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Preparation method of oxidoreduction responsiveness tumor-targeted cis-platinum nanometer drug delivery system, and application thereof

A nano-drug delivery system and tumor-targeting technology, which is applied in the preparation and application of redox-responsive tumor-targeted cisplatin nano-drug delivery system, can solve the problems of lack of specific ligands, large toxic and side effects, and effective drug utilization. Low rate and membrane permeability

Active Publication Date: 2020-02-14
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Traditional small-molecule anti-tumor chemotherapeutic drugs have disadvantages such as high toxicity and side effects, low drug utilization rate and membrane penetration ability, lack of ideal specific ligands, and frequent administration, which limit their clinical application.

Method used

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  • Preparation method of oxidoreduction responsiveness tumor-targeted cis-platinum nanometer drug delivery system, and application thereof
  • Preparation method of oxidoreduction responsiveness tumor-targeted cis-platinum nanometer drug delivery system, and application thereof
  • Preparation method of oxidoreduction responsiveness tumor-targeted cis-platinum nanometer drug delivery system, and application thereof

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Experimental program
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Embodiment 1

[0018] The preparation of embodiment 1 cisplatin complex

[0019] 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.

[0020] 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

[0023] The preparation of embodiment 2 cisplatin polymer prodrug BPEI-SS-Pt

[0024] 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

[0026] Example 3 Preparation of redox responsive tumor targeting cisplatin nano drug delivery system HA-(BPEI-SS-Pt)-1 / 4

[0027] Take the 1:4 mass ratio of HA and BPEI-SS-Pt as an example. Weigh 10.0mg of BPEI-SS-Pt and dissolve it in 10mL of grade III ultrapure water, and incubate at 50°C for 2 hours in the dark to dissolve completely, and obtain a concentration of 1mg·mL -1 BPEI-SS-Pt aqueous solution. Weigh 30.0mg HA and dissolve it in 6mL Grade III ultrapure water, shake until completely dissolved, and obtain a concentration of 5mg·mL -1 HA aqueous solution. Absorb the corresponding volume of HA solution according to the mass ratio of 1:4 (HA:BPEI-SS-Pt), add it to the aqueous solution of BPEI-SS-Pt, avoid light and sonicate at room temperature for 1h to obtain the composite nanoparticle HA-(BPEI-SS-Pt )-1 / 4, protected from light and stored in a refrigerator at 4°C. The particle size and potential of the nanoparticles were measured by a laser nanometer particle size a...

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Abstract

The invention discloses a preparation method of an oxidoreduction responsiveness tumor-targeted cis-platinum nanometer drug delivery system, and application thereof, relates to the building and the preparing of a high-load cis-platinum macromolecule pro-drug and a hyaluronic acid-coated high-load cis-platinum nanometer drug delivery system, and can be applied to active targeting treatment of tumors. Polyethyleneimine is adopted as a framework, and cystamine containing a disulfide bond with oxidoreduction responsiveness is selected to be reacted with butanedioic anhydride so as to be complexedwith cis-platinum, so that a cis-platinum complex is obtained. The obtained cis-platinum complex and the polyethyleneimine are covalently bonded to obtain the high-load cis-platinum macromolecule pro-drug, and a hyaluronic acid targeted group is coated on an outer layer, so that the oxidoreduction responsiveness tumor-targeted cis-platinum nanometer drug delivery system with a tumor active targeting function is obtained. Compared with traditional chemotherapy drug cis-platinum, the oxidoreduction responsiveness tumor-targeted cis-platinum nanometer drug delivery system provided by the invention can realize tumor active targeting drug delivery and oxidoreduction responsiveness drug release, plays a role in anti-tumor treatment, is capable of effectively reducing the toxic and side effects caused by the cis-platinum on other visceral organs of a body, and has a favorable clinic application prospect.

Description

technical field [0001] The invention relates to a preparation method of a high-load cisplatin polymer prodrug and a hyaluronic acid-coated redox-responsive tumor-targeting nano-drug delivery system, which can be used for the treatment of tumors. Background technique [0002] Cisplatin (Cisplatin) is cisplatin dichlorodiamminoplatinum. As a platinum antitumor chemotherapy drug, it has shown good antitumor effect in clinical treatment after being approved by the US FDA. It is widely used in ovarian cancer, prostate cancer, testicular cancer, etc. Cancer, lung cancer, nasopharyngeal cancer, esophageal cancer, breast cancer and other tumors. After cisplatin enters the cell, a dissociation reaction occurs in the cell to generate hydrated complex ions, which are transported to the nucleus, bind to the DNA in the nucleus, hinder DNA replication, and cause cell apoptosis and necrosis. The effect of cisplatin on DNA replication is non-specific, so cisplatin has strong systemic side ...

Claims

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Application Information

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IPC IPC(8): A61K9/51A61K47/36A61K47/58A61K33/243A61P35/00
CPCA61K9/5161A61K47/58A61P35/00A61K33/243
Inventor 张邦乐许经良贾奕扬何炜王伟贾舟延周四元宦梦蕾
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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