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A modified platinum compound and its preparation method and application

A compound and platinum technology, applied in the field of 1--1H indazole-3-carbohydrazide modified platinum compounds and their preparation, can solve toxicity and drug resistance, excipient degradation and metabolism difficulties, load problems such as low drug dosage, to achieve the effect of improving uniformity and controllability, low carrier content, and high drug loading

Active Publication Date: 2020-10-16
HUAZHONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to overcome the current problems of non-target organ toxicity and drug resistance in tumor treatment, as well as the technical problems of low drug loading and difficult excipient degradation and metabolism in nano-medicines

Method used

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  • A modified platinum compound and its preparation method and application
  • A modified platinum compound and its preparation method and application
  • A modified platinum compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: the synthesis of the cisplatin (Pt(IV)-ADD) prodrug of Adudin modification

[0043] Concrete synthetic steps are as follows:

[0044](1) Synthesis of tetravalent platinum compounds

[0045]

[0046] The specific synthesis steps are as follows: weigh 1.2 g of cisplatin (4.00 mmol) into a 100 mL round bottom flask, add 60 mL of 30% hydrogen peroxide solution, and vigorously stir at 70° C. in the dark for 5 h. As the reaction progressed, cisplatin slowly dissolved, eventually producing a clear yellow solution. After the reaction is completed, filter while hot to remove a small amount of insoluble matter, and place it at 4° C. overnight after cooling at room temperature to obtain platinum oxide crystals and precipitates. The product was centrifuged, washed once with deionized water, and dried under vacuum overnight to obtain a pale yellow powder. Yield: 1.26 g (93.3%).

[0047] (2) Synthesis of ADD-TPA

[0048]

[0049] 100 mg of ADD (0.30 mmol) and...

Embodiment 2

[0070] Example 2: Preparation and Characterization of Self-Assembled Nanoparticles of Adudin-Modified Cisplatin (Pt(IV)-ADD) Prodrug

[0071] The specific operation steps of nanoparticle preparation are: the C 2 -Pt-ADD, C 4 -Pt-ADD, C 6 -Pt-ADD, C 8 -Pt-ADD or C 12 -Pt-ADD was dissolved in DMSO at a concentration of 10 mM. Take 100 μL of the drug solution and slowly add it dropwise to 2 mL of deionized water under magnetic stirring at 300 rpm to form a self-assembled nanoparticle solution (Pt(IV)-ADD NPs). Add DSPE-PEG, the mass ratio is drug:DSPE-PEG=1:0.15 (w / w). After mixing evenly, the above solution was transferred to a dialysis bag (MWCO1000), and the external phase of dialysis was deionized water to remove the organic solvent DMSO. After dialysis, the nanoparticles were centrifuged at low speed to remove large particles and precipitates, and then the DSPE-PEG-coated nanoparticles solution (Pt(IV)-ADD@PEG NPs) was obtained. The schematic diagram of the preparatio...

Embodiment 3

[0074] Example 3: In vitro anti-tumor activity of cisplatin-adudin self-assembled nanoparticles

[0075] In order to investigate the cell killing effect of the above compounds and self-assembled nanoparticles, MTT experiments were carried out on cisplatin-resistant cells (triple-negative breast cancer MDA-MB-231) and sensitive cells (liver cancer HepG2 and non-small cell lung cancer A549). IC under the action of each free drug and nanoparticles 50 Values ​​are shown in Table 1, and table 1 is the half maximal inhibitory concentration (IC 50 ), where the enhancement index (fold increase, FI) is defined as IC 50 (cisplatin) / IC 50 (drug).

[0076] Table 1

[0077]

[0078] The following conclusions can be preliminarily drawn from Table 1: (1) The tumor killing effects of self-assembled nanoparticles are stronger than that of the corresponding free drugs. (2) The self-assembled nanomedicine can produce enhanced tumor therapeutic effect in both cisplatin-resistant and sensi...

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Abstract

The invention relates to a modified platinum compound as well as a preparation method and application thereof and belongs to the technical field of antit-umor drugs. The preparation method comprises the following steps: oxidizing a divalent platinum compound into a tetravalent platinum compound; carrying out condensation reaction on 1-(2, 4-dichlorobenzyl)-1H indazole-3-carbohydrazide and 4-formylbenzoic acid to obtain carboxyl modified 1-(2, 4-dichlorobenzyl)-1H indazole-3-carbohydrazide; adding the carboxyl modified 1-(2, 4-dichlorobenzyl)-1H indazole-3-carbohydrazide into the tetravalent platinum compound to obtain an intermediate product; and carrying out a reaction on the intermediate product and isocyanate to obtain a 1-(2, 4-dichlorobenzyl)-1H indazole-3-carbohydrazide modified platinum compound. The compound provided by the invention has good self-assembly performance, can greatly reduce the usage amount of a carrier and improve the encapsulation efficiency and drug loading capacity of a drug, and the compound is simple to prepare, high in controllability and good in stability. Meanwhile, the compound and the nano particles show a remarkably enhanced anti-tumor effect, thekilling index of the compound and the nano particles in drug-resistant cells can be enhanced by 266.4 times to the maximum extent, and the drug resistance problem of platinum drugs can be greatly relieved.

Description

technical field [0001] The present invention relates to the technical field of antitumor drugs, more specifically, to a modified platinum compound and its preparation method and application, especially to a 1-(2,4-dichlorobenzyl)-1H indazole - 3-carbohydrazide modified platinum compound and its preparation method and application. Background technique [0002] Platinum antineoplastic drugs include cisplatin, carboplatin, heptaplatin, lobaplatin, eplatin, lobaplatin, oxaliplatin, nedaplatin, cyclothioplatin and sateplatin, etc., which are widely used and can be used in testicular Cancer, ovarian cancer, cervical cancer, head and neck cancer and non-small cell lung cancer and other tumors. However, with the deepening of research, the clinical application of cisplatin has gradually been limited, mainly facing the following problems such as large side effects and drug resistance. Platinum compounds can cause renal tubular damage and dysfunction through a variety of pathways. A...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F15/00A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07F15/0093
Inventor 张志平杨丛莲
Owner HUAZHONG UNIV OF SCI & TECH
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