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Drug for targeted therapy of Alzheimer's disease (AD) and preparation method thereof

A technology of targeted therapy for Alzheimer's disease, applied in gene therapy, drug combination, pharmaceutical formula, etc., can solve problems such as low efficiency of non-viral carrier interference, safety problems, retinopathy, etc., and achieve the relief of Alzheimer's symptoms, Inhibition of production and deposition, high biocompatibility

Inactive Publication Date: 2015-11-25
RUIJIN HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, there are unexpected side effects for small molecule BACE1 inhibitors, such as severe retinopathy
siBACE1 viral vectors have safety issues, and non-viral vectors have low interference efficiency
Therefore, there is no report on the use of high-throughput siBACE1 vectors for the treatment of Alzheimer's at home and abroad.

Method used

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  • Drug for targeted therapy of Alzheimer's disease (AD) and preparation method thereof
  • Drug for targeted therapy of Alzheimer's disease (AD) and preparation method thereof
  • Drug for targeted therapy of Alzheimer's disease (AD) and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The preparation of the magnetic mesoporous silica / SiRNA nanocomposite of embodiment 1.PHI polypeptide modification

[0038] Preparation:

[0039] 1) Synthesis of M-MSNs materials:

[0040] Synthesis of M-MSNs: Monodisperse Fe 3 o 4 The particles were synthesized by co-precipitation, and the product was stably modified with oleic acid (purchased from Sinopharm Chemical Reagent Co., Ltd.) and then stored in chloroform solution. Magnetic Fe dispersed in chloroform 3 o 4 The nanoparticles were transferred into the aqueous environment by binding the surfactant cetyltrimethylammonium bromide (CTAB, purchased from Sigma-Aldrich). Change the pH of the solution to alkaline by adding NaOH dropwise, then add TEOS to it, and increase the reaction temperature to 70°C to make the two self-assemble in the solution. The product was separated and washed with water, and then the CTAB template in the product was removed with acetone under an ultrasonic environment. The product afte...

Embodiment 2

[0052] Example 2. The biocompatibility experiment of M-MSN_BACE1PEI-KALA / PHI

[0053] Cytotoxicity of M-MSN_siRNAPEI-KALA / PHI transporter: Spread Neuro2 cells on a 96-well plate with an average number of cells per well of 0.5×10 4 indivual. After incubation for 24 hours in a constant temperature incubator at 37°C, the DMEM medium (containing 10% serum and 1% double antibody, denoted as DMEM+ / +) was replaced, and different amounts of M-MSN_siRNAPEI-KALA transporter were added to the wells. Put the cell culture plate back into the incubator, and place it on the magnetic plate corresponding to the 96-well plate for 20 min. Remove the magnetic plate, continue to incubate in the cell culture incubator for 48 hours, and then add the reagents used in the CCK8 kit for counting the number of cells to each well. After further incubation at 37° C. for 2 h, the cell plate was placed in a microplate reader (Synergy2, BioTek), and the absorbance value of each well at 450 nm was read. In ...

Embodiment 3

[0054] Example 3. M-MSN_BACE1PEI-KALA / PHI has a significant inhibitory effect on the expression of BACE1

[0055] The role of M-MSN_siRNAPEI-KALA / PHI transporter in interfering with the expression of BACE1:

[0056] Neuro2 cells were seeded in 6-well plates at a density of 4×10 5 / well, 37℃, 5%CO 2 Incubate under conditions for 24 hours. Using the lipofectmine2000 kit transfection method as a positive reference, the M-MSN_siRNAPEI-KALA / PHI with a concentration of 50nM siRNA was co-incubated with the cells. Put it on the ND-Fe-B magnetic plate, remove the ND-Fe-B magnetic plate after 1 hour. After 48 hours, the total cellular protein was collected. The interference effect of BACE1 was detected by western blot experiment. Such as image 3 As shown, M-MSN_siRNAPEI-KALA / PHI can significantly reduce the expression of BACE1.

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Abstract

The invention discloses a drug for targeted therapy of Alzheimer's disease (AD) and a preparation method thereof. The drug is a magnetic mesoporous silica / siBACE1 nanocomposite modified by PHI polypeptide; the PHI polypeptide refers to C-FRHMTEQ-C, the siBACE1 refers to BACE1_5, the nanocomposite is characterized by taking Fe3O4 nanocrystal as a core, taking magnetic mesoporous structure as a coat, loading siBACE1 in mesoporous, enveloping surface of the coat with PEI and then modifying by KALA peptide and PHI polypeptide. siBACE1 serves as an effective component of the drug, PHI polypeptide serves as a targeted head group and magnetic mesoporous silica nanoparticles modified by high-molecular polymer serves as a carrier; thus, neurons BACE-1 expression is prevented in a targeted form, production and deposition of amyloid beta-protein of AD focal areas are suppressed, and then the purpose of relieving symptom of AD is achieved. The preparation method of the drug is easy and feasible, raw materials for preparing the drug are easy to obtain, the preparation process has good repeatability, and the drug prepared has high biocompatibility.

Description

technical field [0001] The invention belongs to medical preparations, and more specifically relates to a nanometer preparation for treating senile dementia. Background technique [0002] Alzheimer's disease, also known as Alzheimer's disease (AD), is the most common cause of senile dementia, characterized by massive and progressive loss of hippocampal and cortical neurons, leading to memory impairment and cognitive dysfunction. β-amyloidβ-protein (Aβ) has a molecular weight of about 4kDa, is hydrolyzed from β-amyloid precursor protein (APP), is secreted by cells, and has strong neurotoxicity after precipitation and accumulation of cell matrix effect. The deposition of Aβ is not only related to the degeneration of neurons, but also can activate a series of pathological events, including the activation of astrocytes and microglia, the breakdown of the blood-brain barrier and changes in microcirculation, etc. The main cause of neuronal degeneration and death around senile pla...

Claims

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Application Information

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IPC IPC(8): A61K48/00A61K47/42A61K47/04A61K49/14A61P25/28A61K47/64A61K47/69
Inventor 陈生弟古宏晨李渤刘晓英李旭丁健青
Owner RUIJIN HOSPITAL AFFILIATED TO SHANGHAI JIAO TONG UNIV SCHOOL OF MEDICINE
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