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Preparation and application of sugar-targeted modified siRNA nanoparticle

A nanoparticle and targeted modification technology, applied in DNA/RNA fragments, recombinant DNA technology, medical preparations of non-active ingredients, etc., can solve the problem that it is difficult for drugs to reach the lesion effectively, Alzheimer's is difficult to reach, The treatment effect is unsatisfactory and other problems, to achieve the effect of promoting blood circulation time, increasing effective accumulation, and good half-life

Active Publication Date: 2020-06-02
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Viral vectors have higher transfection efficiencies than nonviral vectors, but their association with insertional mutagenesis and immunogenicity limit their use in therapy
[0005] In addition, one of the reasons why Alzheimer's is difficult to achieve effective treatment is that it is hindered by the blood-brain barrier (BBB), and it is difficult for drugs to reach the lesion effectively, so the treatment effect is not satisfactory
In order to solve the problems of difficult drug delivery and low drug action efficiency, it is necessary to select a nanoscale delivery carrier that can cross the blood-brain barrier and target the brain.

Method used

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  • Preparation and application of sugar-targeted modified siRNA nanoparticle
  • Preparation and application of sugar-targeted modified siRNA nanoparticle
  • Preparation and application of sugar-targeted modified siRNA nanoparticle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] This embodiment provides a preparation method of targeting nanocarriers, which specifically includes the following organic synthesis steps. The targeting molecule in this example is galactose (Gal), the first linking compound is maleimidopropionic acid, the second linking compound is CPADB, and the first hydrophilic biomaterial is HS-PEG-NH 2 .

[0071] The structural formulas of dGal and dGal-Mal are as follows:

[0072]

[0073] Maleimide was grafted onto galactose through the esterification reaction of carboxyl and hydroxyl groups. The specific reaction steps were as follows: 3-maleimidopropionic acid (0.50g, 2.96mmol) and 1,2,3 , 4-di-O-isopropylidene-D-α-galactopyranose (0.82g, 3.15mmol) was dissolved in 12mL pyridine / dichloromethane solution (1 / 1=v / v), added N-ethyl-N'-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDC HCl) (0.695g, 3.62mmol), N,N-lutidine-4 - Amine (DMAP) (19 mg, 0.15 mmol), the reaction mixture was stirred at room temperature for 24 ...

Embodiment 2

[0096] This example provides a preparation method of non-targeting nanocarriers (MeO-PEG-PGUA and MeO-PEG-PGUAF), which specifically includes the following organic synthesis steps. The second connection compound in this example is CPADB, and the second hydrophilic biomaterial is MeO-PEG-NH 2 .

[0097] (1) Synthesis of MeO-PEG-CPADB.

[0098] Under ice bath conditions, CPADB (230.4mg, 0.696mmol) and NHS (100.8mg, 0.852mmol) were dissolved in 43.8mL DCM, and the DCM solution of EDC (408.6mg, 1.986mmol dissolved in 8.766mL DCM) The ice bath was removed one hour after the end of the dropwise addition. The reaction mixture was stirred at room temperature for 20 h, MeO-PEG-NH 2 (464 mg, 0.232 mmol), the reaction was allowed to stir at room temperature for 8 hours. MeO-PEG-CPADB was obtained by precipitating in cold ether, centrifuging (8000rpm, 5min, 4°C), collecting the precipitate, and drying in vacuo. The equation of the synthesis reaction is as follows:

[0099]

[010...

Embodiment 3

[0109] This example provides a method for preparing sugar-targeting modified siRNA nanoparticles.

[0110] First, centrifuge the dry siRNA powder (7000 rpm, 4 min) to precipitate the siRNA, then add 500 μL of DEPC water to prepare a 1 mg / mL siRNA solution.

[0111] Then, the polymer (1 mg, including the targeted nanocarrier prepared in Example 1 and the non-targeted fluorine-containing nanocarrier MeO-PEG-PGUAF prepared in Example 2 was dissolved in 10 mM Hepes buffer solution (pH=7.4, 10 mg / mL ), wherein the molar ratio of targeted nanocarriers and non-targeted carriers was 1:3, siRNA (15 μM in 10 mM HEPES buffer) was added and incubated at room temperature for 1 hour. Sugar-targeted nanoparticles were polymerized by mass ratio: siRNA=2.5:1 was prepared.

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Abstract

The invention discloses preparation and application of a sugar-targeted modified siRNA nanoparticle, and relates to the technical field of nanoparticle medicine carrying. The sugar-targeted nanoparticle comprises a targeted nano-carrier; the targeted nano-carrier is formed by sequentially connecting a targeted molecule, a first connecting compound, a first hydrophilic biological material, a secondconnecting compound and a cationic compound through chemical bonds; each of the first connecting compound and the second connecting compound comprises carboxyls; the first connecting compound simultaneously has maleimide groups; and a targeted molecule is cyclic aldohexose. The target molecule is set to be the cyclic aldohexose, so that the targeting of the nanoparticle on GLUT-1 proteins on a capillary endothelial cell membrane on a BBB (Blood-Brain Barrier) is facilitated; and the nanoparticle is efficiently transferred into the brain under the effect of transferring the cyclic aldohexose by the GLUT-1 proteins, so that the BBB is effectively passed, and the BBB penetrating efficiency of the sugar-targeted nanoparticles is favorably improved.

Description

technical field [0001] The invention relates to the technical field of nanoparticle drug loading, in particular to the preparation and application of sugar-targeted modified siRNA nanoparticles. Background technique [0002] Alzheimer's (AD) is a progressive neurodegenerative disease that affects more than 40 million people worldwide, and is the most common age-related neurodegenerative disease to study , memory, and other cognitive functions are characterized by gradual loss. Approved treatments use neurotransmitter modulators such as memantine, which consists of a cholinesterase inhibitor and an NMDAR antagonist. While these treatments target the symptoms of AD and can provide patients with some relief and comfort, they do not prevent the progression of the disease itself. The disease seriously affects human physical and mental health and quality of life, and is one of the world's major medical problems. [0003] RNA interference (RNA interference, RNAi) is a sequence-s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K47/34A61K47/10A61K47/26A61K31/713A61P25/28
CPCA61K9/5146A61K9/5123A61K31/713A61P25/28A61K9/5192C12N15/1137C12N2310/14C12N2320/32C12Y304/23046
Inventor 师冰洋朱飞燕郑蒙刘洋
Owner HENAN UNIVERSITY
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