Dual-sensitive targeted nanoparticle preparation for loading chemotherapeutic drugs and preparation method

A chemotherapeutic drug and preparation technology, applied in the field of pharmaceutical preparations, can solve the problems of strong particle penetration, long blood half-life, and easy damage to tissues and organs, and achieve improved drug loading, good biocompatibility and biodegradability, The effect of enhancing the penetrating power

Inactive Publication Date: 2019-08-16
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the inventors of the present disclosure have studied and found that when the particle size of the nano-preparation is large, the particle penetration ability is weak and the blood half-life is long, making the therapeutic effect poor; and when the particle size of the nano-preparation is small, the particle penetration ability is strong, Easy to damage normal tissues and organs

Method used

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  • Dual-sensitive targeted nanoparticle preparation for loading chemotherapeutic drugs and preparation method
  • Dual-sensitive targeted nanoparticle preparation for loading chemotherapeutic drugs and preparation method
  • Dual-sensitive targeted nanoparticle preparation for loading chemotherapeutic drugs and preparation method

Examples

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Effect test

Embodiment 1

[0074] The synthesis of embodiment 1 paclitaxel-dithiodipropionic acid conjugate (PTX-SS-COOH)

[0075] Synthetic route such as figure 1 shown. Weigh paclitaxel (PTX, 0.020g, 0.023mmol), dithiodipropionic anhydride (DTDPA, 0.044g, 0.023mmol) and DMAP (0.014g, 0.11mmol) respectively (the mol ratio of PTX, DTDPA and DMAP is 1: 1:5), placed in a 25mL round bottom flask, added 2mL of pyridine, and reacted at 35°C for 24h under the protection of nitrogen. The reaction liquid was rotary evaporated at 80°C to remove most of the pyridine, and dilute hydrochloric acid was added to remove unevaporated pyridine. The washing solution was extracted with dichloromethane. This was repeated three times, and the unreacted DTDPA was removed with a 0.22 μm filter membrane. The dichloromethane was evaporated to dryness, and dried overnight in a vacuum oven. The H NMR spectrum of PTX-SS-COOH is as follows figure 2 As shown, the product has the characteristic absorption peaks of PTX and DTDPA,...

Embodiment 2

[0076] The synthesis of embodiment 2 thiolated gelatin (Gel-SH)

[0077]Weigh p-mercaptobenzoic acid (0.008g, 0.05mmol) and EDC (0.010g, 0.05mmol) in a 25mL round bottom flask (the molar ratio of p-mercaptobenzoic acid to EDC is 1:1), add 400 μL absolute ethanol, Sonicate to dissolve. Add 800 μL of sodium hydroxide solution (0.1 M) and 800 μL of deionized water, sonicate to make the solution uniform, and activate at room temperature for 1 h under the protection of nitrogen. NHS (0.012 g, 0.10 mmol) was added to the reaction solution (the molar ratio of NHS to EDC was 2:1), and the activation was continued for 1 h at room temperature under nitrogen protection. Weigh 0.1g type A gelatin, add 10mL deionized water to swell and dissolve, slowly drop the above activation solution into the gelatin solution under ultrasonic conditions, and react under nitrogen protection at 40°C for 4h. The reaction solution was put into a dialysis bag (MWCO=8000-14000), dialyzed with DMSO for 24 ho...

Embodiment 3

[0079] Synthesis of embodiment 3 amphiphilic polymer (Gel-SS-PTX)

[0080] Weigh Gel-SH (0.008g), swell and dissolve with deionized water. Another weighed PTX-SS-COOH (0.008g) and EDC (0.003g) were placed in a 25mL round bottom flask, PTX-SS-COOH:EDC=1:2 (mol / mol), dissolved in acetonitrile, room temperature and Under the protection of nitrogen, react for 1h. Then NHS (0.004g) was added, activated at room temperature under nitrogen protection for 1h. The reaction solution was slowly dropped into the Gel-SH aqueous solution, and the ratio of water-acetonitrile was adjusted to make the reaction solution clear (the volume ratio of acetonitrile to water was 1:1), and the reaction was carried out under nitrogen protection at 40°C for 24h. The reaction solution was transferred to a dialysis bag (MWCO=8000-14000), and dialyzed in DMSO and water for 24 hours each.

[0081] For the NMR spectrum of Gel-SS-PTX see Figure 4 . product of 1 In the H-NMR spectrum, there are not only t...

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Abstract

The invention provides a dual-sensitive targeted nanoparticle preparation for loading chemotherapeutic drugs and a preparation method. The nanoparticle preparation comprises an amphiphilic polymer. The amphiphilic polymer comprises gelatin and at least one chemotherapeutic drug molecule. Each chemotherapeutic drug molecule is chemically bonded to the gelatin via a first chemical group, and the backbone of each first chemical group comprises a disulfide bond. The disulfide bonds with redox sensitivity can be broken to release drugs when the concentration of glutathione around tumor tissues is high. The gelatin, as a substrate of an MMP-2 enzyme, can be degraded into small particles around the tumor tissues by the overexpressed MMP-2 enzyme, so that the permeability in the tumor tissues is improved, and the dual-sensitive drugs are released.

Description

technical field [0001] The disclosure relates to the field of pharmaceutical preparations, in particular to a dual-sensitive targeting nanoparticle preparation loaded with chemotherapy drugs and a preparation method. Background technique [0002] The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art. [0003] As a chronic disease with a high mortality rate, cancer poses a great threat to human health. Chemotherapy is the main means of treating cancer. Its high toxicity and strong side effects are one of the main obstacles in the treatment process. While limiting the dosage of drugs, it may cause toxic side effects on normal tissues and organs. Therefore, as a method to improve drug distribution and reduce toxicity in vivo, nano-targeting technology has received extensive attention and research in the past decade. Encapsulating chemotherapy drugs in nanoparticles can not only control the re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K31/337A61K47/64A61P35/00
CPCA61K9/5169A61K31/337A61K47/6435A61P35/00
Inventor 李凌冰朱艺馨杨敏周可
Owner SHANDONG UNIV
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