Nanogel drug carrier for targeted delivery and consumption of large amount of H2O2 and release of CO at the same time, and preparation method and application thereof

A nano-gel, H2O2 technology, applied in the direction of drug combination, pharmaceutical formula, medical preparation of non-active ingredients, etc., to achieve the effect of being easily absorbed, improving activation and secretion of anti-inflammatory factors, and good therapeutic effect

Active Publication Date: 2020-02-04
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] CO releasing molecules are consuming H 2 o 2 At the same time, it will release CO gas with anti-inflammatory effect, which can not only solve the large amount of H pre

Method used

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  • Nanogel drug carrier for targeted delivery and consumption of large amount of H2O2 and release of CO at the same time, and preparation method and application thereof
  • Nanogel drug carrier for targeted delivery and consumption of large amount of H2O2 and release of CO at the same time, and preparation method and application thereof
  • Nanogel drug carrier for targeted delivery and consumption of large amount of H2O2 and release of CO at the same time, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Based on targeted delivery, consumption of excess H 2 o 2 Construction of CO nanogel drug-loaded system with simultaneous release and anti-inflammatory effect

[0053] First, to obtain folic acid-modified hyaluronic acid HA-EDA-FA material, mix folic acid with HOBt and EDC and dissolve in DMSO solution (the molar ratio of folic acid to HOBt and EDC is 1:8:8), and stir for 1 h in the dark Afterwards, mix with hyaluronic acid aqueous solution, add EDA, avoid light and stir for 48 hours, dialyze to remove unreacted substances (dialysis molecular weight cut-off is 3000Da), and freeze-dry to obtain the product HA-EDA-FA.

[0054] Then, through three generations of dendrimer POSS-G 3 -Lys was cross-linked with the cross-linking agent 3,3'-dithiodipropionate bis(N-hydroxysuccinimide) ester (DSP) to obtain blank nanogel PDNs with rich internal cavity structure. Dissolve the joint agent in DMF, add dropwise to the DMF solution containing macromolecular POSS-G3-Lys, stir for 8...

Embodiment 2

[0059] Extracellular detection of CO release

[0060] In order to explore the conditions for the CO release molecule CORM401 to release CO, we detected the release of CO by ultrasonic detection and CO gas detector. Weigh 5 mg of nanogel and dissolve it in 2.5 mL of aqueous solution, place it in a 5 mL centrifuge tube, add 2.5 mL of different concentrations of H 2 o 2 (PBS, 50 μM, 500 μM, 10 mM), after placing at room temperature for 2 h, observe whether CO gas is produced by ultrasound imaging. Weigh 4mg of nanogel and dissolve it in 2mL of aqueous solution and place it in a small glass bottle, place the small glass bottle in a closed space, add 2mL of different concentrations of H 2 o 2(PBS, 50μM, 500μM, 10mM), to add H 2 o 2 The time point is 0 minute, and the readings (ppm) of the CO gas detector are recorded every 10 minutes.

[0061] Such as figure 1 As shown, CO release is not only H 2 o 2 Concentration-related, but also related to the incubation time, that is, ...

Embodiment 3

[0063] Phagocytosis and CO Release of Nanogels in Cells

[0064] To track the phagocytosis of nanogels in cells, nanogels labeled Cy5.5 were shown red fluorescence by confocal microscopy. Macrophages were seeded in laser confocal culture dishes (4X10 5 / dish), after incubation for 24h, add LPS (5μg / mL) to induce normal cells to transform into activated macrophages, incubate for 24h, then add medium containing different nanogel materials (CPs 100μg / mL, CPHs 150μg / mL , Control) 400 μL, after incubation for 4 hours, add cell nucleus staining solution Hoechst33342 probe and incubate for 30 minutes, rinse twice with PBS, and observe the cell state under a confocal laser microscope.

[0065] Such as figure 2 As shown, less nanogels were phagocytosed in normal macrophages, and there were only a small amount of cells that did not encapsulate targeting material HA-EDA-FA, only encapsulated a targeting material HA, and targeted receptors were blocked. The nanogels were phagocytosed,...

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Abstract

The invention provides a nanogel drug carrier for targeted delivery and consumption of a large amount of H2O2 and release of CO at the same time, and a preparation method and application thereof. Thenanogel drug carrier is a dendritic polypeptide nanogel drug carrier. The drug carrier comprises dendritic polypeptide nanogel as a carrier, and a carbon monoxide release molecules CORM401 loaded in an internal cavity of the dendritic polypeptide nanogel, and also comprises hyaluronic acid which is modified by folic acid and coats the surface of the dendritic polypeptide nanogel. A multifunctionalanti-inflammatory drug (CPHs) is prepared on the basis of the nanogel drug carrier disclosed by the invention. The drug carrier can enter activated macrophages in a HA-FA targeting manner, and rapidly release a large amount of CO is by consuming excessive H2O2. The generated CO not only can effectively inhibit cell proliferation, but also can obviously inhibit secretion of inflammatory factors byinducing activation (HO-1) of heme oxygenase and down-regulating expression of p38MAPK, NF-kB (p50/p65) and TLR-2. The CPHs can consume a large amount of ROS at the osteoarthritis joint part, and effectively inhibit degradation of articular cartilage and extracellular matrix.

Description

technical field [0001] The invention relates to the technical field of nanogel drug-carrying systems, especially targeted delivery, consumption of a large amount of H 2 o 2 A nanogel drug-loaded system that simultaneously releases CO to target the elimination of a large amount of H secreted from osteoarthritis sites 2 o 2 , At the same time, it can release CO molecules with anti-inflammatory function, aiming at the anti-inflammatory treatment of osteoarthritis. Background technique [0002] Inflammation is closely related to various diseases, such as cancer, infection, atherosclerosis, neurodegenerative diseases, osteoarthritis, etc. Osteoarthritis (OA) is a chronic disease caused by joint inflammation. It has been listed as the three major killers that seriously threaten human health along with cancer and cardiovascular disease. The generation of OA can be attributed to the dysregulation of pro-inflammatory and anti-inflammatory pathways caused by the damage of articula...

Claims

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Application Information

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IPC IPC(8): A61K9/06A61K47/36A61K47/22A61K33/00A61P29/00A61P19/02
CPCA61K9/06A61K33/00A61K47/22A61K47/36A61P19/02A61P29/00
Inventor 蔡晓军杨广贞樊梦妮祝精武陈俊鹏杨超
Owner NANJING UNIV OF TECH
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