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Protein-mediated brain-targeting gene delivery system and application thereof

A brain-targeting and gene-based technology, applied in the biological field, can solve problems such as transferrin application limitations, and achieve the effects of improving brain targeting, increasing the number, and improving the level

Inactive Publication Date: 2012-08-01
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, recent studies have shown that the dissociation constant (Kd) of transferrin and its receptor is 1 μM, while the concentration of free transferrin in the circulation system under physiological conditions is very high, about 25 μM, which is very important for transferrin receptors. In general, it is almost saturated, which limits the application of transferrin as a drug transporter targeting the head group

Method used

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  • Protein-mediated brain-targeting gene delivery system and application thereof
  • Protein-mediated brain-targeting gene delivery system and application thereof
  • Protein-mediated brain-targeting gene delivery system and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] PAMAM and PEG containing bifunctional groups are dissolved in phosphate buffer (PBS) with a molecular ratio of 1:2, and stirred at room temperature for 15 minutes to generate PAMAM-PEG. Unreacted PEG is removed by ultrafiltration and replaced. The buffer is PBS with pH 7.0. At the same time, lactoferrin reacts with sulfhydryl reagent N-succinyl-S-acetylthioacetate (SATA) to introduce sulfhydryl groups, and after purification, mix with PAMAM-PEG in a 1:1 molecular ratio, at room temperature After stirring and reacting for 12 hours, PAMAM-PEG-Lf is generated, and the unreacted lactoferrin is removed by size exclusion chromatography to obtain PAMAM-PEG-Lf.

Embodiment 2

[0085] PAMAM and bifunctional group-containing PEG are dissolved in PBS pH 8.0 according to the molecular ratio of 1:4, and the reaction is stirred at room temperature for 15 minutes to generate PAMAM-PEG. Unreacted PEG is removed by ultrafiltration and the buffer is changed to pH 7.0 PBS . At the same time, lactoferrin reacts with sulfhydryl reagent SATA and introduces sulfhydryl groups. After purification, it is mixed with PAMAM-PEG at a molecular ratio of 2:1, stirred at room temperature and reacted for 12 hours to generate PAMAM-PEG-Lf. Size exclusion chromatography Method to remove unreacted lactoferrin to obtain PAMAM-PEG-Lf.

Embodiment 3

[0087] PAMAM and PEG containing bifunctional groups are dissolved in PBS pH 8.0 according to the molecular ratio of 1:8, and the reaction is stirred at room temperature for 15 minutes to generate PAMAM-PEG. Unreacted PEG is removed by ultrafiltration and the buffer is changed to PBS pH 7.0 . At the same time, lactoferrin reacts with sulfhydryl reagent SATA and introduces sulfhydryl groups. After purification, it is mixed with PAMAM-PEG at a molecular ratio of 4:1, stirred at room temperature and reacted for 12 hours to produce PAMAM-PEG-Lf. Size exclusion chromatography Method to remove unreacted lactoferrin to obtain PAMAM-PEG-Lf.

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Abstract

The invention, belonging to the technical field of biology, relates to a protein-mediated brain-targeting gene delivery system and an application thereof, particularly an application in medicines for treating Parkinson disease. The gene delivery system is formed by modifying lactoferrin on a cationic high-molecular material through hydrophilic polymers to compound plasmid DNA by electrostatic action. According to the invention, the transfection efficiency and expression efficiency of genes on brain capillary vessel endothelial cells can be effectively improved, especially the brain targeting and the expression of the genes in the brain are significantly raised after administration through noninvasive intravenous injection; compared with a targeting head-constructed gene delivery system used in the prior art, the brain targeting effect is significantly improved. The results of the experiment of animal model prove that the gene delivery system can significantly improve the behavior disorder of animal pattern with Parkinson, obviously increase the number of dopaminergic neurons in corpus striatum and substantia nigra, and simultaneously raise the level of corpus striatum monoamine neurotransmitters.

Description

technical field [0001] The invention belongs to the field of biological technology, and relates to a protein-mediated brain-targeted gene delivery system and its application, especially the application in the medicine for treating Parkinson's disease. Background technique [0002] Parkinson's disease is a neurodegenerative disease commonly seen in middle-aged and elderly people. Its main pathogenesis is the selective damage of dopaminergic neurons in the substantia nigra compacta, which leads to the loss of striatal neurotransmitter dopamine (DA for short). missing. At present, the treatment of Parkinson's disease is mainly through oral administration of levodopa (L-DOPA, the precursor of DA) to increase the level of striatal DA and relieve the clinical symptoms of Parkinson's disease, but it cannot fundamentally improve the pathological state of dopaminergic neurons. , can not delay and prevent the decline process of nerve cells. With the continuous loss of dopaminergic n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61K47/42A61K47/32A61K47/34A61K47/36A61P25/16
Inventor 黄容琴蒋晨裴元英
Owner FUDAN UNIV
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