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Low molecular weight polyetherimide (PEI) derivative, preparation method and application thereof

A low-molecular-weight, derivative technology, used in other methods of inserting foreign genetic materials, pharmaceutical formulations, genetic material components, etc., can solve the problems of general transfection activity, reduced transfection efficiency, instability, etc., and achieve low cytotoxicity. , high transfection activity, simple structure effect

Inactive Publication Date: 2013-07-24
SHANGHAI JIAO TONG UNIV
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Problems solved by technology

[0004] People such as Sung Wan Kim of the University of Utah published "Polyethyleneimine with acid-labile linkages as a biodegradable gene carrier" (Journal of Controlled Release 2005, 103: 209-219) Gene Carrier)", which uses glutaraldehyde as a linker to cross-link with low molecular weight PEI (1800Da) to generate characteristic degradable polyethyleneimines linked by imine bonds. Its structural characteristics are: After the complex formed by the gene is taken up by the cell, the condensed gene is in the acidic condition of the endosome and lysosome in the cell, and the imine bond directly connected with the low-molecular-weight PEI is broken to generate a non-cytotoxic low-weight PEI. However, the polymer structure containing imine bonds cannot ensure that the carrier is stable enough before carrying nucleic acid into cells. In addition, compared with PEI 25 KDa, its transfection activity is also average.
[0005] Jin et al. applied for a PCT patent (WO2009 / 100645A1) entitled "Polycationic gene carriers formed of endogenous amino group-bearing monomers (endogenous amino group monomers formed of polycationic gene carriers)", which used The small molecular monomer spermine of the human endogenous professional condensation gene is condensed with three linking agents such as 1,4-butanediol dichloroformate, 1,4-succinoyl chloride and glyoxal respectively to obtain ammonia Polyspermine cations such as ester bond, amide bond and imine bond, these polyspermine cations all exhibit good nucleic acid delivery capabilities, and the polymer can return to the original endogenous monomer of spermine through bioresponsive degradation. State, has good biocompatibility, but the defect of this technology is: the degradation rate of containing urethane bond and amide bond is relatively slow, resulting in the inability of nucleic acid substances to escape from endosomes in time, affecting the efficiency of nucleic acid delivery; containing imine bond The degradation rate is relatively fast, but the instability of the carrier causes the nucleic acid material transported by it to be released from the extracellular space before it reaches the cytoplasm, and the transfection efficiency is greatly reduced

Method used

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  • Low molecular weight polyetherimide (PEI) derivative, preparation method and application thereof
  • Low molecular weight polyetherimide (PEI) derivative, preparation method and application thereof
  • Low molecular weight polyetherimide (PEI) derivative, preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0045] The synthetic route of PEI-OP in the present embodiment is as follows figure 1 shown. The entire synthesis reaction is carried out in an anhydrous and oxygen-free environment. Specifically, in this example, high-purity nitrogen protection is used to react PEI800Da and o-phthalaldehyde at a molar ratio of 1:2.5. The reaction solvent is anhydrous Ethanol, wherein the treatment process of the dehydrated ethanol is: add anhydrous magnesium sulfate to the dehydrated ethanol and let stand for 48 hours, then distill, and obtain fresh dehydrated ethanol for later use. Dissolve 1.2g of PEI800Da and 0.268g of o-phthalaldehyde with the fresh absolute ethanol obtained above to prepare 20mL and 50mL solutions. The reaction is carried out with stirring at room temperature. The method of mixing PEI800Da and o-phthalaldehyde can be adopted: add the o-phthalaldehyde solution to the PEI800Da solution drop by drop with a constant pressure dropping funnel, and react for 24 hours.

[0046...

Embodiment 2

[0051] The PEI-OP obtained in Example 1 is used to prepare the gene material delivery complex, and the specific methods and steps are as follows:

[0052] Weigh a certain amount of polymer PEI-OP and dissolve it in ultrapure water at a concentration of 2.0mg / mL, and filter it with a 0.45μm microporous membrane for use; draw a certain amount of pDNA solution and dilute it with ultrapure water to 20μg / mL pDNA stock solution. According to a set mass ratio of PEI-OP and pDNA: 0, 0.5, 1, 3, 5, 10, 20, 30, 50, dilute the PEI-OP solution to the corresponding concentration, and then quickly add it to the same volume and In the pDNA solution with a constant concentration, the final concentration of pDNA was 2 μg / mL, and finally gently pipetted, mixed evenly, and incubated at room temperature for 20 to 30 minutes to obtain a series of gene substance delivery complex solutions with different mass ratios.

[0053] The complex solution obtained above is characterized by the following phys...

Embodiment 3

[0069] The difference between this example and Example 1 is that iso-phthalaldehyde is used instead of o-phthalaldehyde, and the same preparation method as Example 1 is used to obtain PEI-IP. For its synthetic route, see Figure 14 .

[0070] Figure 15 The FT-IR spectrum (potassium bromide tablet) of PEI-IP obtained for this example shows the characteristic diffraction peaks of imine bonds, which proves that this example successfully obtained the target product PEI-IP.

[0071] The complex solution obtained above is characterized by the following physical and chemical properties:

[0072] 1. Particle Size Distribution and Zeta Potential Measurement

[0073] Prepare complex solutions with different mass ratios according to the above-mentioned complex preparation method, and select and determine the mass ratio of PEI-IP / pDNA as 0.5, 1, 3, 5, 10, 20, 30, 50, and the sample sizes are 2mL.

[0074] The measurement process is as follows: under greenhouse conditions, first prehe...

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Abstract

The invention discloses a low molecular weight polyetherimide (PEI) derivative, a preparation method thereof and an application thereof to nucleic acid medicine delivery. The formula of the low molecular weight PEI derivative is shown in the specification, wherein x is 1-20, and y is 1-20. The preparation method comprises steps of: preparing an absolute ethyl alcohol solution through low molecular weight polyetherimide and o-phthalaldehyde or isophthalaldehyde according to a molar ratio of 1:1-1:3.5, completing the condensation reaction of aldehyde groups and amino groups at room temperature in a water-free and oxygen-free environment, and thus obtaining the low molecular weight PEI derivative. The derivative has high transfection activity and low cytotoxicity, good biological activity in different cells and is an efficient low-toxicity gene delivery carrier.

Description

technical field [0001] The present invention relates to a kind of low-molecular-weight PEI derivative and its preparation method and application, particularly a kind of degradable low-molecular-weight PEI derivative containing imine bond, its preparation method and its application in nucleic acid drug (DNA and RNA) delivery application. Background technique [0002] Gene therapy is to introduce exogenous genetic material (DNA or RNA) into cells to promote or inhibit the expression of specific proteins, or replace or repair problematic genes, so as to achieve the purpose of disease treatment. Gene therapy has encountered a series of technical bottlenecks during its development, one of the most important bottlenecks is the safe and effective delivery of genetic material in vivo. [0003] Currently commonly used gene delivery vectors can be divided into viral vectors and non-viral vectors. Among them, although the viral vector has a high transfection efficiency, the mutation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G73/04A61K48/00C12N15/87
Inventor 袁伟恩吴飞苏靖徐东陈顺王一格
Owner SHANGHAI JIAO TONG UNIV
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