEI / miR-195 complex:

[0117] Dissolve 6.0 μg PEI and 7.33 μg miR-195 in 500 μL DEPC saline respectively, stir the PEI solution and slowly add it into the miR-195 solution, and let stand at room temperature for 30 minutes to form the PEI / miR-195 complex.

[0118] 2. Preparation of MAN+TAT-LIP:

[0119] Prepare EPC, CHO, DSPE-PEG2000-MAN prepared in Example 1, DSPE-PEG600-TAT prepared in Example 2 and PEI / miR-195 complexes in molar ratio 60:30:7:3:0.1; EPC, CHO, DSPE-PEG2000-MAN and DSPE-PEG600-TAT were dissolved in absolute ethanol, spin-dried under reduced pressure to obtain the primary lipid film, and the obtained primary lipid film was redissolved in absolute ethanol and spin-dried again to obtain the secondary lipid film. For the plasma membrane, ...

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Abstract

The invention relates to a brain-targeted nanoliposome loaded with a positively charged polymer / miR-195 complex, a preparation method and application thereof, and belongs to the technical field of targeted drug delivery. In order to improve the stability and blood-brain barrier penetration of nucleic acid therapeutic drugs, the present invention provides a brain-targeted nanoliposome loaded with a positively charged polymer / miR-195 complex to contain glycosyl-modified polyethylene Liposomes of glycolated phospholipids and cell-penetrating peptides modified with PEGylated phospholipids entrapped positively charged polymer / miR‑195 complexes as drug carriers. The present invention improves the stability of miR-195 through positively charged polymers and drug carriers, and improves the ability of drugs to target the brain and penetrate cell membranes through the brain-targeted nanoliposomes modified by sugar groups combined with cell-penetrating peptides. Make the carried drugs efficiently and specifically target brain tissue to treat Alzheimer's disease and vascular dementia, especially cognitive dysfunction caused by Alzheimer's disease and cerebral ischemia.

Description

technical field [0001] The invention belongs to the technical field of targeted drug delivery, and in particular relates to a brain-targeted nanoliposome loaded with a positively charged polymer / miR-195 complex and a preparation method and application thereof. Background technique [0002] As the population ages, the prevalence of dementia, including vascular dementia and Alzheimer's disease, increases year by year. Clinically commonly used drugs are mainly cholinesterase inhibitors such as donepezil and galantamine, and glutamate receptor antagonist memantine. However, these drugs only have a weak symptom-relieving effect and cannot delay the progress of the disease. With the development of molecular biology theory and technology, the design of gene drugs closely related to cognitive dysfunction is expected to become a new hope for the treatment of Alzheimer's disease. [0003] Although the mechanism of Alzheimer's disease has not been fully elucidated, β-amyloid (amyloid...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/127A61K47/24A61K47/26A61K47/28A61K47/42A61K31/7088A61P25/28A61P9/10
CPCA61K9/1271A61K31/7088A61K47/24A61K47/26A61K47/28A61K47/42A61P9/10A61P25/28
Inventor 艾静彭海生苏丹陈重
Owner HARBIN MEDICAL UNIVERSITY
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