Virus-like structure gene vector, drug delivery system, and preparation method and application thereof

A structural gene and gene drug technology, applied in the field of biomedicine, can solve the problems of lack of non-viral gene delivery vectors, poor targeting of gene transfection, inability to achieve targeted delivery, etc., and achieve strong anti-tumor immune response and tumor growth inhibition. , good effect of gene transfection

Pending Publication Date: 2022-05-13
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

For example, the prior art CN109152830A discloses a lipid bilayer-shielded core-shell structure mRNA delivery carrier, which can stabilize the inner core and promote macropinocytosis of the complex by antigen-presenting cells; however, lipid bilayer-coated After the compound is injected intravenously, it will accumulate in large quantities in the liver, making it impossible to achieve targeted delivery to other organs
Prior art CN 105906800A discloses a gene delivery system containing a pH-sensitive and breakable shielding material, which uses polyethylene glycol to shield the inner core complex; however, this shielding design has poor stability and is easy to enter the body after entering the body. fall off
Prior art CN 112641952A discloses a nucleocapsid gene delivery system containing a masking layer of polyethylene glycol and polyglutamic acid copolymer, which can obtain significant transfection efficiency in vivo; however, this masking layer is difficult to add target To the group, poor targeting of gene transfection
In summary, non-viral gene delivery vectors that can achieve stable masking and good in vivo targeting are still scarce

Method used

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  • Virus-like structure gene vector, drug delivery system, and preparation method and application thereof
  • Virus-like structure gene vector, drug delivery system, and preparation method and application thereof
  • Virus-like structure gene vector, drug delivery system, and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0041] The preparation of embodiment 1 poly (L-glutamic acid)-graft cyclodextrin (PLG-g-CD)

[0042] 300 mg of PLG (with approximately 120 L-glutamic acid repeating units), 64 mg of N,N-diisopropylethylamine (DIPEA) and 184 mg of 2-(7-azabenzotriazole)- N,N,N',N'-Tetramethyluronium hexafluorophosphate (HATU) was dissolved in 10mL of N,N-dimethylformamide (DMF) solution, stirred at room temperature until all solid substances were dissolved, and 900mg of aminocyclodextrin (CD-NH 2 ) was dissolved in 3 mL of DMF, added to the above DMF mixture, and reacted at room temperature for 48 h. The product was purified by dialysis with sterile water for injection, and freeze-dried to obtain the final product PLG-g-CD.

[0043] The PLG-g-CD is analyzed, the results can be found in figure 2 , figure 2 For the PLG-g-CD obtained in Example 1 1 H NMR spectrum.

Embodiment 2

[0044] The preparation of embodiment 2 amantadine-polyethylene glycol (Ad-PEG)

[0045] 120 mg of polyethylene glycol (PEG, molecular weight 2000Da), 12 mg of DIPEA and 32 mg of HATU were dissolved in 3 mL of DMF solution, and 16 mg of aminoamantadine (Ad-NH 2 ) was dissolved in 4 mL of DMF, and added to the above DMF reaction system, and reacted for 48 h under stirring at room temperature. The product was purified by dialysis with sterile water for injection, and freeze-dried to obtain the final product Ad-PEG.

[0046] The Ad-PEG is analyzed, the results can be found in image 3 , image 3 for the obtained Ad-PEG 1 HNMR spectrum.

Embodiment 3

[0047] Embodiment 3 Preparation of amantadine-polyethylene glycol-aminoethylanisamide (Ad-PEG-AEAA)

[0048] First prepare aminoethylanisamide (AEAA): 410mg of 2-bromoethylamine and 800mg of DIPEA were dissolved in 4mL of acetonitrile, 300mg of p-methoxyphenylacetyl chloride was dissolved in 3mL of acetonitrile, and the above two solutions Mix and react for 6h under stirring at room temperature.

[0049] Next, bond AEAA on one side of the bifunctional PEG: add 200 mg of hydroxypolyethylene glycol amino (HO-PEG-NH 2 ), stirred and reacted at 80°C for 12h.

[0050] Finally, amantadine (Ad) was bonded to the other end of the bifunctional PEG: 60 mg of N,N'-carbonyldiimidazole (CDI) was dissolved in 2 mL of acetonitrile and slowly added to the above mixed solution, and reacted at 50 °C 5h to activate CDI, 160mg of Ad-NH 2 Dissolved in 4mL DMF and injected into the above reaction system, stirred at 50°C for another 48h. The product was purified by dialysis with sterile water fo...

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Abstract

The invention provides a virus-like structure gene vector, which comprises a cationic polymer, cyclodextrin-grafted poly (L-glutamic acid) and a hydrophilic polymer with an amantadine terminal group, when the virus-like structure gene vector is used for loading a gene drug, the negatively charged gene drug and the like and the positively charged cationic polymer form a cationic core through electrostatic interaction; poly (L-glutamic acid) grafted with cyclodextrin wraps the surface of the cation core to form a shielding layer, so that the core can be stabilized; the amantadine end group of the hydrophilic polymer is assembled to the surface of a particle through the host-guest interaction of adamantane and cyclodextrin, so that the core is better protected, the gene drug is prevented from being degraded, and meanwhile, the hydrophilic compound can endow the drug delivery system with other characteristic virus-like gene vectors with high transfection efficiency, simple structure and low cost. And the carrier can be widely used for carrying DNA, mRNA, siRNA, microRNA and the like. The invention also provides a drug delivery system, and a preparation method and application thereof.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a virus-like structural gene carrier, a drug delivery system, its preparation method and its application. Background technique [0002] Gene therapy is a promising treatment method, mainly through the repair or replacement of disease-causing genes by transferring genes into human cells to achieve the treatment of diseases. The key problem of gene therapy is to solve the problem of delivery of therapeutic nucleic acid, because if a single gene is directly injected into the body, it will be rapidly degraded and destroyed by substances and enzymes in body fluids, and it is difficult for the negatively charged macromolecular DNA itself to pass through the cell membrane and enter into the cells. Therefore, it is necessary to carry the target gene with the help of a gene carrier to complete the process of transporting to the target cell and entering the nucleofection. [0003] At...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/60A61K47/59A61K45/00A61K31/7088A61P35/00
CPCA61K47/6939A61K47/59A61K47/60A61K45/00A61K31/7088A61P35/00
Inventor 宋万通高雨茜赵汉秦黄子超赵佳雨陈学思
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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