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Temozolomide prodrug nano-micelles and preparation method therefor and application of temozolomide prodrug nano-micelles

A temozolomide and nanotechnology, applied in the field of amphiphilic block polymers, can solve the problems of inability to release drugs, increase the accumulation of drug carriers, reduce drug efficacy, etc., and achieve the effects of not easy dissociation, drug stability, and prolongation of half-life

Active Publication Date: 2020-06-05
XUZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although drug carriers such as nanoparticles, nanomicelles, and polymer vesicles formed by self-assembly of amphiphilic copolymers can prolong the circulation time of drugs in the body and increase the accumulation of drug carriers in tumor sites, they are often ineffective. to release the drug, thereby reducing the efficacy of the drug

Method used

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  • Temozolomide prodrug nano-micelles and preparation method therefor and application of temozolomide prodrug nano-micelles
  • Temozolomide prodrug nano-micelles and preparation method therefor and application of temozolomide prodrug nano-micelles
  • Temozolomide prodrug nano-micelles and preparation method therefor and application of temozolomide prodrug nano-micelles

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Experimental program
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Effect test

Embodiment 1

[0037] The synthesis method of polyoxazoline-polytemozolomide is similar except that the hydrophilic segment is different. Therefore, this embodiment only takes the synthesis of poly(2-methyl-2-oxazoline)-polytemozolomide as an example.

[0038] (1) Synthesis of temozolomide-methacrylate

[0039]

[0040]Dissolve 4.58g, 0.024mmol temozolomide (TMZ) in concentrated sulfuric acid, add 47.2mL of sodium nitrite aqueous solution dropwise under ice bath, keep stirring at room temperature for 17h and then drop to 0°C, add 122.0g of ice water to the system , to quench the reaction, filter, wash with ice water and dry to give temozolomide-8-carboxylic acid (TMZ-COOH).

[0041] Add 1.185g, 6.10mmol TMZ-COOH to the dichloromethane solution, then add 0.706mL of hydroxyethyl methacrylate (5.82mmol, HEMA), 1.348g of 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (7.02mmol, EDC) and 0.072g of 4-dimethylaminopyridine (0.58mmol, DMAP), continued to stir at room temperature fo...

Embodiment 2

[0062]

[0063] This embodiment is another preparation method of temozolomide nano-prodrug micelles (amphiphilic polyethylene glycol-polytemozolomide block polymer), and its preparation method is basically similar to that of Example 1, mainly comprising: anhydrous and oxygen-free Under the condition of environment, react polyethylene glycol (PEG) with 4-cyano-4-(thiobenzoyl)valeric acid (CTA) through esterification reaction, and then use PEG-CTA as macromolecular RAFT reagent, in Under the catalysis of azobisisobutyronitrile (AIBN), react with temozolomide-methyl methacrylate to obtain polyethylene glycol-polytemozolomide block polymer. The molecular weight of polyethylene glycol is 3000-10000Da, the molecular weight of polytemozolomide is 3000-10000Da, the degree of polymerization of polyethylene glycol is 39-131, and the degree of polymerization of polytemozolomide is 10-32.

Embodiment 3

[0065] Dissolve the hydrophobic drug in the organic solution first, then stir together with the organic solution of the amphiphilic block polymer, then add dropwise secondary water twice the volume of the organic solution, and stir the obtained solution for 1 hour Dialysis to obtain nanomicelles encapsulating the drug; the hydrophobic drug is selected from but not limited to: one of adriamycin, paclitaxel, methotrexate, curcumin or camptothecin.

[0066] The encapsulation of anticancer drugs in polyoxazolin-polytemozolomide micelles and polyethylene glycol-polytemozolomide micelles is all realized by dialysis. Taking PMeOx-PTMZ as an example, 2.4 mg of the polymer was dissolved in 1.0 mL of dimethyl sulfoxide, and the designed doxorubicin (DOX) required for a drug loading of 15% was added therein, and after ultrasonication for 0.5 h, Under the condition of stirring at room temperature, 1.8 mL of secondary water was slowly added dropwise to the dimethyl sulfoxide solution, and ...

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Abstract

Temozolomide prodrug nano-micelles each comprise a hydrophilic shell and a hydrophobic core; each hydrophilic shell is polyoxazoline or polyethylene glycol, and the hydrophobic cores are each polytemozolomide. A preparation method for the temozolomide prodrug nano-micelles is characterized in that the polyoxazoline or polyethylene glycol reacts with 4-cyano-4-valeric acid through an esterificationreaction, and as a macromolecular reversible addition-fragmentation chain transfer polymerization (RAFT) reagent, an obtained product reacts with temozolomide-methyl methacrylate under catalysis of azodiisobutyronitrile to obtain amphiphilic block polymers. According to the temozolomide prodrug nano-micelles, the amphiphilic block polymers can extend the half-life period of temozolomide; two amphiphilic block polymer nano-micelles both belong to the prodrugs of the temozolomide, and meanwhile, the cores of the micelles can entrap other anticancer drugs to realize combination therapy of different drugs. After entering a tumor cell, the polyoxazoline-polytemozolomide micelles crack in the acidic environment of the cancer cell, and encapsulated drugs are quickly released, and thereby, a high-efficiency therapeutic effect is generated, and the problems that a drug carrier is slow in drug release, and is prone to be drug-resistant are solved.

Description

technical field [0001] The invention relates to an amphiphilic block polymer, and relates to a temozolomide nano-prodrug micelle and a preparation method and application thereof. Background technique [0002] In recent decades, various nanocarriers have been widely developed to improve the efficacy of cancer chemotherapy, and these nanocarriers have the ability to target and control the release of anticancer drugs due to their enhanced permeability and retention (EPR) effect. Among them, micelles formed by amphiphilic block polymers have attracted great interest in the field of drug release. Polymer micelles of amphiphilic block polymers are a kind of nanocarriers for anticancer drugs, which are widely used in drug delivery, and they have several excellent salient features, including long circulation time, good drug solubility, and tumor site localization. Passive targeting capabilities. Amphiphilic polymers can self-assemble in water to form polymer nanomicelles (Micelles...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K31/4188A61K47/60A61K47/59A61K31/704A61K31/337A61K31/519A61K31/12A61K31/4745A61P35/00
CPCA61K9/1075A61K31/12A61K31/337A61K31/4188A61K31/4745A61K31/519A61K31/704A61K47/59A61K47/60A61P35/00A61K2300/00
Inventor 李玉玲张诃娜许康杜百祥
Owner XUZHOU NORMAL UNIVERSITY
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