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Metformin-based multi-drug mixed micelle as well as preparation method and application thereof

A technology of mixing micelles and metformin, which is applied in drug combination, drug delivery, and pharmaceutical formulations, and can solve the problems of tumors that are difficult to completely cure and treat

Inactive Publication Date: 2021-06-22
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the process of tumor treatment, conventional treatment methods such as chemotherapy can be used for orthotopic tumor treatment and achieve curative effect. However, these treatment methods lack the treatment for the process of metastasis, which makes it difficult to completely cure the tumor; the mechanism of metastasis formation has gradually become the focus of technical personnel. important target for cancer therapy

Method used

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  • Metformin-based multi-drug mixed micelle as well as preparation method and application thereof
  • Metformin-based multi-drug mixed micelle as well as preparation method and application thereof
  • Metformin-based multi-drug mixed micelle as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1: Preparation and characterization of metformin-based multi-drug mixed micelles

[0052] Micelles (OPTs) in which OA-Met was mixed with pro-DHA and loaded with Trip were prepared by nanoprecipitation method. Measure 280 μL of Trip ethanol stock solution (1.5 mg / mL) into an EP tube, and dry the solvent with a nitrogen blower. Weigh 2 mg of pro-DHA and dissolve in 500 μL of OA-Met ethanol stock solution (10 mg / mL), add to the EP tube containing Trip, and vortex to dissolve Trip. The mixed solution was slowly added dropwise to 1 mL of stirred distilled water (500 rpm), and stirred at room temperature for 3 hours. Ethanol was distilled off under reduced pressure in a water bath at 25°C to obtain a suspension of OPTs micelles, which was stored at 4°C for future use.

[0053] HA-wrapped OPTs (HOPTs) were prepared by electrostatic adsorption. Centrifuge the OPTs micelle suspension at 3000rpm for 5min, measure 300μL of the supernatant of the OPTs micelle suspension,...

Embodiment 2

[0055] Example 2: In vivo orthotopic breast tumor targeting evaluation of metformin-based multi-drug mixed micelles

[0056] Take 4T1 cells in logarithmic growth phase and resuspend in serum-free medium, adjust the concentration of cell suspension to 1×10 8 cells / mL, store at 4°C for later use. Female Balb / c mice were anesthetized by intraperitoneal injection of 120 μL of 5% chloral hydrate, the body hair of the third and fourth pair of milk fat pads on the left side of the mouse was removed, and the cell suspension was inoculated on the fourth pair of left side of the mouse. In the milk fat pad, after the milk fat pad of the mouse was obviously filled, the needle was slowly removed, an appropriate amount of antibiotics was applied to the wound, and the mice were continued to be fed. When the tumor volume increased to 100-200mm after inoculation 3 , the mice were randomly divided into 3 groups, 3 in each group, respectively injected DiR-labeled OPTs, DOPTs and HOPTs (OPTs-Di...

Embodiment 3

[0058] Example 3: In vitro toxicity study of metformin-based multi-drug mixed micelles on breast cancer cells

[0059] In vitro toxicity was investigated by MTT assay. 4T1 cells in 1×10 3 The density per well was inoculated in a 96-well plate, with 3 replicate wells in each group. After culturing for 24 hours, the supernatant was discarded, and different concentration gradients of OA-Met, pro-DHA, Trip, HOTs, DOPTs, HOPTs and serum-free medium were added for co-incubation. After 24 hours, 20uL of MTT solution was added to each well and incubated for 4 hours. Discard the supernatant and add 150uL of DMSO, shake for 10 minutes to fully dissolve the formazan produced by the surviving tumor cells. Finally, a multifunctional microplate reader was used to detect the absorbance of each well at 570 nm, and the IC of the drug administration group was calculated. 50 values ​​and plot cell survival curves.

[0060] The results showed that the IC of OA-Met itself on 4T1 cells 50 The...

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Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to a metformin-based nano drug delivery system and a preparation method thereof. The metformin-based nano drug delivery system is characterized in that a metformin amphiphilic derivative and a histone deacetylase inhibitor pro-DHA are mixed and self-assembled in water, triptolide is entrapped at the same time to form cationic micelles OPTs, the cationic micelles OPTs are used for preparing the metformin-based nano drug delivery system, HA is adsorbed on the surface through electrostatic adsorption, and a multi-drug mixed micelle is constructed. According to the mixed micelle, OA-Met (or metformin), pro-DHA and Trip are simultaneously delivered to in-situ tumor tissues in a targeted manner through high affinity of HA and tumor cell surface overexpression CD44, the three medicines play a synergistic effect through different action mechanisms to prevent EMT and tumor metastasis, growth of in-situ tumors is effectively inhibited, the lifetime is prolonged, and the mixed micelle has a good application prospect. The metastatic tumor treatment effect is improved, and good in-vivo safety is achieved.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and relates to a metformin-based multi-drug mixed micelle and a preparation method thereof. In the invention, an amphiphilic derivative OA-Met having an activity similar to metformin is mixed with an HDAC inhibitor pro-DHA , self-assembled in water and simultaneously loaded Trip to form mixed micelles, and at the same time electrostatically adsorbed polysaccharide HA on the surface of micelles to obtain metformin-based multi-drug mixed micelles. The multi-drug mixed micelles simultaneously target and deliver three drugs to the in situ tumor tissue, synergistically prevent the occurrence of EMT and tumor metastasis through different mechanisms of action, and at the same time synergistically inhibit the growth of the in situ tumor to improve the therapeutic effect of metastatic tumors the goal of. Background technique [0002] The prior art discloses that tumor metastasis is th...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/61A61K31/585A61P35/00A61P35/04A61K31/202A61K31/155
CPCA61K31/155A61K31/585A61K31/202A61K47/6907A61K47/61A61P35/04A61P35/00
Inventor 陈钧蒋天泽
Owner FUDAN UNIV
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