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

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

Active Publication Date: 2020-03-17
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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

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Embodiment 1

[0023] The preparation of embodiment 1 cisplatin complex

[0024] Weigh 675.0mg (2.23mmol) of cisplatin and add it into 225mL Grade III ultrapure water, stir at 37°C until completely dissolved, then cool to room temperature, add 758.2mg (4.45mmol) of silver nitrate, and continue to cool at room temperature 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 collected 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 and stirred for 30 min. Weigh 202.4 mg (1.98 mmol) of succinic anhydride and dissolve it in 36.97 mL of anhydrous 1,4-dioxane at room temperature, add the above solution to the methanol solution of ...

Embodiment 2

[0028] The preparation of embodiment 2 cisplatin polymer prodrug BPEI-SS-Pt

[0029] Weigh 48.8 mg (2 μmol) of branched polyethyleneimine (BPEI) and dissolve it in 5 mL of grade III ultrapure water, and ultrasonicate at 60°C for 15 minutes until completely dissolved to obtain a colorless and clear BPEI aqueous solution; cisplatin complex 77.3 mg (143 μmol) Dissolve in 10mL grade III ultrapure water, stir at room temperature until completely dissolved, and obtain a yellow, clear and transparent aqueous solution of cisplatin complex. Add 25.6 mg (158 μmol) of carbonyldiimidazole to the aqueous solution of the cisplatin complex, stir in an ice bath for 1 hour, then remove the ice bath. After the reaction solution returns to room temperature, add BPEI aqueous solution to the reaction solution, and stir at room temperature for 24 hours in the dark. After the reaction, the reaction solution was transferred to a dialysis bag with a molecular weight cut-off of 7000, dialyzed in 2000 m...

Embodiment 3

[0031] Embodiment 3 two-terminal formaldehyde PEG 2000 Preparation of material PEG-DiAlde

[0032] Put 387.2mg (2.5mmol) of p-formylbenzoic acid in 50mL of dichloromethane, add 721.8mg (3.75mmol) of EDCI under stirring at room temperature, and add 9.4mg (75μmol) of DMAP under ice bath after the reaction solution is clear and transparent. Stir for 0.5h. After going to the ice bath and returning to room temperature, add 1g (2.5mmol) 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 allowed to stand overnight. After filtering, add 10 times the volume of glacial ether to the filtrate, place it at 4°C for 6 hours, and then filter it with suction. The obtained crude product was purified twice by dissolving in dichloromethane-precipitating with glacial ether, and the obtained solid was vacuum-dried at 20° C. ...

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Abstract

The invention discloses a preparation method and application of a tumor microenvironment and redox step-by-step responsive nano drug delivery system, and relates to preparation of a high-load cis-platinum polymer prodrug and a double-terminal aldehyde polyethylene glycol cross-linked cis-platinum nano drug delivery system, and can be used for tumor treatment. According to the invention, polyethyleneimine serves as a framework; cystamine containing redox responsive disulfide bonds is selected to react with succinic anhydride and then complexed with cis-platinum to acquire a cis-platinum complex; the acquired cis-platinum complex is covalently bound with polyethyleneimine to acquire the high-load cis-platinum polymer prodrug, and the outer layer is crosslinked by adopting double-terminal aldehyde polyethylene glycol to acquire the cis-platinum nano drug delivery system with tumor microenvironment and redox step-by-step responsiveness; compared with traditional chemotherapeutic drug cis-platinum, the cis-platinum drug delivery system provided by the invention has the advantages that polyethylene glycol shell removal and intracellular redox step-by-step responsive drug release in an extracellular microenvironment of tumors can be realized, and effective uptake of the cis-platinum drug delivery system and responsive release of drugs in tumors are ensured; the antitumor effect of thecis-platinum drug delivery system is better exerted; and the cis-platinum drug delivery system has a good clinical treatment application prospect.

Description

technical field [0001] The invention relates to a preparation method of a cisplatin-loaded tumor microenvironment and a redox step-by-step responsive nano 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. It is currently the first-line treatment drug for a variety of solid tumors. tumor effect. After cisplatin enters the cells, it inhibits the replication of DNA by cross-linking DNA and triggers apoptosis and necrosis of tumor cells. Since cisplatin inhibits DNA replication is non-specific, cisplatin has strong systemic side effects, such as kidney damage, neurotoxicity, bone marrow toxicity, anemia, etc. It is widely used in clinical practice. Therefore, it is of great clinical application value to improve the medicinal chemistry and formulation of cisplatin to improve its therapeutic effect and reduce its to...

Claims

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Application Information

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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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