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Amphipathic triblock copolymer containing morpholine-2,5-diketone derivative copolymer as well as preparation method and application thereof

A technology of block copolymers and copolymers, applied in the fields of gene carrier materials, biomedical polymer materials and biocompatibility modification, can solve the limitation of PEI25kDa high toxicity and wide application, low molecular weight PEI has no transfection efficiency, gene Carrying capacity and other issues, to achieve the effect of good biocompatibility, simple method and low cytotoxicity

Inactive Publication Date: 2014-04-09
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The transfection efficiency of PEI nanoparticles increases with the increase of molecular weight, however, its cytotoxicity also increases
The reason is that high-molecular-weight PEI has a strong positive charge, which causes it to interact strongly with the cell surface due to electrostatic attraction, resulting in cell death.
In order to reduce the toxicity of PEI, polyethylene glycol (PEG) and polysaccharides are modified on PEI, or negatively charged propionic acid or succinic acid is introduced to neutralize the positive charge of PEI, and the chemical reaction makes the PEI molecules Aminoacetylation to reduce the positive charge carried by PEI, but it has an impact on the carrying capacity of the gene
[0004] The high toxicity of PEI25k Da limits its wide application as a gene carrier, especially in vivo
Although low-molecular-weight PEI has very low toxicity and can meet the requirements of gene transfection for low toxicity to cells, low-molecular-weight PEI has almost no transfection efficiency

Method used

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  • Amphipathic triblock copolymer containing morpholine-2,5-diketone derivative copolymer as well as preparation method and application thereof
  • Amphipathic triblock copolymer containing morpholine-2,5-diketone derivative copolymer as well as preparation method and application thereof
  • Amphipathic triblock copolymer containing morpholine-2,5-diketone derivative copolymer as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: a kind of preparation method that contains the amphiphilic triblock copolymer of morpholine-2,5-diketone derivative copolymer, comprises the steps:

[0042] (1) Weigh polyethylene glycol monomethyl ether, morpholine-2,5-dione derivative monomer and L-lactide according to the mass ratio of 100:140:60, add stannous octoate in the isolated air Under the conditions of 150°C for 1h, react at 120°C for 48h to obtain a mixture: the amount of stannous octoate is equal to the mass of morpholine-2,5-dione derivative monomer and L-lactide and 2%; The molecular weight of the polyethylene glycol monomethyl ether is 5000;

[0043] The structure of the morpholine-2,5-dione derivative monomer is formula (I):

[0044]

[0045] where R 1 :-H;R 2 :-H;

[0046] (2) Dissolve 25g of the mixture in 50mL of dimethyl sulfoxide to make a solution, add 150mL of anhydrous ether, filter, and precipitate as a copolymer of polyethylene glycol monomethyl ether and morpholine-2,5-d...

Embodiment 2

[0050] Embodiment 2: a kind of preparation method that contains the amphiphilic triblock copolymer of morpholine-2,5-diketone derivative copolymer, comprises the steps:

[0051] (1) Weigh polyethylene glycol monomethyl ether, morpholine-2,5-dione derivative monomer and L-lactide according to the mass ratio of 100:70:30, add tin octoate in the isolated air Under certain conditions, react at 140°C for 2h, then react at 100°C for 72h to obtain a mixture: the amount of tin octoate added is 0.001 of the sum of the mass of morpholine-2,5-dione derivative monomer and L-lactide %; The molecular weight of polyethylene glycol monomethyl ether is 600;

[0052] The structure of the morpholine-2,5-dione derivative monomer is formula (I), wherein R 1 : -H,R 2 :-CH 3 ;

[0053] (2) Dissolve 25g of the mixture in 50mL of dimethyl sulfoxide to make a solution, add 150mL of anhydrous ether, filter, and precipitate as a compound composed of polyethylene glycol monomethyl ether and morpholine...

Embodiment 3

[0056] Embodiment 3: a kind of preparation method that contains the amphiphilic triblock copolymer of morpholine-2,5-diketone derivative copolymer, comprises the steps:

[0057] (1) Weigh polyethylene glycol monomethyl ether, morpholine-2,5-dione derivative monomer and L-lactide according to the mass ratio of 100:280:120, add dibutyltin oxide Under the condition of isolated air, react at 155°C for 0.5h, then react at 130°C for 1h to obtain a mixture: the amount of dibutyltin oxide added is morpholine-2,5-dione derivative monomer and L-propane 5% of the sum of the lactide quality; the molecular weight of the polyethylene glycol monomethyl ether is 20000;

[0058] The structure of the morpholine-2,5-dione derivative monomer is formula (I): wherein R 1 : -H,R 2 :-CH 2 CH 3 ;

[0059] (2) Dissolve 50g of the mixture in 100mL dimethyl sulfoxide to make a solution, add 300mL of anhydrous ether, filter, and precipitate as a compound composed of polyethylene glycol monomethyl eth...

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Abstract

The invention discloses an amphipathic triblock copolymer containing a morpholine-2,5-diketone derivative copolymer as well as a preparation method and application thereof. The copolymer is formed by connecting methoxy polyethylene glycol, the morpholine-2,5-diketone derivative copolymer and polyethylene imine in sequence, wherein molecular weight of the amphipathic triblock copolymer is 2000-105000; the morpholine-2,5-diketone copolymer is a copolymer of a morpholine-2,5-diketone derivative monomer and one or two cyclic monomers. An experiment proves that the copolymer disclosed by the invention is low in cell toxicity and high in transfection efficiency. The preparation method disclosed by the invention is simple and pollution-free. The surface of a nano-particle prepared by the copolymer disclosed by the invention is linked with a plurality of low molecular weight PEI (Polyetherimide) and hydrophilic PEG (Polyethylene Glycol) chain segments, so that transfection efficiency of the nano-particle is improved while cell toxicity of the nano-particle is lowered. Besides, the amphipathic triblock copolymer has good biocompatibility and can effectively carry genes to enter cells.

Description

technical field [0001] The invention belongs to the technical field of gene carrier materials, and specifically relates to a degradable polymer-modified polyethyleneimine nano-gene carrier containing a morpholine-2,5-dione derivative copolymer with low toxicity and high transfection rate and Preparation. It also involves the fields of biomedical polymer materials and biocompatibility modification. technical background [0002] With the development of gene therapy, non-viral gene vectors have been widely used due to their stable performance, easy production, strong nucleic acid loading capacity and low immunogenicity. Cationic polymer gene carrier materials include: polyethyleneimine (PEI), polyamidoamine, polypropyleneimine, poly-L-lysine, polypropyleneamine and chitosan, etc. These materials have long-term safety and biocompatibility. Nanoparticles made of these materials have become a research field in the field of gene therapy because of their stable structure, easy pha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G81/00C08G69/48C08G69/44C08G69/40C12N15/87C12N15/85
Inventor 冯亚凯石长灿李茜于丽吕娟
Owner TIANJIN UNIV
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