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A method of loading doxorubicin through folic acid targeted multifunctional hyperbranched polyethylenimine

A polyethyleneimine and folic acid targeting technology, which is applied in the directions of pharmaceutical formulations, medical preparations without active ingredients, and medical preparations containing active ingredients, etc., to achieve the effect of improving the inhibitory effect and having broad application prospects.

Inactive Publication Date: 2016-11-09
DONGHUA UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] According to relevant literature or patents at home and abroad, the synthesis of FA-targeted polyethyleneimine as a drug carrier for anti-tumor drug delivery and tumor-targeted therapy has not been reported yet.

Method used

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  • A method of loading doxorubicin through folic acid targeted multifunctional hyperbranched polyethylenimine
  • A method of loading doxorubicin through folic acid targeted multifunctional hyperbranched polyethylenimine
  • A method of loading doxorubicin through folic acid targeted multifunctional hyperbranched polyethylenimine

Examples

Experimental program
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Effect test

Embodiment 1

[0071] (1) EDC / NHS-activated mPEG-COOH solution (40 mg, 10 mL DMSO) was added dropwise to PEI solution (25.0 mg, 5 mL DMSO), stirred for 72 hours, dialyzed with PBS solution for one day, and then dialyzed with water for 2 days. Freeze-dried to obtain a white powder labeled as PEI-mPEG.

[0072] (2) in NH 2 - FA solution (11mg, 10mL DMSO) activated by EDC / NHS was added to PEG-COOH solution (20.0mg, 5mL DMSO), stirred and reacted for 72h, dialyzed with PBS solution for one day, then dialyzed with water for 2 days, and freeze-dried to obtain Pale yellow powder, marked as FA-PEG-COOH.

[0073] (3) Add EDC / NHS-activated FA-PEG-COOH (4.64 mg, 5 mL DMSO) dropwise to the above PEI-mPEG solution (11.0 mg, 5 mL DMSO) and stir for 48 h, then add FI (0.39 mg , 2mLDMSO), stirred for 24h, then added triethylamine (63.6μL) for 30min, then added acetic anhydride (53.0μL) for 24h. The reaction solution was dialyzed against PBS solution for one day, then dialyzed against water for 2 days, an...

Embodiment 2

[0080] Dissolve the FA-mPEI / DOX prepared in Example 1 with pH=7.0 and pH=5.4 buffers respectively to a solution with a concentration of 1mg / mL, take 1mL and put it into a dialysis bag for fixation, and place 9mL of buffer containing different pH Place in a liquid container and shake in a shaker at 37°C. Samples were taken at different time points. Take 1mL of the liquid outside the dialysis bag each time, measure its absorbance at 480nm, and then add 1mL of the corresponding buffer solution to the outside of the dialysis bag. Using this method, the release curves of DOX released from FA-mPEI / DOX under different pH conditions were obtained in vitro. See attached image 3 b, In 50 hours, the release amount of DOX was 51% in a weakly acidic environment (pH=5.0), which was greater than 31.5% in a physiological environment (pH=7.4). It shows that this drug-loading system has a certain pH responsiveness, and the release rate in the weakly acidic environment similar to tumor tissu...

Embodiment 3

[0082] 8000 HeLa cells per well were seeded in 96-well plates and cultured overnight. The original medium was discarded, and the culture solution containing different materials (FA-mPEI, FA-mPEI / DOX and pure DOX) was added and co-cultivated for another 24 hours. Pour off the culture medium, wash twice with PBS, add culture medium containing CCK-8 reagent (20 μL CCK-8 reagent per well, 180 μL complete culture medium) and incubate for another 3 h. Afterwards, the absorbance value of each well at λ=450nm was detected with a microplate reader, and the corresponding cell viability was calculated accordingly, wherein the cells treated with physiological saline were used as a blank control, and the cell viability was recorded as 100%. attached Figure 4 The results showed that, compared with the blank control group, the cell viability of the experimental group treated with the carrier material FA-mPEI was above 80%, indicating that the carrier material FA-mPEI had no obvious cytotox...

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Abstract

The invention relates to a method of loading doxorubicin through folic acid targeted multifunctional hyperbranched polyethylenimine. The method includes adding an activated mPEG-COOH solution into a PEI solution, adding an activated FA-PEG-COOH solution, reacting under stirring to obtain PEI-mPEG-(PEG-FA), adding an FI solution into the PEI-mPEG-(PEG-FA) solution, reacting under stirring in dark, adding triethylamine and acetic anhydride, stirring, dialyzing, freeze-drying to obtain FA-mPEI, adding doxorubicin hydrochloride DOX.HCl deacidified in advance into an aqueous solution of the FA-mPEI, stirring in a dark place with an opening being uncovered, centrifuging, selecting a supernatant and drying. The PEI which is cheap and easily available is adopted as a base carrier, and the FA is adopted as a targeting agent, thus reducing the material cost. The method is free of adverse effects on a living body, simple, mild in conditions and easy to operate, and has a good prospect.

Description

technical field [0001] The invention belongs to the field of preparation of drug-loaded sustained-release systems, in particular to a method for folic acid-targeted multifunctional hyperbranched polyethyleneimine loaded with doxorubicin. Background technique [0002] Cancer has always been regarded as one of the major problems that human beings need to overcome. Chemotherapy, as one of the important means of cancer treatment, has attracted much attention for a long time. However, common antineoplastic drugs have problems such as poor water solubility, high toxicity and side effects, and fast drug release. Antineoplastic drugs are transported to various parts of the body along with the blood, causing serious damage to normal tissues and organs of patients. In recent years, the use of nanomaterials as carriers to load anti-tumor drugs can significantly increase the water solubility of drugs and achieve sustained release of drugs; prolong the action time of drugs in tumor site...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/34A61K47/22A61K31/704A61P35/00
CPCA61K47/10A61K47/22A61K47/34A61K31/704
Inventor 史向阳周本青赵晋华赵凌舟
Owner DONGHUA UNIV
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