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Method for carrying out liposome modification on compound with free hydroxyl groups

A technology of liposomes and compounds, applied in the direction of steroids, chemical instruments and methods, organic chemistry, etc., can solve the problems of epothilone clinical application limitations, limited tumor treatment applications, and lack of side effects, so as to improve anticancer effect, improve hydrophobicity, and reduce systemic toxicity

Active Publication Date: 2019-04-26
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, epothilones also have strong cytotoxicity to normal proliferating cells and tissues, which limits the clinical application of epothilones.
[0006] Since most chemotherapy drugs achieve anti-tumor effects by interfering with the DNA synthesis process of cancer cells, they often have side effects such as bone marrow suppression, and there is currently a lack of effective preventive measures for these accompanying side effects, which limits the application of tumor therapy

Method used

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  • Method for carrying out liposome modification on compound with free hydroxyl groups
  • Method for carrying out liposome modification on compound with free hydroxyl groups
  • Method for carrying out liposome modification on compound with free hydroxyl groups

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Example 1: Preparation and characterization of liposome N, N'-two-long chain alkane-L-glutamate diamide (LG)

[0049] Add Boc-glutamic acid and two times the equivalent of long-chain amines (octacyl, dodecyl, octadecylamine) to the reaction flask, add dichloromethane to dissolve, then add 1.1 times the equivalent of EDC and HOBt for amide condensation, and then After filtration, washing, and recrystallization, N,N'-di-long-chain alkyl-L-Boc-glutamate diamide was obtained, and then de-Boc protected with trifluoroacetic acid, washed and dried to obtain white powder N,N'-di - long-chain alkyl-L-glutamic acid diamides (LG).

[0050] The reaction steps are as follows:

[0051]

[0052] The prepared LGC12 was characterized by H NMR spectroscopy, the results are as follows figure 1 shown. The peaks in the H NMR spectrum were all assigned successfully, indicating the successful synthesis of LGC12.

[0053] The prepared LGC12 was characterized by MALDI-TOF-MS, and the res...

Embodiment 2

[0054] Example 2: Preparation method of LGC12 modified Paclitaxel, 10-Hydroxycamptothecin, Irinotecan, Epothilone B

[0055] ①Modify various original drugs with cis-aconitic anhydride (CA) (referred to as R, R = paclitaxel (PTX), 10-hydroxycamptothecin (HCPT), irinotecan (CPT-11), epothilone B (EpoB)), hereafter referred to as CAR, was synthesized by a ring-opening reaction between R and CA using triethylamine as a catalyst. The original drug R (0.4mmol) and CA (0.44mmol) were added into a completely dry flask and dissolved in 20.0 mL of anhydrous DMF, and then 67.0 μL of triethylamine was added. The mixture was placed at room temperature, in the dark, under nitrogen (N 2 ) under the protection of the atmosphere and stirred for 24 hours. Next, the solution was mixed with 200.0 mL of cold ethyl acetate, washed first with a saturated sodium chloride solution of pH 2-3, and then with a saturated sodium chloride solution of pH 7.4. The obtained organic layer was dried over anhy...

Embodiment 3

[0060] Example 3: Structural characterization of LGC12 modified drugs

[0061] 1. Nuclear Magnetic Resonance (NMR)

[0062] Using tetramethylsilane (TMS) as an internal standard, the N,N'-two-dodecane glutamic acid diamide (LGC12) modified PTX prepared in Example 2 was characterized, and deuterated chloroform (CDCl 3 ) as the solvent, adopt 400MHZ nuclear magnetic resonance instrument to its 1 HNMR scans.

[0063] The H NMR spectrum of PTX-LGC12 is as follows image 3 As shown, the peaks in the PTX-LGC12 NMR spectrum were all assigned successfully.

[0064] 2. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS)

[0065] In order to further confirm the compound synthesized in Example 2, its mass spectrum was tested by MALDI-TOF-MS and matrix-selective gentisic acid (DHB).

[0066] The MALDI-TOF-MS mass spectrum of PTX-LGC12 is as follows Figure 4 shown. Figure 4 In 1683.1 is PTX-LGC12+Na + .

[0067] The experimental results of...

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Abstract

The invention relates to a method for carrying out liposome modification on compound with free hydroxyl groups, in particular to liposome modified taxol and analogues thereof, as well as nanoparticlescontaining the liposome modified drug. According to the method disclosed by the invention, the taxol modified by liposome N,N'-di-dodecyl-L-glutamate diamide (LG-C12), 10-hydroxycamptothecine, irinotecan and epothilone B are specifically designed and successfully prepared, and the hydrophobicity of drugs is improved; then NH2-mPEG-DSPE bonded by mPEG-DSPE and mitochondrial targeted molecular triphenylphosphonium bromide (TPP) is utilized to coat liposome modified drugs to assemble into nanoparticles which improve the cytotoxic effect of the drugs on cancer cells and also reduce the toxic andside effects of the drugs on humans or animals.

Description

technical field [0001] The present invention relates to the field of drug modification, in particular to a method for liposome modification of compounds with free hydroxyl groups, more specifically to a liposome-modified paclitaxel and its analogues, and liposome-modified drugs containing the nanoparticles, etc. Background technique [0002] There were an estimated 4,292,000 new cancer cases and 2,814,000 cancer deaths in China in 2015. Over the past few decades, great efforts have been made to treat these serious diseases. Among various therapies, chemotherapy is currently one of the most effective ways to treat cancer clinically. Although a variety of anticancer drugs have been developed and used in chemotherapy, they often cause adverse side effects in patients, cause physical and mental pain, and the treatment efficiency is very low. Chemotherapeutic drugs commonly used in clinical practice include doxorubicin, paclitaxel, 10-hydroxycamptothecin, irinotecan and so on....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/54A61K47/62A61K47/69A61K31/337A61K31/365A61K31/427A61K31/4745A61K31/475A61K31/7048A61K31/7068A61P35/00C07D305/14C07D491/22C07D493/04C07D519/04C07H1/00C07H19/06C07J73/00
CPCA61K31/337A61K31/365A61K31/427A61K31/4745A61K31/475A61K31/7048A61K31/7068A61K47/542A61K47/545A61K47/62A61K47/6925A61P35/00C07D305/14C07D491/22C07D493/04C07D519/04C07H1/00C07H19/06C07J73/003
Inventor 肖海华陈志刚康晓旭
Owner INST OF CHEM CHINESE ACAD OF SCI
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