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A kind of composite nanoparticle loaded with miRNA and its preparation method and application

A technology of composite nanoparticles and membrane materials, applied in the field of biomedicine, can solve the problems of non-degradation and metabolism, poor biocompatibility, complicated preparation, etc., to promote selective release and gene regulation, and improve targeting accuracy Sexuality and efficiency, enhance the effect of gene regulation

Active Publication Date: 2020-08-07
SHENZHEN INST OF ADVANCED TECH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no effective means to activate TAMs into M1 macrophages with anti-tumor effect, and there is also a lack of efficient and safe carriers that can deliver miRNAs to TAMs to block the intracellular immunosuppressive signaling pathways
In addition, there are still many deficiencies in the existing nanocarriers, such as poor stability of most nanocarriers, poor biocompatibility, inability to completely degrade and metabolize in vivo, etc. The size of the diameter, etc., the existence of these shortcomings greatly limits the application of polymer nanocarriers

Method used

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  • A kind of composite nanoparticle loaded with miRNA and its preparation method and application
  • A kind of composite nanoparticle loaded with miRNA and its preparation method and application
  • A kind of composite nanoparticle loaded with miRNA and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The preparation of embodiment 1 galactose-polylysine-polycysteine ​​polymer Gal-PLL-PLC (GPP)

[0062] Dissolve n-butane (12.58 μL) and Lys(Z)-NCA (0.78 g) into 20 mL of dimethylformamide DMF, stir at 30° C. under nitrogen protection, and react for 72 hours. After the reaction, add 5 to 50 times of diethyl ether to precipitate, filter and dry to obtain PLL(Z).

[0063] Through the method of NCA ring-opening polymerization, the initiator PLL(Z) (0.41g) and Cys(Z)-NCA (0.22g) were heated to 30°C under the protection of nitrogen, and reacted at constant temperature for 48 hours to synthesize polylysine Acid-polycysteine ​​(PLL(Z)-PLC(Z)) diblock polymer. Dissolve the PLL(Z)-PLC(Z) diblock polymer in trifluoroacetic acid at 0°C, add 30% HBr / HAc to react for 2 hours, add 10 times of diethyl ether to precipitate, filter, and dissolve the obtained product in Polar organic solvents were dialyzed in water for 48 hours using a dialysis bag with a molecular weight cut-off of 350...

Embodiment 2

[0065] Embodiment 2 has the preparation of the polyethylene glycol-polylysine polymer of acid-sensitive effect

[0066] Ring-opening polymerization via NCA with initiator PEG-NH 2 (0.4g) reacted with Lys(Z)-NCA (0.49g) at constant temperature for 48 hours under the protection of nitrogen to synthesize PEG-PLL polymer. 3,4,5,6-tetrahydrophthalic anhydride DCA (49 mg) was added to the PEG-PLL solution (5.7 mg, 10 mg / mL) and stirred in the dark at 25°C for 2 hours. Add 3M NaOH to the above mixture to maintain pH8.5, dialyze for 48 hours, change the dialysis water every 2 hours, and then freeze-dry to obtain PEG-PLL (DCA), that is, PPD.

Embodiment 3

[0067] Example 3 Preparation of composite nanoparticles loaded with microRNA:

[0068] Combine the synthesized microRNA-CY3 with galactose-polylysine-polycysteine ​​polymer and the polyethylene glycol-polylysine polymer aqueous solution (microRNA:GPP:PPD=1:40: 40) mixed and oscillated, and left to stand at room temperature for 5 minutes to obtain miRNA-loaded composite nanoparticles ( figure 1 ). The particle size distribution and electron microscope characterization are as follows Figure 5 shown.

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Abstract

The invention discloses an miRNA-supported composite nanoparticle. The miRNA-supported composite nanoparticle is prepared from a cation targeted membrane material, an acid sensitivity membrane material and at least one miRNA, wherein the cation targeted membrane material is selected from a galactose-polylysine-polycysteine polymer; the acid sensitivity membrane material is selected from a polyethylene glycol-polylysine polymer of which a side chain is modified by 3,4,5,6-tetrahydrophthalic anhydride ligand; and the miRNA is selected from miRNA for inducing differentiation from tumor-associatedmacrophage to M1 type macrophage. According to the miRNA-supported composite nanoparticle disclosed by the invention, accurate delivery of the tumor-associated macrophage is realized by pH value targeting and active targeting, and the function of promoting the differentiation from the tumor-associated macrophage to the M1 type macrophage is realized.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a targeted delivery carrier. Background technique [0002] As an important class of immune cells, macrophages can be divided into classically activated M1 type and alternatively activated M2 type. Among them, M1 macrophages are an important type of effector cells, which not only can secrete a large number of pro-inflammatory cytokines (IL-12, IL-23, etc.) and reactive oxygen intermediates, but also have a strong ability to kill microorganisms and tumor cells ability. In contrast, the M2 type mainly secretes anti-inflammatory cytokines such as IL-10, various chemokines and growth factors, which can inhibit immune response and inflammation, and promote tissue repair. Tumor-associated macrophages (TAMs) are differentiated from peripheral monocytes under the regulation of various cytokines, growth factors, hypoxia and other factors in the tumor microenvironment. Its cell phenotype is ma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/51A61K9/107A61K31/7088A61K47/34A61K47/54A61K47/69A61K47/60A61K47/10A61P35/00
CPCA61K9/1075A61K9/5146A61K31/7088
Inventor 马轶凡蔡林涛刘兰兰何华美
Owner SHENZHEN INST OF ADVANCED TECH CHINESE ACAD OF SCI
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