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PH response type lipid based on dendrimers as well as preparation method and application of pH response type lipid

A dendrimer and responsive technology, applied in the field of biomedical materials, can solve the problem that non-viral vectors are difficult to obtain high transfection efficiency in vivo and in vitro

Active Publication Date: 2015-09-16
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, it is often difficult for non-viral vectors to obtain high transfection efficiency in vivo and in vitro. In order to improve the transfection ability of non-viral vectors, it is necessary to allow non-viral vectors to obtain the ability to respond to complex body environments like viruses.
However, at present, the research on non-viral vectors that can simulate viral vectors well and respond to complex body environments is still in the preliminary research stage, and the corresponding carrier materials need to be further developed.

Method used

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  • PH response type lipid based on dendrimers as well as preparation method and application of pH response type lipid
  • PH response type lipid based on dendrimers as well as preparation method and application of pH response type lipid
  • PH response type lipid based on dendrimers as well as preparation method and application of pH response type lipid

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Experimental program
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Effect test

Embodiment 1

[0063] (1) Adopt divergence method or convergence method or the method that divergence-convergence combines to synthesize dendrimers of more than two generations (can refer to the method described in the patent literature of CN 103554923A), also can adopt commercially available dendrimers molecular;

[0064] (2) Carry out end group modification on the periphery of the dendritic molecule, and graft a large number of amino groups and / or guanidine groups on the periphery. When lysine or arginine or histidine is selected as the repeating unit of the dendrimer, the above-mentioned end group modification step is not required;

[0065] (3) Protect the peripheral functional groups of the resulting dendrimers containing amino groups and / or guanidine groups, and only expose one or two functional groups at one end, and then connect one end of the dendrimers through the exposed functional groups branched hydrophobic groups;

[0066](4) Removing the protecting group of amino group and / or...

Embodiment 2

[0072] (1) Dissolve plasmid DNA or RNA in sterile HBG buffer solution (20 mmoles of 4-hydroxyethylpiperazineethanesulfonic acid, 5% glucose) to prepare a 0.1 mg / mL gene solution; Dissolve in HBG buffer solution, and prepare solution A of 0.1-10 mg / mL; add any pH-responsive lipid material prepared in Example 1 into HBG buffer solution, and prepare solution A of 0.1-10 mg / mL B; or add the two pH-responsive lipid materials containing A-type groups and B-type groups prepared in Example 1 respectively into the HBG buffer solution by ethanol injection, and prepare a solution of 0.1-10 mg / mL B and C.

[0073] (2) Mix the solution A obtained in the above steps with the gene solution, and incubate at room temperature for 20 minutes to obtain a binary complex, then add solution B or solutions B and C in proportion, and incubate at room temperature for 20 minutes After that, a ternary complex is obtained.

[0074] Optionally, the cationic carrier is a cationic lipid or a commercially a...

Embodiment 3

[0079] Embodiment 3: citraconic anhydride-second-generation lysine-glutamic acid-n-undecylamine (CIT-Lys(G2)-Glu-UA 2 ,CLG2C 11 ) preparation

[0080] Take the fan-shaped dendrimers (protected by the second-generation amino Pbf / Boc) of lysine as the repeating unit of the 1st generation and the 2nd generation, glutamic acid-n-undecylamine, condensing agent (such as: 1-ethyl-(3- Dimethylaminopropyl) carbodiimide hydrochloride EDC, catalyst 1-hydroxybenzotriazole (HOBt), base (N, N-diisopropylethylamine DIPEA) according to 1:1:2: The molar ratio of 2:4, at 0 ℃, under the condition of nitrogen protection, add dichloromethane solvent, react for 0.5 hours; then react at room temperature for 24 hours, after the reaction is completed, the obtained solution is sequentially washed with sodium bicarbonate solution, sodium bisulfate solution and Wash with aqueous sodium chloride, dry over anhydrous magnesium sulfate for 12 hours, concentrate under reduced pressure, use ethyl acetate:pet...

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Abstract

The invention discloses a pH response type lipid based on dendrimers as well as a preparation method and application of the pH response type lipid, and belongs to the field of biological materials. The pH response type lipid disclosed by the invention has different surface charges under different pH environments. The specific forms are that negative electricity, neutrality or micro positive electricity are shown in an in vivo physiological environment to ensure that the pH response type lipid can have good biocompatibility, and amino groups are gradually exposed to expose more positive charges or realize charge reversal by using the pH differences between tumor tissues and normal tissues or between the inside and outside of tumor cells when the pH response type lipid reaches tumor tissue places, so that the contact between a positive electric carrier and a negative electric cell membrane is finished, and then the process of cell endocytosis is promoted. In a cytolysosome, a cationic vector continuously gives play to proton sponge effect or lysosome membrane splitting action so as to escape from lysosome.

Description

technical field [0001] The invention relates to the field of biomedical materials, in particular to a dendrimer-based pH-responsive lipid and its preparation method and application. technical background [0002] More and more gene-related diseases are considered to be curable by gene therapy, which usually requires the delivery of nucleic acid drugs to target cells to treat some tumors, asthma and cardiovascular diseases. But so far, the bottleneck limiting the clinical trials of gene drugs has been the development of safe and effective carriers. Given the high immunogenicity of viral vectors, non-viral vectors have become a hot topic for research. However, it is often difficult for non-viral vectors to obtain high transfection efficiency in vivo and in vitro. In order to improve the transfection ability of non-viral vectors, it is necessary to allow non-viral vectors to acquire the ability to respond to complex body environments like viruses. However, the research on non-...

Claims

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Application Information

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IPC IPC(8): C07K5/037C12N15/87C12N15/85A61K47/18A61K9/127A61K9/107A61K48/00
Inventor 顾忠伟聂宇姜倩岳冬徐翔晖张仕勇
Owner SICHUAN UNIV
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