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Nucleic acid molecule-loaded acid response polymer modified bismuth elementary substance nanosheet as well as preparation method and application thereof

A technology of nucleic acid molecules and polymers, applied in the field of medicine, can solve problems such as toxic and side effects hindering the development and application of nano-medicines

Pending Publication Date: 2021-02-05
THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] While bringing therapeutic effects, the toxic side effects caused by organ accumulation have greatly hindered the development and application of nano-medicines

Method used

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  • Nucleic acid molecule-loaded acid response polymer modified bismuth elementary substance nanosheet as well as preparation method and application thereof
  • Nucleic acid molecule-loaded acid response polymer modified bismuth elementary substance nanosheet as well as preparation method and application thereof
  • Nucleic acid molecule-loaded acid response polymer modified bismuth elementary substance nanosheet as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Preparation of bismuth elemental nanosheets loaded with siRNA modified by acid-responsive polymer

[0085] (1) Preparation of acid-responsive polymers

[0086] ① Dissolve 40mmol p-formobenzoic acid (6g), 4mmol DCC (8.2g), 10mmol DMAP (1.2g) and 4mmolmPEG (8g) in 150ml dichloromethane, react at room temperature for 24h, filter the solution until clear, and filter the filtrate Concentrate to 20ml by rotary evaporation to obtain solution A;

[0087] ② Add solution A to 80 mL of isopropanol, freeze overnight, collect the precipitate, wash with isopropanol and ether to obtain precipitate B, which is aldehyde-modified polyethylene glycol (mPEG-CHO);

[0088] ③ Precipitate B and branched polyethyleneimine PEI were stirred and reacted in alkaline water (pH=7.4) for 30 min according to the mass ratio of 1:2 to prepare solution C, which is the PEG-modified PEI complex mPEG-PEI.

[0089] (2) Preparation of bismuth elemental nanosheets

[0090] ①Dissolve 1mmol of bismuth nitrate...

Embodiment 2

[0100] Characterization of bismuth elemental nanosheets loaded with siRNA modified by acid-responsive polymer

[0101] Get the mPEG-CHO prepared in Example 1 to carry out nuclear magnetic detection, figure 1 For the 1H-NMR spectrum of mPEG-CHO, the chemical shift of each proton was assigned. To demonstrate the acid responsiveness of mPEG-d-PEI, we dissolved mPEG-d-PEI in D at pH 6.5 and 7.4 2 In O, 1H-NMR test was carried out after 10 min. We found that under the condition of pH 7.4, no -CHO proton characteristic absorption peak (δ ~ 10.0ppm) appeared; under the condition of pH 6.5, there appeared obvious -CHO proton characteristic absorption peak, which proved that the The acid-responsive shedding of PEG indicates that mPEG-d-PEI has good acid-responsive properties, and can break the imine bond in an acidic environment to shed PEG.

[0102] Get the bismuth elemental nanosheet prepared in Example 1 to take a transmission electron microscope picture, as figure 2 As shown, ...

Embodiment 3

[0107] Application of acid-responsive polymer-modified bismuth elemental nanosheets loaded with siRNA

[0108] Figure 8 Indicates the uptake of 4T1 cells to the Bi@PP / siRNA prepared in Example 1, measured by flow cytometry, the specific method is as follows:

[0109] 1) Cell culture

[0110] The murine breast cancer cells 4T1 were cultured in DMEM or 1640 liquid medium containing 10% fetal bovine serum, and cultured in an incubator at 37°C and 5% carbon dioxide.

[0111] 2) Cellular uptake assay

[0112] 4T1 cells were inoculated into a 6-well plate at a density of 6x 104, added Bi@PP / siRNA (20nM siRNA) after overnight culture, and incubated for 12h. A group of cells was irradiated with a LWRL808 laser at a power of 0.5W / cm2 for 5min, and incubated for 24h. Wash 3 times with PBS. After the cells were collected by trypsinization, they were resuspended in 200 μL PBS, and the fluorescence intensity was detected by flow cytometry. Cellular uptake results such as Figure 8 A...

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Abstract

The invention discloses a preparation method of a bismuth elementary substance nano-drug which simultaneously has the functions of thermal therapy combined with immunotherapy, and imaging and acid response, can carry nucleic acid molecules and can be metabolized. The nano-drug is an acid response polymer modified bismuth elementary substance nano-sheet carrying the nucleic acid molecules. The nanosheet not only can be used for photo-thermal combined immunotherapy and CT imaging, but also has a large specific surface area as a two-dimensional material, improves the drug loading rate, and provides guarantee for subsequent biomedical application due to the fact that the element is single and the biological safety is higher. In tumor slight acidic environment, mild heat is generated through laser irradiation to release nucleic acid molecules in a controlled manner, and besides, on one hand, the mild heat triggers tumor immunogenic death, promotes DC cell maturation and T cell immune response, and on the other hand, aggregation and permeation of a nano material are promoted at a tumor part through an EPPR effect, so that the limitation of ICB therapy is solved. In addition, the nano material can be metabolized out of a body, and a safe platform is provided for clinical popularization of the nano-drug. The safe nano-drug with integrated diagnosis and treatment overcomes the defects of a traditional tumor diagnosis and treatment method, and is suitable for tumor diagnosis and treatment with complex requirements.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to an acid-responsive polymer-modified bismuth nanosheet loaded with nucleic acid molecules, a preparation method thereof, and an application in tumor diagnosis and treatment. Background technique [0002] Although in the past few decades, human beings have made great progress in understanding and overcoming cancer, cancer is still a major disease that affects human health and longevity. The "Global Cancer Report 2014" issued by the World Health Organization pointed out that "the world is facing a major cancer outbreak, and China has the highest incidence rate". The National Cancer Registry Center pointed out that in 2012, there were more than 3 million new cancer patients in my country, and about 2.5 million people died of cancer every year. Such high morbidity and mortality are largely due to the poor efficacy of traditional cancer treatment methods, large toxic side effects, ...

Claims

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Application Information

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IPC IPC(8): A61K33/245A61K31/7105A61K31/713A61K41/00A61K9/51A61K47/34A61K47/60A61K47/69A61P35/00A61K49/04A61K49/00
CPCA61K33/245A61K31/7105A61K31/713A61K41/0052A61K9/5146A61K47/60A61K47/6935A61P35/00A61K49/04A61K49/0045
Inventor 陈春英刘晶郭梦雨谷战军
Owner THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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