Camptothecin prodrug as well as preparation method and application thereof

A camptothecin and prodrug technology, applied in the field of camptothecin-low molecular weight heparin prodrug self-assembly nano-delivery system, can solve problems such as poor water solubility, unstable active ester structure, and low loop closure rate

Pending Publication Date: 2022-01-21
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in clinical application, camptothecin drugs face the problems of poor water solubility and low ring closure rate caused by unstable active ester structure under physiological conditions.
In recent years, researchers have proposed two strategies to solve the problem of unstable camptothecin structure: to treat the drug with an acidic medium so that it has a high rate of loop closure at the initial stage of administration, or to use the barrier effect of polymer carriers to reduce its physiological stability. However, these strategies have not fundamentally solved the problem of structural instability of camptothecins
Making camptothecin drugs into polymer prodrugs can improve its solubility and increase drug loading capacity. At present, there are many works in this direction. However, for making camptothecin drugs into polymer prodrugs to improve There are few reports on the self-closing rate and increasing its stability in vivo

Method used

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  • Camptothecin prodrug as well as preparation method and application thereof
  • Camptothecin prodrug as well as preparation method and application thereof
  • Camptothecin prodrug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Synthesis of Camptothecin Prodrug LMWH-CP

[0027] 1. Synthesis of intermediate product LMWH-ADH

[0028] Accurately weigh 30 mL (4 mg / mL) of LMWH (MW=4500 Da, Nanjing Nanda Pharmaceutical Co., Ltd.) and add it to an appropriate amount of phosphate buffer solution with pH 6.8. After it is fully dissolved, add ADH 141.10 mg, EDCI 155.28 mg, HOBT109.59 mg, stirred at room temperature, adjusted the reaction system with 0.1M hydrochloric acid to make the pH value about 6.7, and reacted for at least 24 hours. The crude product obtained was dialyzed against distilled water in order to remove remaining reactants as well as small molecule by-products. The dialyzed filtrate was filtered and lyophilized to obtain the intermediate product LMWH-ADH.

[0029] 2. Synthesis of intermediate product CPT-OA

[0030] Accurately weigh camptothecin 100mg (0.3mmol), DMAP 73.30mg (0.6mmol), EDCI 93.17mg (0.6mmol), OA 104.52mg (0.6mmol) in a dry round bottom flask, add anhydrous dichloromet...

Embodiment 2

[0034] Preparation of LMWH-CPT nanoparticles

[0035] Precisely weigh 10 mg of camptothecin prodrug LMWH-CPT, dissolve it in 2 mL of tetrahydrofuran solution, drop it into 10 mL of ultrapure water while stirring with a magnetic stirrer, and stir until the tetrahydrofuran is completely volatilized, The probe was sonicated for 30 minutes in an ice bath (power 200W, working 1s, intermittent 2s), and then passed it through a 0.45 μm filter membrane to obtain a light yellow LMWH-CPT nanoparticle solution with Tyndall effect.

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Abstract

The invention discloses a camptothecin prodrug as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. According to the invention, a prodrug strategy is utilized, camptothecin is chemically bonded to a low molecular weight heparin (LMWH) molecular chain to form a prodrug, and the synthesized LMWH-CPT is self-assembled to form the nanoparticles by virtue of the hydrophobicity of the camptothecin and the hydrophilicity of the low molecular weight heparin. The camptothecin prodrug LMWH-CPT not only has the advantages of a polymer prodrug, but also the equilibrium constant pKa of camptothecin molecules in a nanoparticle core is remarkably increased by virtue of the unique hydrophobic interaction of the camptothecin molecules, so that the camptothecin prodrug LMWH-CPT is ensured to have a relatively high closed-loop rate after being stored in a neutral environment and being subjected to injection administration.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, in particular to a redox-sensitive camptothecin-low molecular weight heparin prodrug self-assembled nano delivery system. Background technique [0002] Tumor metastasis has always been a major problem for researchers. Solid tumors can "release" millions of tumor cells into the blood circulation every day. Even if the tumor is surgically removed in the early stage, a large number of tumor cells will still enter the blood. In order to avoid cancer recurrence caused by tumor metastasis, there are currently two main solutions: one is postoperative treatment, and the other is increasing the dose of chemotherapy drugs alone. Increasing the dose of chemotherapy drugs can significantly reduce the number of circulating tumor cells and even kill the remaining tumor cells, but it is often accompanied by serious side effects. Therefore, it is meaningful to design a low-toxic and effectiv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/61A61K31/4745A61K9/52A61K47/36A61P35/00A61P35/04B82Y5/00B82Y40/00
CPCA61K47/61A61K31/4745A61K9/5161A61P35/00A61P35/04B82Y5/00B82Y40/00
Inventor 柯学乔颖玉
Owner CHINA PHARM UNIV
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