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Cholesterol-modified biodegradable polycation carrier as well as preparation method and application thereof

A technology of polycation and cholesterol, applied in the directions of non-active ingredient medical preparations, medical preparations containing active ingredients, pharmaceutical formulas, etc., can solve the problems of low transfection efficiency and toxicity, achieve high gene delivery efficiency, cell Low toxicity and good biocompatibility

Active Publication Date: 2013-05-22
NANJING GENELEAP BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In these reported amphiphilic carrier materials, the hydrophilic polymer chain segments are mostly non-biodegradable materials. Although they are modified with cholesterol, they still show low transfection efficiency and high toxicity when using these materials to deliver gene drugs. The problem

Method used

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  • Cholesterol-modified biodegradable polycation carrier as well as preparation method and application thereof
  • Cholesterol-modified biodegradable polycation carrier as well as preparation method and application thereof
  • Cholesterol-modified biodegradable polycation carrier as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Synthesis of the polyamide-amine of embodiment 1 cholesterol modification (brominated quaternary ammonium salt connection)

[0047] Synthesis of rPAA Accurately measure two commercially available monomers N,N'-dimethyldipropylenetriamine (DMDPTA) and N,N'-bis(acryloyl)cystamine (CBA) in equimolar ratio, Dissolve in an appropriate amount of mixed solvent of methanol and water, the concentration of each monomer is 2mmol / 3.5mL, under the condition of argon protection at 37°C, react in the dark for 3 days, after the reaction solution becomes viscous, add excess ( 10mol%) DMDPTA continued to react for 2 days, and the product was dialyzed with absolute ethanol (molecular weight cut-off 3.5KDa), and the ethanol solvent was removed by rotary evaporation, and the product was vacuum-dried for 24 hours to finally obtain polyamide-amine cationic polymer (rPAA) ( figure 1 ).

[0048] Synthesis of Brominated Cholesterol (CH-Br) The synthesis of this material used the method reporte...

Embodiment 2

[0050] Example 2 Synthesis of polyamide-amine (rPAA-Ch) modified by cholesterol (directly linked by amide bond)

[0051]Synthesis of P(CBA-DMDPTA) polymer Precisely measure two commercially available monomers N, N'-dimethyldipropylenetriamine (DMDPTA) and N, N'-bis(acryloyl) in equimolar ratio ) Cystamine (CBA), dissolved in an appropriate amount of mixed solvent of methanol and water, the concentration of each monomer is 2mmol / 3.5mL, under the condition of argon protection at 37°C, react in the dark for 3 days until the reaction solution becomes viscous After thickening, add excessive (10mol%) DMDPTA and continue to react for 2 days, the product is dialyzed with dehydrated alcohol (molecular weight cut-off 3.5KDa), and the ethanol solvent is removed by rotary evaporation, and the product is vacuum-dried for 24 hours to finally obtain the polyamide-amine polymer ( rPAA).

[0052] Synthesis of Cholesterol Modified (Direct Amide Linkage) Polyamide-Amine (rPAA-Ch) Dissolve 100mg...

Embodiment 3

[0053] Example 3 Evaluation of physical and chemical properties of rPAA-Ch polymer in vitro

[0054] Determination of Critical Micelle Concentration (CMC) This example illustrates the determination of the critical micelle concentration (CMC) of the cholesterol-modified rPAA of the present invention. According to the reference (Biomaterials 2007; 28: 4132-42.), the CMC of the polymer was determined by the fluorescent probe method. In short, an equal volume of pyrene in acetone solution was added to 10 mL glass tubes one by one. After the acetone evaporated, 6 mL of polymer solutions with different concentrations (0.01-1000 μg / mL) were added to each tube. The final concentration of pyrene was 6.0× 10 -7 M. Under the condition of avoiding light, the aqueous polymer solution was sonicated in a bath at 37°C for 2 hours, and then shaken on a shaker at 37°C for 20 hours. The fluorescence spectrum of the solution was measured with a fluorescence spectrophotometer, the scattering wa...

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Abstract

The invention provides a cholesterol-modified biodegradable polycation carrier as well as a preparation method and application of the cholesterol-modified biodegradable polycation carrier. The carrier material is a functionalized linear poly(amide-amine)-cholesterol comb grafting which is formed by connecting functionalized linear poly(amide-amine) with average molecular weight being 2kD20kD and cholesterol through amido bonds or ester bonds; the carrier can be self-assembled in an aqueous phase medium to form nanoparticles, wherein the particle diameter of each nanoparticle is 20-200nm; the surfaces of the nanoparticles are positively charged; and the cholesterol grafting rate is 1-90 percent. The cationic polymer nanoparticles prepared by using the preparation method are low in toxicity, have the functions of rapidly penetrating cell membranes and easily degrading and escaping in lyase and can be used as a gene transfection reagent. In addition, fat-soluble chemicals can be carried by using a lyophobic area in a nanoparticle carrier structure, and therapeutic DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) gene medicines or polypeptide protein medicines can be carried by using positive charge characteristics.

Description

technical field [0001] The invention relates to a non-viral drug carrier material. In particular, it relates to a cholesterol-modified biodegradable polycation carrier and its preparation method and use, specifically, a functionalized linear poly(amide-amine) with an average molecular weight of 2kD-20kD is chemically coupled with cholesterol to form a functionalized linear poly(amide-amine) through an amide bond or an ester bond. Poly(amide-amine)-cholesterol comb-like grafts, critical micelle concentration>1mg / L, can self-assemble in aqueous media to form nanoparticles, the particle size is between 20-200nm, the surface of the nanoparticles is positively charged, cholesterol The grafting rate is 10%-90%. The nanoparticle can be used to carry chemical drugs, gene drugs and polypeptide protein drug delivery. technical background [0002] The success of gene delivery depends on safe and effective delivery vehicles. Delivery vehicles include viral vectors and non-viral ve...

Claims

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Application Information

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IPC IPC(8): A61K47/34A61K48/00A61K45/00A61K38/00C08G73/02
Inventor 王坚成张强陈成军高玲燕
Owner NANJING GENELEAP BIOTECHNOLOGY CO LTD
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