Conjugates and nanoparticles of hyaluronic acid and epigallocatechin-3-O-gallate and uses thereof

A technology of epigallocatechin and gallocatechin, applied to the conjugates and nanoparticles of hyaluronic acid and epigallocatechin-3-O-gallate and the fields of their uses, can solve the limited availability , lack of specificity and efficacy

Pending Publication Date: 2021-09-07
AGENCY FOR SCI TECH & RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the availability of such differentiation inducers for AML is limited, mainly due to lack of specific...

Method used

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  • Conjugates and nanoparticles of hyaluronic acid and epigallocatechin-3-O-gallate and uses thereof
  • Conjugates and nanoparticles of hyaluronic acid and epigallocatechin-3-O-gallate and uses thereof
  • Conjugates and nanoparticles of hyaluronic acid and epigallocatechin-3-O-gallate and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1. Preparation of HA-EGCG nanoparticles comprising small molecule inhibitors

[0184] One of the HA-EGCG conjugates (A)-(C) with FLT3 inhibitor was used to synthesize the HA-EGCG nanoparticles of the present invention. Sunitinib and sorafenib were selected as representative type I and type II FLT3 inhibitors, respectively, to prepare these nanoparticles. Sunitinib is a type I inhibitor that blocks FLT3 signaling by binding to its intracellular ATP-binding site when the receptor is in the active conformation, while sorafenib blocks FLT3 signaling when the receptor is inactivated Type II inhibitors that bind to hydrophobic regions near the only accessible ATP-binding site (M. Larrosa-Garcia, M.R. Baer, ​​Mol. Cancer Ther. 2017, 16, 991-1001).

[0185] Unlike type II inhibitors, which can only kill AML cells with FLT3-ITD mutations, type I inhibitors can be used to treat AML cells with FLT3-ITD mutations as well as those with FLT3 tyrosine kinase domain (TKD) muta...

Embodiment 2

[0200] Example 2. Characterization of HA-EGCG nanoparticles comprising sunitinib or sorafenib

[0201] The prepared HA-EGCG nanoparticles of Example 1 were characterized by dynamic light scattering to determine the hydrodynamic size of the particles. In addition, the drug loading efficiency and drug loading content of the nanoparticles were determined.

[0202] experiment

[0203] dynamic light scattering

[0204] The hydrodynamic diameter of the nanoparticles was examined by dynamic light scattering using a Nano ZS zetasizer (Malvern Instruments, UK). All measurements were performed in triplicate at 37°C.

[0205] Drug loading efficiency and drug loading content

[0206] To examine the loading of sunitinib in nanoparticles, each sample was diluted 50-fold in 25% ethanol-water solution and the absorbance at 431 nm was measured on a Hitachi U-2810 spectrophotometer. Various concentrations of sunitinib malate (1-10 μg mL -1 ) to build a calibration curve.

[0207] The...

Embodiment 3

[0225] Example 3. In vitro anti-leukemia activity of prepared HA-EGCG nanoparticles comprising sunitinib or sorafenib

[0226] The in vitro anti-leukemic activity of selected HA-EGCG nanoparticles comprising sunitinib or sorafenib (in Example 2) was evaluated on MOLM-14 and MV-4-11 cells.

[0227] experiment

[0228] MOLM-14 and MV-4-11 cells (ATCC, USA) were maintained in RPMI 1640 culture supplemented with 10% (v / v) fetal bovine serum (FBS) and 1% (v / v) penicillin / streptomycin Base. Cells (1×10 4 cells / well) were incubated in 100 μL of 10% FBS-supplemented medium containing various concentrations of sunitinib or sorafenib-loaded nanoparticles and the respective free drug. In the case of free sorafenib, a stock solution of sorafenib tosylate was prepared in dimethyl sulfoxide (DMSO), and then diluted to a final DMSO concentration of 1% with RPMI 1640 medium; this for DMSO Both concentrations had no detectable effect on leukemia cell growth. After 3 days of treatment, 100...

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Abstract

Disclosed herein is a nanoparticle composition comprising nanoparticles formed from one of: a conjugate of dimeric epigallocatechin-3-O-gallate and hyaluronic acid; a conjugate of epigallocatechin-3-O-gallate and hyaluronic acid; or a epigallocatechin-3-O-gallate-terminated hyaluronic acid conjugate; and an active agent or a pharmaceutically acceptable salt, solvate or prodrug thereof suitable to treat acute myeloid leukaemia, wherein the active agent is encapsulated in the nanoparticles.

Description

[0001] field of invention [0002] The present invention relates to a nanoparticle composition comprising a conjugate of hyaluronic acid and epigallocatechin-3-O-gallate and an active agent, and the use of said conjugate and nanoparticle composition in the treatment of acute myeloid The use of leukemia. [0003] technical background [0004] Acute myeloid leukemia (AML) has become a major global health problem, accounting for an estimated 1,000,000 new cases and 147,100 deaths per year worldwide (Lancet. 2016, 388, 1545–1602). AML is a biologically complex and heterogeneous blood cancer characterized by infiltration of bone marrow, blood and other tissues by malignant cells of the myeloid lineage (medulloblasts). Such cells suffer from blockage in the differentiation pathway, which results in the extrusion of normal blood cells and platelets. The stage at which differentiation is arrested defines the subtype of AML (AML-MO to M7). Despite advances in diagnostic and therapeut...

Claims

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Application Information

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IPC IPC(8): A61K9/51A61K31/404A61K31/44A61K31/353A61K47/36A61K47/61A61P35/02B82Y5/00
CPCA61K31/404A61K31/44A61P35/02B82Y5/00A61K47/6939A61K47/545A61K47/61
Inventor 栗泽元一梁坤大里元美裴基贤努纳帕斯·永旺松托郑主恩陈清烽赖宪忠余治升
Owner AGENCY FOR SCI TECH & RES
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