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Drug-loaded micelles with particle size reduction and surface charge reversal in response to acidic microenvironment and preparation method thereof

A technology of drug-loaded micelles and particle size, which can be used in pharmaceutical formulations, medical preparations with non-active ingredients, and medical preparations containing active ingredients, etc., can solve problems such as limited tumor penetration ability, and improve anti-tumor effects. , Improve the ability of penetration, the effect of long cycle time

Active Publication Date: 2021-08-27
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to overcome the deficiencies of the prior art, and provide drug-loaded micelles that respond to the acidic microenvironment to achieve particle size reduction and surface charge reversal and its preparation method, so as to solve the problem that the existing nano-drug delivery system is difficult to achieve particle size reduction at the tumor site. The problem of limited tumor penetration ability due to the reduced diameter, endows the drug-loaded micelles with long-term circulation and the ability to penetrate tumors efficiently

Method used

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  • Drug-loaded micelles with particle size reduction and surface charge reversal in response to acidic microenvironment and preparation method thereof
  • Drug-loaded micelles with particle size reduction and surface charge reversal in response to acidic microenvironment and preparation method thereof
  • Drug-loaded micelles with particle size reduction and surface charge reversal in response to acidic microenvironment and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] In this embodiment, the polymer prodrug is synthesized, and the synthetic route and steps are as follows:

[0053]

[0054] (1) Chain transfer agent 4-cyano-4-(thiobenzoyl)valeric acid (CPDB), 2-(hexamethyleneimine) ethanol methacrylate (HEME) monomer and initiator azo Diisobutyronitrile (AIBN) was dissolved in redistilled 1,4-dioxane (1,4-Dioxane), the molar ratio of HEME to CPDB was 80:1, and the molar ratio of AIBN to CPDB was 0.2: 1. The concentration of CPDB in 1,4-dioxane is 0.02mmol / mL. The resulting mixed solution was transferred to a pre-deoxygenated reaction bottle, followed by freezing-vacuum-nitrogen circulation three times to remove the oxygen in the reaction bottle, and then nitrogen protection and sealing the reaction bottle, and polymerized at 65 °C reaction, after 24 hours of polymerization reaction, the reaction was quenched with liquid nitrogen, dichloromethane was added to the obtained reaction liquid to dilute and precipitate in excess cold hexa...

Embodiment 2

[0075] In this example, the drug-loaded micelles were prepared on the basis of the polymer prodrug synthesized in Example 1, and the steps were as follows:

[0076] Take 3 mg of the polymer prodrug prepared in Example 1 and dissolve it in 200 μL of DMF to form a polymer prodrug solution, and slowly drop the polymer prodrug solution into 3 mL of pH=7.4 under ice bath and ultrasonic conditions with a power of 200 W. After the dropwise addition, continue to sonicate for 5 minutes in an ice bath, and then transfer to PBS with pH=7.4 to fully dialyze to remove DMF to obtain drug-loaded micelles.

[0077] Take 3 mg of the polymer prodrug prepared in Example 1 and dissolve it in 200 μL of DMF to form a polymer prodrug solution, and slowly drop the polymer prodrug solution into 3 mL of pH=6.7 under ice bath and ultrasonic conditions with a power of 200 W. After the dropwise addition, continue to sonicate for 5 minutes in an ice bath, and then transfer to PBS with pH=6.7 to fully dialy...

Embodiment 3

[0083] In this example, the particle size of the drug-loaded micelles prepared in Example 2 and Comparative Examples 3-4 was characterized by dynamic light scattering (DLS). Take the drug-loaded micelles prepared in Example 2 and Comparative Examples 3-4 under different pH conditions, and use PBS with corresponding pH values ​​to prepare drug-loaded micellar solutions with a concentration of 1 mg / mL and pH values ​​of 7.4 and 6.7, respectively. , the particle size of drug-loaded micelles was characterized by dynamic light scattering test. Measuring conditions: temperature 25°C, scattering angle 173°, each sample was measured three times. The results are shown in Table 2.

[0084] The drug-loaded micelles prepared in Example 2 and Comparative Example 3 were diluted with PBS of corresponding pH value to a drug-loaded micelle solution with a concentration of 100 μg / mL, and the drug-loaded micelles were characterized by transmission electron microscope (TEM) and atomic force micr...

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Abstract

The present invention provides a polymer prodrug. Based on the polymer prodrug, drug-loaded micelles are provided that can achieve particle size reduction and surface charge inversion in response to an acidic microenvironment. The drug-loaded micelles are composed of the polymer. The prodrug is formed by self-assembly. Under the physiological pH conditions of the human body, the surface of the drug-loaded micelles is negatively charged. When the environment of the drug-loaded micelles changes from the physiological pH conditions of the human body to the slightly acidic pH conditions of the tumor, the drug-loaded micelles will Drug-loaded micelles undergo charge flipping and particle size reduction. The present invention can solve the problem that existing nano drug delivery systems have difficulty in achieving particle size reduction at tumor sites and have limited penetrating ability into tumors. It can break the limiting conditions for nano drugs to exert excellent anti-tumor effects and make drug-loaded micelles It has excellent long circulation and ability to accumulate into tumor sites, and at the same time improves the ability of drug-loaded micelles to penetrate deep into tumors, which can effectively improve the anti-tumor effect of drugs.

Description

Technical field [0001] The invention belongs to the field of anti-tumor drug delivery systems and relates to polymer prodrugs, drug-loaded micelles based on the polymer prodrug that can achieve particle size reduction and surface charge flipping in response to an acidic microenvironment, and their preparation methods. Background technique [0002] Cancer is one of the greatest threats to human life and health and the second leading cause of death in the world. Traditional chemotherapy drugs have the following shortcomings: poor water solubility and stability, low bioavailability, and high toxic and side effects, which limit their clinical application. Nano drug delivery systems have been extensively studied in recent years due to their unique advantages such as extending the circulation time of drugs in the body, having low side effects, and achieving sustained and controlled release of drugs. The development of nano-drug delivery systems has gone through processes such as ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/69A61K47/60A61K31/704A61P35/00C08F8/32C08F293/00C08F2/38
CPCA61K31/704A61K47/60A61K47/6907A61P35/00C08F2/38C08F8/32C08F2438/03C08F293/005
Inventor 孙勇赵明达樊渝江马孟城随俊慧张兴栋
Owner SICHUAN UNIV
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