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Thiourea modified polyethyleneimine copolymer as well as method thereof

A polyethyleneimine copolymer and polyethyleneimine technology, applied in the field of thiourea-modified polyethyleneimine copolymer and its preparation, can solve the problems of restricting clinical application, limiting gene transfection efficiency, macrocytic toxicity, etc. problem, achieve the effect of improving transfection efficiency, reducing cytotoxicity, and good biocompatibility

Active Publication Date: 2014-02-05
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the high charge density of homopolymer PEI also restricts its further clinical application. Its high charge density can lead to great cytotoxicity, and at the same time cause it to be too close to the nanoparticles formed by electrostatic attraction with genetic material. Cells cannot effectively transfer genetic material to the cytoplasm and nucleus in the future, limiting their ability to achieve better gene transfection efficiency

Method used

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  • Thiourea modified polyethyleneimine copolymer as well as method thereof
  • Thiourea modified polyethyleneimine copolymer as well as method thereof
  • Thiourea modified polyethyleneimine copolymer as well as method thereof

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preparation example Construction

[0033] The invention also discloses a preparation method of a thiourea-modified polyethyleneimine copolymer, comprising the following steps:

[0034] Under anhydrous conditions, the polyethyleneimine represented by formula (V) or formula (IV) reacts with the compound represented by formula (III) in an organic solvent to obtain the compound represented by formula (I) or formula (II) Polyethyleneimine copolymer modified with thiourea;

[0035]

[0036] Among them, R is a straight chain or branched chain alkyl, cycloalkyl or aryl group, preferably a straight chain or branched chain alkyl group of C1~C10, a cycloalkyl group of C1~C10 or an aryl group of C1~C10, more preferably is methyl, n-hexyl, cyclohexyl or benzyl;

[0037] i, j, k, m, n is the degree of polymerization, i / m+j / m+k / m=1, 0<i / m<1, 0<j / m<1, 0≤k / m<1 ;i / n+j / n=1, 0<i / n<1, 0<j / n<1;

[0038] The number average molecular weight of the thiourea-modified polyethyleneimine copolymer is 423-100000, preferably 2000-60000...

Embodiment 1～7

[0047] Under anhydrous conditions, weigh 1.0 g of branched or linear polyethyleneimine (PEI) with different molecular weights into different dry reaction bottles, add 30 ml of dichloromethane, and stir until completely dissolved; Weigh 0.01% to 100% of the total molar amino groups in the amine molecule and weigh methyl isothiocyanate (as shown in Table 1), dissolve them in 20 ml of dichloromethane, and slowly dissolve methyl isothiocyanate drop by drop. The ester solution in dichloromethane was added dropwise to the polyethyleneimine solution. React at 25°C for 24 hours. After the reaction was complete, the solvent dichloromethane was removed by rotary evaporation. Then redissolve the product in water, dialyze with distilled water once to remove unreacted impurities, and freeze-dry to obtain pure methylthiourea-modified polyethyleneimine.

[0048] Using deuterated water as a solvent, the above-mentioned methylthiourea-modified polyethyleneimine is subjected to nuclear magnet...

Embodiment 8～14

[0055] Under anhydrous conditions, weigh 1.0 grams of branched or linear polyethyleneimines with different molecular weights in different dry reaction bottles, respectively add 30 ml of dichloromethane, and stir until completely dissolved; Weigh n-hexyl isothiocyanate (as shown in Table 2) from 0.01% to 100% of the total molar number of amino groups, dissolve them in 20 ml of dichloromethane, and slowly dilute the n-hexyl isothiocyanate The methyl chloride solution was added dropwise to the polyethyleneimine solution. React at 25°C for 24 hours. After the reaction was complete, the solvent dichloromethane was removed by rotary evaporation. Then redissolve the product in water, dialyze with distilled water once to remove unreacted impurities, and freeze-dry to obtain pure polyethyleneimine modified by n-hexylthiourea.

[0056] NMR analysis was performed on the n-hexylthiourea-modified polyethyleneimine, and its number-average molecular weight and average thiourea molar modifi...

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Abstract

The invention provides a thiourea modified polyethyleneimine copolymer which is shown in a formula (I) or a formula (II). The preparation method comprises the following step: under an anhydrous condition, reacting polyethyleneimine shown in the formula (I) or the formula (II) with a compound shown in a formula (III) in an organic solvent to obtain the thiourea modified polyethyleneimine copolymer which is shown in the formula (I) or the formula (II). Due to introduction of the thiourea structure, the polyethyleneimine copolymer has low electric density, so that the cytotoxicity caused by high electric density of polyethyleneimine is reduced, and the biocompatibility is good. Meanwhile, the thiourea modified polyethyleneimine copolymer used as a gene carrier can interact with generic matters through non-charge attracted hydrogen bonds. The nanoparticles formed are slightly slack in structure. After entering cells, the nanoparticles can more effectively release the generic matters into cytoplasm and cell nucleus, so that the transfection efficiency is improved.

Description

technical field [0001] The invention relates to the field of polymer copolymers, in particular to a thiourea-modified polyethyleneimine copolymer and a preparation method thereof. Background technique [0002] With the completion of the Human Genome Project and the advancement of molecular biology, it has gradually become possible for humans to treat diseases at the molecular level. As a candidate for next-generation drugs, gene medicine has begun to show its promise in the treatment of tumors, tissue engineering and other gene-related diseases. In order to achieve high-efficiency gene therapy, it is necessary to use high-efficiency and low-toxicity gene carriers. Viral gene carriers (including retrovirus, adenovirus, adeno-associated virus, herpes simplex virus, vaccinia virus, etc.) Death and adverse consequences such as the French "bubble baby" incident. In contrast, artificially synthesized cationic polymer-based gene carriers have the advantages of higher safety, no ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G73/04C12N15/87
Inventor 田华雨李钰策陈学思林琳陈杰郭兆培焦自学
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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