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Preparation method of hyaluronic acid-targeted multifunctional branched polyethyleneimine drug carrier

A technology of branched polyethyleneimine and polyethyleneimine, which is applied in the direction of drug combination, pharmaceutical formula, medical preparations of non-active ingredients, etc., to achieve the effect of cost reduction, obvious inhibition effect and low cost

Inactive Publication Date: 2015-12-23
DONGHUA UNIV
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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 research on the synthesis of hyaluronic acid-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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  • Preparation method of hyaluronic acid-targeted multifunctional branched polyethyleneimine drug carrier
  • Preparation method of hyaluronic acid-targeted multifunctional branched polyethyleneimine drug carrier
  • Preparation method of hyaluronic acid-targeted multifunctional branched polyethyleneimine drug carrier

Examples

Experimental program
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Effect test

Embodiment 1

[0046] (1) in 5mLNH 2 - PEG-COOH in DMSO (12 mg / mL), add 5 mL of LEDC in DMSO (7.6 mg / mL), stir for 0.5 hour, then add 5 mL of NHS in DMSO (4.6 mg / mL), continue to stir for 3 hours. Then it was added dropwise to 10 mL PEI in DMSO solution (5 mg / mL), and reacted with rapid stirring for 3 days. The reaction product was dialyzed against PBS buffer solution for 1 day (3×2 L), then deionized water for 2 days (6×2 L), and freeze-dried to obtain white solid powder PEI-PEG.

[0047] (2) In 10mL HA aqueous solution (9.57mg / mL), add 5mL LEDC aqueous solution (3.0mg / mL), stir for 0.5 hours, then add 3mL NHS aqueous solution (2.75mg / mL), and stir for 3 hours. Then it was added dropwise to the above 10 mL PEI-PEG solution in water (2.5 mg / mL), and reacted with rapid stirring for 3 days. The reaction product was dialyzed against deionized water for 3 days (6×2L), and freeze-dried to obtain PEI-(PEG-HA) as a white solid powder.

[0048] (3) Add 2 mL of FI aqueous solution (0.48 mg / mL) dro...

Embodiment 2

[0055] Add 10 μL triethylamine to 1.7 mg / mL DOX methanol solution, add it dropwise to 10 mL PEI-FI-(PEG-HA) aqueous solution (3.0 mg / mL), and stir at room temperature for 24 hours. After the reaction, the solution was transferred to a 15mL centrifuge tube, centrifuged at 8000rpm for 5 minutes, and the supernatant was lyophilized to obtain the reaction product PEI-FI-(PEG-HA) / DOX. See attached Figure 4 , the supernatant is analyzed by ultraviolet light, and the ultraviolet absorption peak of DOX is located at 480nm. According to the comparison between the ultraviolet absorption value of the prepared nano-drug sustained-release system at 480nm and the DOX standard curve, the content of DOX can be obtained, and the DOX can be calculated. The upload rate is 88%. The molar equivalent of DOX to PEI-FI-(PEG-HA) is 17.5:1.

Embodiment 3

[0057] Dissolve the PEI-FI-(PEG-HA) / DOX prepared in Example 2 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, place in Place in a container containing 9mL of buffer solution of different pH and shake in a shaker at 37°C. Samples were taken at 0.5, 1, 2, 3, 5, 8, 12, 16, 24, 36, 48 hour 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. This method was used to obtain the release curves of DOX released from PEI-FI-(PEG-HA) / DOX under different pH conditions in vitro. See attached Figure 5 , DOX in PEI-FI-(PEG-HA) / DOX is released faster under acidic conditions than under normal conditions, and the release of DOX reaches a stable level after 8 hours of release. The release rate of DOX from PEI-FI-(PEG-HA) / DOX in the weak acidic environment of...

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Abstract

The invention relates to a preparation method of a hyaluronic acid-targeted multifunctional branched polyethyleneimine drug carrier. The method includes: dropwise adding EDC (1-ethyl-3-(3-dimethylaminepropyl)carbodiimide) and NHS (N-hydroxysuccinimide) activated NH2-PEG-COOH into PEI (polyethyleneimine) solution, performing stirring for reacting, and performing freeze-drying after dialysis to obtain PEI-PEG (polyethyleneimine-polyethylene glycol); dropwise adding EDC and NHS activated HA (hyaluronic acid) into PEI-PEG solution, performing dialysis after stirring, and performing freeze-drying to obtain PEI-(PEG-HA); dropwise adding FI solution into PEI-(PEG-HA) aqueous solution, and performing stirring in the shade, dialysis and freeze-drying to obtain the carrier. The method is low in cost and simple, has mild conditions, is easy to operate and has a promising application prospect. The PEI-FI-(PEG-HA) carrying DOX serves as a nano drug controlled-release system having good drug controlled-release effect and having significant targeting effect and inhibitory effect for CD44 receptor expressed tumor cells.

Description

technical field [0001] The invention belongs to the field of preparation methods of drug carriers, in particular to a method for preparing hyaluronic acid-targeted multifunctional branched polyethyleneimine drug carriers. 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 anti-tumor drugs have problems such as poor water solubility, high toxicity and side effects, fast drug release, and anti-tumor drugs cannot be concentrated in the tumor site, causing 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, achieve sustained release of drugs, and prolong the action time of drugs in tumor sites; at the same time, by modifying targeting molecules, d...

Claims

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Application Information

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IPC IPC(8): A61K47/34A61K47/36A61K31/704A61P35/00C08G81/00C08B37/08
Inventor 史向阳陈晨周本青
Owner DONGHUA UNIV
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