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Camptothecin (CPT) predrug as well as preparation method and application thereof

A camptothecin and prodrug technology, which is applied in the field of camptothecin-vitamin B6 prodrug self-assembled nano-delivery systems, can solve the problems of low equilibrium loop closure rate, drug carrier entry, poor water solubility, etc., and achieves improved safety and effectiveness. sexual effect

Inactive Publication Date: 2020-05-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The clinical application of camptothecin mainly faces two problems: first, poor water solubility; second, its active ester will hydrolyze and open the ring under neutral and alkaline conditions, and the equilibrium ring closing rate is low under physiological conditions
However, the disadvantage of small molecule nanoprodrugs is that the drug carrier will still enter normal tissues

Method used

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  • Camptothecin (CPT) predrug as well as preparation method and application thereof
  • Camptothecin (CPT) predrug as well as preparation method and application thereof
  • Camptothecin (CPT) predrug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of camptothecin prodrug (CPT-s-s-VitB6)

[0029]Dichloromethane was first anhydrous. Weigh 100 mg camptothecin (CPT), 70.7 mg 4-dimethylaminopyridine (DMAP), 222.7 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC ), 304.5 mg 3,3'-dithiodipropionic acid (DPA) was placed in a 500 mL three-neck bottle, dissolved in 250 mL anhydrous dichloromethane, fully dissolved by ultrasonication, and kept at 40°C under the protection of nitrogen Reaction 24h. Using dichloromethane / methanol (v / v=20:1) as developing solvent to carry out TLC tracking reaction, the RF value of camptothecin is about 0.6, and CPT-20-O-3,3'-dithiobis The RF value of propionate is about 0.3, and the progress of the reaction can be judged according to the fluorescent spots of camptothecin and CPT-20-O-3,3'-dithiodipropionate. After the reaction was completed, the organic phase was extracted twice with 0.01M hydrochloric acid, and then extracted twice with distilled water, and t...

Embodiment 2

[0032] The nanoparticle solution was prepared by the direct water dissolution method. 5 mg of the product CPT-s-s-VitB6 prepared in Example 1 was dissolved in 10 mL of deionized water, and then the probe was sonicated for 30 min (with a power of 400 W). After the sonication of the probe, filter with a syringe filter with a pore size of 0.45 μm to obtain a nanoparticle solution.

Embodiment 3

[0034] The nanoparticle solution was prepared by dialysis, 5 mg of the product CPT-s-s-VitB6 prepared in Example 1 was fully dissolved in 10 mL of dimethyl sulfoxide (DMSO), and transferred to a dialysis bag with a molecular weight cut-off of 5000 Da . The dialysate was 1 L of deionized water, which was changed every 6 h and dialyzed for 24 h. After the end of dialysis, the liquid probe in the dialysis bag was ultrasonicated for 30 min (with a power of 400 W). After the sonication of the probe, filter with a syringe filter with a pore size of 0.45 μm to obtain a nanoparticle solution.

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Abstract

The invention discloses a camptothecin (CPT) predrug as well as a preparation method and application thereof. The CPT predrug takes vitamin B6 as a hydrophilic end and CPT as a hydrophobic end, and the two parts are connected through a disfulfide bond. The CPT predrug can realize self-assembly in water to form a pH / redox double-sensitive nano-drug delivery system, the nano-drug delivery system hascertain acid sensitivity and redox sensitivity, under the action of high-concentration glutathione in a tumor microenvironment, the disulfide bond can be broken quickly and release the CPT, the drugCPT can be delivered to a tumor part efficiently, and the safety and effectiveness of CPT drug delivery are expected to be further improved.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a pH / oxidation-reduction double sensitive camptothecin-vitamin B6 prodrug self-assembly nano delivery system. Background technique [0002] Camptothecin (CPT) is a kind of tryptophan-terpene alkaloid extracted from the unique plant camptotheca in our country. It is the compound with the most significant anticancer effect among the isolated monomers of camptothecin. Isomerase I plays an anti-cancer role and is mainly used for diseases such as liver cancer and leukemia. The clinical application of camptothecin mainly faces two problems: first, poor water solubility; second, its active ester will hydrolyze and open the ring under neutral and alkaline conditions, and the equilibrium ring closing rate is low under physiological conditions. In recent years, researchers have proposed many camptothecin antitumor drug delivery systems, such as micelles, li...

Claims

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Application Information

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IPC IPC(8): A61K47/54A61K47/52A61K31/4745A61K9/14A61P35/00A61P35/02
CPCA61K9/14A61K31/4745A61K47/52A61K47/545A61P35/00A61P35/02
Inventor 柯学戴佳伶王梦然慈天元
Owner CHINA PHARM UNIV
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