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Cis-platinum nano pharmaceutical preparation, preparation method and application

A nano-drug, cisplatin technology, applied in the field of medicinal chemistry and preparation, can solve the problems of poor drug stability, low maximum tolerated dose, poor water solubility of cisplatin, etc., to achieve increased tolerated dose, high internal and external stability, high The effect of water solubility

Active Publication Date: 2018-11-20
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to solve the problems of poor water solubility of cisplatin, poor drug stability, and low maximum tolerated dose of the drug in vivo, the invention provides a cisplatin (CDDP) nano drug preparation

Method used

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  • Cis-platinum nano pharmaceutical preparation, preparation method and application
  • Cis-platinum nano pharmaceutical preparation, preparation method and application
  • Cis-platinum nano pharmaceutical preparation, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 2

[0063] The synthesis of embodiment 1 dihydroxy diamine dichloroplatinum II, such as figure 1 Shown:

[0064] A 100 mL round bottom flask was charged with CDDP (1 g, 3.33 mmol) and 15 ml of 30% hydrogen peroxide (30%, w / v). Stir at 75°C in the dark for 5 hours, cool at 4°C for 2 hours, filter under reduced pressure to obtain light yellow crystals, wash with water, ethanol and ether, and dry to obtain product II (998 mg, yield 90%).

Embodiment 2

[0065] Example 2 Synthesis of CDDP prodrug 1 containing saturated alkane chain compound, such as figure 2 Shown:

[0066] Add II (100mg, 0.3mmol) and n-hexanoic anhydride (127mg, 0.6mmol) to a 100mL round bottom flask, dissolve in (DMF), and add N,N'-dicyclohexylcarbodiimide (0.3mmol). Stir at 70°C for 3 hours. After the reaction, add water to precipitate a light yellow solid; then wash with water and petroleum ether, and filter to obtain product 1 (95 mg, yield 60%).

[0067] product 1 1 The H NMR nuclear magnetic data is as follows:

[0068] 1 H NMR(400MHz,DMSO-d6):δ0.84-0.88(t,6H),1.23-1.27(m,8H),1.42-1.51(m,4H),2.16-2.22(m,4H),6.38- 6.63 (m, 6H).

Embodiment 3

[0069] Example 3 Synthesis of CDDP prodrug 2 containing saturated alkane chain compound, such as image 3 Shown:

[0070] In a 100 mL round bottom flask, add II (100 mg, 0.3 mmol) and n-heptanoic anhydride (146 mg, 0.6 mmol), dissolve in 2 mL of anhydrous dimethylformamide (DMF), add 1-(3-dimethylaminopropyl )-3-Ethylcarbodiimide (0.3 mmol). Stir at 70°C for 3 hours, add water to precipitate after the reaction to obtain a yellowish solid; then wash with water and petroleum ether, and filter to obtain product 2 (109 mg, yield 65%).

[0071] product 2 1 The H NMR nuclear magnetic data is as follows:

[0072] 1 H NMR(400MHz,DMSO-d6):δ0.83-0.88(t,6H),1.21-1.25(m,12H),1.41-1.50(m,4H),2.17-2.22(m,4H),6.39- 6.63 (m, 6H).

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Abstract

The invention discloses a tetravalent platinum pharmaceutical preparation, and a preparation method and application thereof. The tetravalent platinum pharmaceutical preparation comprises a prodrug andan amphipathic high molecular material. The prodrug has a structural formula (I). Dynamic light scattering and a transmission electron microscopy show that nanoparticles are uniformly distributed andare about 40-60 nm; an in vitro cytotoxicity test shows that the nanoparticles coated with platinum prodrug can inhibit proliferation of tumor cells (MDA-MB-468 and HT-29) obviously. An in vivo experiment shows that compared with a cis-platinum injection liquid, the cis-platinum nano pharmaceutical preparation has an effect of inhibiting subcutaneous tumor MDA-MB-468 on the basis of reducing thesystemic toxicity and has good market prospect and clinical application value.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and preparations, and in particular relates to a series of cisplatin nano-medicine preparations and their preparation methods and applications. Background technique [0002] Cis-diammine dichloroplatinum (cis-damminedichloroplatinum (II), cis-Pt (II) (NH 3 ) 2 Cl 2 , [0003] CDDP) is a heavy metal compound that is centered on divalent platinum and coordinated with two amino molecules and two chlorine atoms respectively. It was approved for clinical use by the U.S. Food and Drug Administration in 1978 ( Bristol-Myers Squibb). Its structural formula is as follows: [0004] [0005] As a clinical chemotherapy drug, CDDP is widely used in the treatment of osteosarcoma, soft tissue tumors such as testicular cancer, ovarian cancer, head and neck squamous cell carcinoma and lung cancer (Ana-Maria Florea and Dietrica Büsselbery, Cisplatinas an Anti-Tumor Drug: Cellular Mechanisms of Activity...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K9/107A61K47/10A61K31/282A61P35/00C07F15/00
CPCA61K9/00A61K9/1075A61K31/282A61K47/10A61P35/00C07F15/0093
Inventor 王杭祥
Owner ZHEJIANG UNIV
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