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Reduced responsive drug-drug conjugate preparation method

A conjugate and responsive technology, which is applied in the field of preparation of reduction-responsive drug-drug conjugates, can solve the problems of large drug side effects, high carrier mass ratio, and low drug loading, and achieve the effect of increasing the loading capacity

Inactive Publication Date: 2018-11-13
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the small-molecule prodrugs prepared by the above-mentioned disclosed prior art all have the problem of high mass ratio of the carrier itself and low loading of the drug. Therefore, the drug has a large side effect and the therapeutic effect is not good.

Method used

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  • Reduced responsive drug-drug conjugate preparation method
  • Reduced responsive drug-drug conjugate preparation method

Examples

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Embodiment 1

[0023] Such as Figure 1 to Figure 7 Shown, a kind of preparation method of reduction-responsive drug-drug conjugate comprises the following steps:

[0024] The first step is to prepare the camptothecin intermediate (CPT-SS) containing reduction-responsive bonds: under the condition of argon (Ar) reaching 5-10Pa, the original molecule of camptothecin (CPT) is first dissolved in Water dichloromethane (DCM) solvent, then add 4-dimethylaminopyridine (DMAP) and solid triphosgene respectively, the molar ratio of the three drugs is 1:3:1 / 3, after stirring for 20 minutes under dark conditions , then slowly drop into anhydrous tetrahydrofuran (THF) solution of dithiodiethanol (BHD) 5 times the molar amount of CPT, and stir overnight; then, after extraction and column chromatography purification, pure monohydroxyl substituted camptothecin intermediate (CPT-SS);

[0025] In the second step, preparation of reduction-responsive drug-drug conjugates:

[0026] Under the condition of temp...

Embodiment 2

[0034] The first step in the preparation steps is completely consistent with the specific embodiment one, only the second step of the preparation steps is different from the specific embodiment one, and its specific preparation process is as follows:

[0035] The specific steps for preparing the reduction-responsive drug-drug conjugate BT-CPT are as follows: at a temperature ≤ 0°C and in an atmosphere where argon (Ar) reaches 5-10Pa, the camptophyllin prepared in the first step Base intermediate (CPT-SS), biotin (BT) dissolved in anhydrous N,N-dimethylformamide (DMF) solution, the above camptothecin intermediate (CPT-SS), biotin (BT ) The molar ratio of the two drugs is 1:1. After stirring for 30 minutes at 0 ℃ and protected from light, add 1-ethyl-(3-dimethylaminopropyl) carbonyl dicarboxylate with 2 times the molar amount of biotin Imine hydrochloride (EDC·HCl) and 0.1 times biotin molar amount of 4-dimethylaminopyridine (DMAP) in N,N-dimethylformamide (DMF) solution, raised...

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Abstract

The invention discloses a reduced responsive drug-drug conjugate preparation method which is characterized in that the method includes the steps: preparing a camptothecin intermediate (CPT-SS) containing a reduced responsive bond; preparing a reduced responsive drug-drug conjugate (GT-CPT) or (BT-CPT). The reduced responsive drug-drug conjugate has advantages of a small-molecule prodrug and a nano-drug, the uploading capability of the reduced responsive drug-drug conjugate can be effectively improved, the reduced responsive drug-drug conjugate solves the problems of targeting delivery of a current small-molecule prodrug delivery system and controlled release of drug selectivity, and accurate diagnosis and efficient treatment of tumors are facilitated. Gemcitabine (drug) and biotin (target)molecules are introduced, fluorescence of drug molecules can be temporarily shielded, the conjugate is combined with specificities of cancer cells, so that nano-micelles are disassembled and assembled, the fluorescence of the drug molecules can be reduced, and a drug releases drug properties under stimulation response, so that accurate diagnosis and treatment of cancers are combined.

Description

technical field [0001] The invention relates to a preparation method of a reduction-responsive drug-drug conjugate. Background technique [0002] Camptothecin (CPT, chemical structural formula: C20H16N2O4, CAS number: 7689-03-4, relative molecular weight: 348.43) is a plant anticancer drug extracted from camptothecin distributed in south-central and southwest China. It has a good curative effect on gastrointestinal tract and head and neck cancer. Camptothecin is a cytotoxic quinoline alkaloid that inhibits DNA topoisomerase (TOPO I). As a hydrophobic molecule, CPT has a small molecular size and low solubility in water, so there are problems such as non-specificity, low drug utilization, and strong side effects during drug delivery. [0003] Gemcitabine (Gemcitabine, GT, chemical structural formula: C9H11F2N3O4, CAS number: 95058-81-4, relative molecular mass: 263.20), as a hydrophilic drug, is a difluoronucleoside anti-metabolite that destroys cell replication. Cancer dru...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/55A61K9/14A61K31/4745A61K31/7068A61K31/4188A61K49/00A61P35/00
CPCA61K9/14A61K31/4188A61K31/4745A61K31/7068A61K49/0019A61K2300/00
Inventor 许志刚侯美丽高永娥马晓倩康跃军
Owner SOUTHWEST UNIVERSITY
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