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Three-dimensional spherical alpha-helix cationic polypeptide with high-efficiency gene delivery capability, and preparation method and application thereof

A technology of gene delivery and cationic polymerization, applied in gene therapy, non-effective ingredients of genetics, non-effective ingredients of polymer compounds, etc., can solve problems such as cytotoxicity

Active Publication Date: 2019-11-15
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, when used in high doses or in contact with cells for a long time, the polypeptide will open too many pores on the biofilm, resulting in significant cytotoxicity

Method used

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  • Three-dimensional spherical alpha-helix cationic polypeptide with high-efficiency gene delivery capability, and preparation method and application thereof
  • Three-dimensional spherical alpha-helix cationic polypeptide with high-efficiency gene delivery capability, and preparation method and application thereof
  • Three-dimensional spherical alpha-helix cationic polypeptide with high-efficiency gene delivery capability, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Dissolve L-glutamic acid in water (375 mL) and heat to 70 °C with stirring, then add aqueous solution (375 mL) of copper acetate hydrate (18.6 g, 103 mmol) dropwise to L-glutamic acid in solution. After that, the stirring was stopped, and after standing at room temperature for 48 h, the precipitate was stirred and washed with water, ethanol, and petroleum ether for 24 h, and the blue solid was obtained by suction filtration, that is, copper (II) L-glutamate complex, which was freeze-dried Store in a desiccator for later use;

[0095] Potassium carbonate (15.2 g, 0.11 mol) and p-hydroxybenzyl alcohol (9.3 g, 0.075 mol) were dissolved in acetone (150 mL), and propyne bromide (6.75 mL, 0.09 mol) and 18-crown Ether-6 (0.1 g). After the solution was refluxed at 75 °C for 12 h, the acetone was removed by a rotary evaporator, and water (200 mL) was added to dissolve the remaining solid. The solution was extracted with dichloromethane (30 mL×3), and the organic phases were c...

Embodiment 2

[0100] 1, 6-Dibromohexane (1.26 mL, 8 mmol) and sodium azide (1.6 g, 24 mmol) were dissolved in DMF (19 mL), and reacted at 60 °C for 24 h. Then water (150 mL) was added to dissolve the insoluble matter, extracted with diethyl ether (20 mL×3) and the organic phase was collected. After the organic phase was dried with sodium sulfate, it was filtered and rotary evaporated to obtain a white oily substance, that is, compound 4, which was subjected to NMR with deuterated chloroform. Figure 5 its NMR spectrum.

[0101] Compound 4 (3.33 g, 20 mmol) was dissolved in a mixed solvent of diethyl ether (15 mL) and ethyl acetate (15 mL), and 5 % hydrochloric acid solution (30 mL) was added, and triphenyl Phosphorus (5.51 g, 22 mmol), ensured that the two phases were separated and stirred slowly for 1 h, then reacted at room temperature for 24 h. Subsequently, 1M hydrochloric acid solution (30 mL) was added to wash the organic phase, and the aqueous phase was collected after separation. ...

Embodiment 3

[0104] In a glove box, dissolve γ-(4-propargyloxybenzyl)-L-glutamic acid-N-carboxylic acid anhydride monomer (50 mg, 1.6 mmol) in anhydrous N,N-dimethylformaldehyde Amide (1 mL), and the third-generation dendrimer (0.68 mg, 0.001 mmol) was added, and the reaction was stirred at room temperature for 72 h. Subsequently, the reaction phase was added dropwise into ice methanol (50 mL) to precipitate, and the methanol was removed after centrifugation to obtain polymer A, which was subjected to NMR with deuterated chloroform. Figure 8 its NMR spectrum.

[0105] Dissolve γ-(4-propargyloxybenzyl)-L-glutamic acid-N-carboxylic anhydride monomer (50 mg, 1.6 mmol) in anhydrous dichloromethane (1 mL) in the glove box , and the third-generation dendrimers (0.68 mg, 0.001 mmol) were added, and the reaction was stirred at room temperature for 30 min. Subsequently, the reaction phase was added dropwise into ice methanol (50 mL) to precipitate, and the methanol was removed after centrifugati...

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Abstract

The invention provides a three-dimensional star-shaped alpha-helix polypeptide with high-efficiency gene delivery capability, and a preparation method and application thereof. Dendritic molecules areused as an initiator and dichloromethane is used as a reaction solvent to initiate high-speed ring-opening polymerization of different types of N-carboxylic anhydride monomers, and groups with different electric properties are introduced at the tail ends through a click chemical reaction. Rich amino groups on the surfaces of the dendrimers provide enough polymerization sites, so that the polypeptide forms a three-dimensional spherical topological structure, and meanwhile, the topological structure provides an opportunity for acceleration of the initial stage of a ring-opening polymerization reaction. The polypeptide side chain modified guanidino / amino groups and the like bring higher positive charge density, high-efficiency gene loading capacity can be obtained through electrostatic interaction between positive charges and negative charges, and an alpha spiral rigid structure on a secondary structure is enhanced, so that the polypeptide has higher membrane penetrating capacity. The polypeptide has a great development prospect in the field of biomedical materials, particularly gene delivery through properties of the polypeptide.

Description

technical field [0001] The invention relates to the field of gene loading and delivery, in particular to a three-dimensional spherical α-helical cationic polypeptide with high-efficiency gene delivery capability and its preparation method and application, which can be applied to combined photothermal-gene therapy of breast cancer. Background technique [0002] Gene delivery vectors are necessary media for loading nucleic acid molecules, introducing them into target cells and successfully expressing them. They are mainly divided into two types: viral vectors and non-viral vectors. Viral vectors have been widely used due to the advantages of high transduction efficiency and expression efficiency, but their own antigenicity, potential tumorigenic risk and insufficient gene loading have seriously restricted their development. Based on this, non-viral vectors have gradually gained attention. Commonly used non-viral vectors include liposomes, nanoparticles, cationic polymers, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G69/48C08G69/16A61K47/42A61K48/00A61P35/00
CPCC08G69/48C08G69/16A61K48/0008A61K47/42A61P35/00C08G69/10C08G73/028C08G83/004C12N15/88C12N15/1138C12N15/111C12N2310/14C12N2310/351C12N2320/32A61K9/5146
Inventor 殷黎晨叶桓党娟娟侯梦滢朱蓉英
Owner SUZHOU UNIV
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