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Preparation method and application of tumor microenvironment and redox stepwise responsive nano-drug delivery system

A nano-drug delivery system and tumor microenvironment technology, applied in anti-tumor drugs, nano-drugs, nano-technology, etc., can solve the problems of weakened anti-tumor effect, decreased nanoparticle uptake, and poor effective accumulation ability at tumor target sites.

Active Publication Date: 2022-07-05
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, while traditional PEG-modified nanoparticles reduce the uptake of macrophages in the blood circulation, it also reduces the uptake of nanoparticles by tumor cells in tumor tissues, hindering the entry of drugs into cells to exert pharmacological effects, and weakening the anti-tumor effect to a certain extent.
Moreover, the general single-end polyethylene glycol (PEG) modification cannot effectively compress the particle size of the nano drug delivery system, and the effective accumulation ability of the tumor target site is poor [Biomacromolecules, 2017, 18, 1342-1349]

Method used

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  • Preparation method and application of tumor microenvironment and redox stepwise responsive nano-drug delivery system
  • Preparation method and application of tumor microenvironment and redox stepwise responsive nano-drug delivery system
  • Preparation method and application of tumor microenvironment and redox stepwise responsive nano-drug delivery system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 Preparation of cisplatin complex

[0024] Weigh 675.0 mg (2.23 mmol) of cisplatin into 225 mL of grade III ultrapure water, stir at 37 °C in the dark until it is completely dissolved, then cool to room temperature, add 758.2 mg (4.45 mmol) of silver nitrate, and continue at room temperature in the dark. The reaction was stirred for 48h. After the reaction, the reaction solution was centrifuged twice (5000 rpm, 1 h each time), and the supernatant was taken and filtered with a 0.1 μm water filter to obtain a hydrated cisplatin solution.

[0025] Cystamine dihydrochloride 499.4 mg (2.18 mmol) was dissolved in 24.6 mL of methanol at room temperature. Under ice bath conditions, 445.7 mg (4.36 mmol) of triethylamine was added to the methanol solution of cystamine dihydrochloride, followed by stirring for 30 min. Weigh 202.4 mg (1.98 mmol) of succinic anhydride, dissolve it in 36.97 mL of anhydrous 1,4-dioxane at room temperature, add the above solution to the meth...

Embodiment 2

[0028] Example 2 Preparation of cisplatin polymer prodrug BPEI-SS-Pt

[0029] Weighed 48.8 mg (2 μmol) of branched polyethyleneimine (BPEI) and dissolved it in 5 mL of grade III ultrapure water, and ultrasonicated at 60 °C for 15 min to completely dissolve to obtain a colorless and clear BPEI aqueous solution; cisplatin complex 77.3 mg (143 μmol) Dissolved in 10 mL of grade III ultrapure water, stirred at room temperature until completely dissolved, to obtain a yellow, clear and transparent cisplatin complex aqueous solution. 25.6 mg (158 μmol) of carbonyldiimidazole was added to the aqueous solution of cisplatin complex, stirred for 1 h in an ice bath, and then removed from the ice bath. After the reaction solution returned to room temperature, an aqueous solution of BPEI was added to the reaction solution, and the reaction was stirred at room temperature in the dark for 24 h. After the reaction, the reaction solution was transferred to a dialysis bag with a molecular weight ...

Embodiment 3

[0031] Example 3 Aldehydated PEG at both ends 2000 Preparation of material PEG-DiAlde

[0032] Place 387.2 mg (2.5 mmol) of p-aldehyde benzoic acid in 50 mL of dichloromethane, add 721.8 mg (3.75 mmol) of EDCI under stirring at room temperature, and add 9.4 mg (75 μmol) of DMAP under ice bath after the reaction solution is clear. Stir for 0.5h. After removing the ice bath and returning to room temperature, add 1 g (2.5 mmol) PEG 2000 , continue to stir the reaction for 1h. The reaction solution was concentrated to 5 mL under reduced pressure, washed 5 times with saturated aqueous sodium chloride solution, added with anhydrous sodium sulfate and left overnight. After filtration, 10 times the volume of glacial ether was added to the filtrate, placed at 4°C for 6 hours, and then suction filtered. The obtained crude product was dissolved in dichloromethane and purified twice by glacial ether precipitation method, and the obtained solid was vacuum-dried at 20° C. for 12 h. The...

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Abstract

The invention discloses a preparation method and application of a nano-drug delivery system responsive to tumor microenvironment and redox stepwise, and relates to a high-loaded cisplatin macromolecule prodrug and double-end aldehyde-based polyethylene glycol cross-linked cisplatin The preparation of nano-drug delivery system can be used for tumor treatment. In the invention, polyethyleneimine is used as the skeleton, and cystamine containing redox-responsive disulfide bonds is selected to react with succinic anhydride and then complexed with cisplatin to obtain a cisplatin complex. The obtained cisplatin complex is covalently combined with polyethyleneimine to obtain a high-load cisplatin polymer prodrug, and the outer layer is then cross-linked with double-end aldehyde-based polyethylene glycol to obtain a tumor microenvironment and oxidation. Reduction of a stepwise responsive cisplatin nano-drug delivery system. Compared with the traditional chemotherapeutic drug cisplatin, the present invention can realize the removal of the polyethylene glycol shell in the extracellular microenvironment of the tumor and the step-by-step responsive drug release of the intracellular redox, which ensures the effective uptake of the cisplatin drug delivery system and the release of the drug in the tumor. It can be released in response to the tumor, so as to better exert its anti-tumor effect, and has a good clinical application prospect.

Description

technical field [0001] The invention relates to a preparation method of a cisplatin-loaded tumor microenvironment and a redox stepwise responsive nanometer drug delivery system, which can be used for tumor treatment. Background technique [0002] Cisplatin (cis-diamminedichloroplatinum (II), CDDP) is a platinum-based anti-tumor chemotherapy drug approved by the US FDA and is currently the first-line treatment for a variety of solid tumors. tumor effect. After cisplatin enters cells, it cross-links DNA and inhibits DNA replication to induce apoptosis and necrosis of tumor cells. Since the inhibition of DNA replication by cisplatin is non-specific, cisplatin has strong systemic side effects, such as kidney damage, neurotoxicity, bone marrow toxicity, anemia, etc. Its severe side effects and easy tumor resistance limit It is widely used in clinical practice. Therefore, the transformation of cisplatin in medicinal chemistry and formulation to improve its therapeutic effect an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/60A61K47/58A61K33/243A61P35/00B82Y5/00B82Y30/00B82Y40/00
CPCA61K33/243A61K47/58A61K47/60B82Y5/00B82Y30/00B82Y40/00A61P35/00
Inventor 张邦乐贾奕扬何炜王伟周四元蔡泽东贾舟延
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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