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Antiserum and low cytotoxicity polyamino acid gene delivery carrier material with transmembrane activity and nuclear localization function

A polyamino acid and cytotoxic technology, which is applied in gene therapy, medical preparations of non-active ingredients, drug delivery, etc., to achieve high-efficiency targeted delivery, low cytotoxicity, and good antiserum ability

Active Publication Date: 2022-07-05
GUANGZHOU MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The carrier material of the present invention is a polyamino acid cationic gene delivery carrier with side chain guanidinylation, has a longer molecular chain, and the length can be adjusted, and overcomes the problem of insufficient gene loading efficiency of CPPs; it can also simulate the membrane penetration of CPPs activity, the gene is directly delivered to the cytoplasm, avoiding the lysosomal trap of the nanoparticle, thereby improving the transfection efficiency; more importantly, the carrier material of the present invention can pass through the membrane directly after loading the gene to form a nanocomplex into the cell by means of the method, and even directly carry the gene into the nucleus, with the function of "nuclear localization"

Method used

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  • Antiserum and low cytotoxicity polyamino acid gene delivery carrier material with transmembrane activity and nuclear localization function
  • Antiserum and low cytotoxicity polyamino acid gene delivery carrier material with transmembrane activity and nuclear localization function
  • Antiserum and low cytotoxicity polyamino acid gene delivery carrier material with transmembrane activity and nuclear localization function

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preparation example Construction

[0102] The present invention also provides a method for preparing the above-mentioned polyamino acid gene delivery carrier material, comprising the following steps: (1) synthesizing an esterified product of glutamic acid at the γ-position; (2) preparing step (1) corresponding to the esterified product (3) N-carboxyl cyclic anhydride (NCAs) monomers were ring-opened to prepare polyamino acids; (4) side chains containing both primary amine groups and oligomers were prepared by photoclick reaction Polyamino acid of ethylene glycol; (5) Converting the side chain amino group into guanidine group to obtain a polyamino acid gene delivery vector.

[0103] Specifically, the above-mentioned preparation method comprises the following steps:

[0104] (1) Make α,ω-enol, α,ω-alkynol, oligoethylene glycol containing α,ω-enol end group, or oligoethylene glycol containing α,ω-alkynol end group It undergoes esterification reaction with the γ-position carboxyl group of glutamic acid to synthesi...

Embodiment 1

[0112] Example 1: Ring cPALG and Linear L Synthesis of PALG

[0113] Weigh 34 moles of L-glutamic acid and 153 moles of propenyl alcohol, mix them evenly in a flask, slowly add 41 moles of concentrated sulfuric acid dropwise under ice bath conditions, and complete the dropwise addition within 30 min. After cooling for 1 h, the ice bath was removed and the temperature was raised to room temperature, and the reaction was continued for 48 h. After the reaction is completed, a sufficient amount of triethylamine is added to the system for neutralization, then a sufficient amount of acetone is added to stir, and the precipitate is obtained by filtration. The precipitate was dried in a vacuum oven at room temperature overnight, and the crude product was recrystallized from isopropanol / water, filtered, washed with sufficient cold acetone, and dried in vacuo. The product γ-allyl-L-glutamate was a white flake crystal with a yield of 47%.

[0114] Suspend 10 mole parts of γ-allyl-L-gl...

Embodiment 2

[0131] Example 2: Synthesis of cPALGgAET

[0132] Weigh the ring-shaped cPALG prepared in Example 1 containing 0.59 mole parts of C=C bond and dissolve it in 3 parts by volume of DMF, stir to dissolve it completely, and then add 1.18 mole parts of -SH bond to the mercaptoethylamine hydrochloride; Weigh 12.3 parts by mass of benzoin dimethyl ether (Irgacure 651) and add it to the reaction solution, react under ultraviolet flashlight irradiation (λmax=365nm, the intensity is 3-5mW cm -2 ) at room temperature for 120 min. After the reaction, the obtained reaction solution was put into a dialysis bag (1000 Mw) for dialysis for two days. Freeze-dried to give a nearly white solid, named cPALGgAET, yield 92%, 1 H NMR see attached image 3 , the structural formula is as follows:

[0133]

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Abstract

The invention belongs to the technical field of biomedical polymer materials, and discloses a kind of antiserum and low cytotoxicity polyamino acid gene delivery carrier material with membrane penetrating activity and cell nucleus positioning function, and a preparation method and application thereof. The polyamino acid gene delivery carrier material of the present invention has a structure as shown in Figure 1, and its side chain has guanidine cations and oligoethylene glycols with different degrees of substitution, which can effectively form nano-complex particles with genes, and can also It can effectively reduce the cytotoxicity of the carrier and improve the serum stability of the nanoparticle, and can transfer the exogenous gene into the target cell, and the transfection efficiency is good; when the carrier of the present invention delivers the gene, the transmembrane activity of the carrier can directly penetrate the gene The cell membrane enters the cytoplasm, and the nuclear localization function can make the genes carried directly enter the nucleus from the cytoplasm, effectively avoiding the lysosome trap of nanoparticles, and is especially suitable for the targeted delivery of exogenous genes to the cytoplasm and nucleus.

Description

technical field [0001] The invention belongs to the technical field of biomedical polymer materials, in particular to a class of antiserum and low cytotoxicity polyamino acid gene delivery carrier materials with membrane-penetrating activity and cell nucleus localization functions, and a preparation method and application thereof. Background technique [0002] According to the definition of the U.S. Food and Drug Administration (FDA), gene therapy refers to the regulation of cell function through transcription or translation of genetic material transferred or integrated into the host genome to achieve the purpose of treating diseases. Of the gene therapy clinical trials being carried out around the world, more than 60% are malignant tumors, and the rest are single-gene genetic diseases, cardiovascular diseases, infectious diseases, and autoimmune diseases. Regardless of the disease targeted, gene therapy requires a method of delivering the foreign gene through a vector and d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G81/00C08G69/14C08G69/16C08G69/40A61K47/54A61K47/60A61K47/64A61K47/69A61K48/00A61P35/00B82Y5/00B82Y40/00
CPCC08G81/00C08G69/14C08G69/16C08G69/40A61K48/0041A61K48/005A61K47/64A61K47/60A61K47/54A61K47/6935A61P35/00B82Y5/00B82Y40/00
Inventor 黄玉刚姜欣林
Owner GUANGZHOU MEDICAL UNIV
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