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Sulfydryl-containing zwitterionic polypeptide modified doxorubicin derivative, nano-micelle and preparation methods of doxorubicin derivative and nano-micelle

A zwitterion and polypeptide modification technology, which is applied in the field of biomedicine, can solve the problems of low drug loading, low tumor targeting performance, and weak interaction of nano-drugs, achieve excellent anti-protein non-specific adsorption performance, and increase the enrichment amount , the effect of reducing toxicity

Active Publication Date: 2020-09-11
YANSHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method of delivering doxorubicin by encapsulating or chemically bonding modified doxorubicin with nano-drug carriers has improved the bioavailability of doxorubicin to a certain extent, but there are still problems of low drug loading and large side effects.
This is mainly due to the fact that polyethylene glycol is often used as the hydrophilic layer in the prepared nano-medicine, and polyethylene glycol has the disadvantage of weak interaction with protein molecules, so that the nano-medicine in vivo not only causes a certain immune response but also causes tumors. low targeting performance
In addition, the drug loading of PEG-modified nanomedicines is generally low

Method used

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  • Sulfydryl-containing zwitterionic polypeptide modified doxorubicin derivative, nano-micelle and preparation methods of doxorubicin derivative and nano-micelle
  • Sulfydryl-containing zwitterionic polypeptide modified doxorubicin derivative, nano-micelle and preparation methods of doxorubicin derivative and nano-micelle
  • Sulfydryl-containing zwitterionic polypeptide modified doxorubicin derivative, nano-micelle and preparation methods of doxorubicin derivative and nano-micelle

Examples

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Embodiment 1

[0064] This example provides a doxorubicin complex modified by a zwitterionic polypeptide, and nanomicelles formed by its self-assembly. The preparation steps are as follows: figure 1 As shown, specifically include:

[0065] (1) Use zwitterionic polypeptide (EK) composed of glutamic acid (E) and lysine (K) 3 -C, add 3mg (EK) per 1mL methanol 3 -C peptide configuration 3mg / mL (EK) 3 -C methanol solution. According to the thiol-containing zwitterionic polypeptide (EK) 3 The molar ratio of -C to 2-methacrylohydrazide hydrogen bromide is 1:2. Dissolve 6 mg of 2-methacrylohydrazide hydrogen bromide in 2 mL of methanol solution, add 5 mL of 3 mg / mL(EK) 3 -C methanol solution and stirred with nitrogen for 10 minutes, removed the nitrogen and sealed off the oxygen, then put it in a water bath at 50°C and stirred for 24 hours. Concentrate the reacted solution to 1 / 10 times the original volume, then add it to 15 mL of acetonitrile for recrystallization twice, wash and dry with et...

Embodiment 2

[0077] This embodiment provides a doxorubicin complex modified by a zwitterionic polypeptide, and nanomicelles formed by its self-assembly, specifically including:

[0078] (1) Use zwitterionic polypeptide (EK) composed of glutamic acid (E) and lysine (K) 1 -C, add 3mg (EK) per 1mL methanol 1 -C peptide configuration 3mg / mL (EK) 1 -C methanol solution. According to the thiol-containing zwitterionic polypeptide (EK)1 The molar ratio of -C to 2-methacrylohydrazide hydrogen bromide is 1:1.5, dissolve 9.5mg of 2-methacrylohydrazide hydrogen bromide in 2mL of methanol solution, add 5 mL of 3mg / mL(EK) 1 -C methanol solution, add 0.5 mg of 4-dimethylaminopyridine (DMAP) catalyst and stir for 10 min with nitrogen gas, remove nitrogen gas and seal with oxygen, place at room temperature at 25°C and irradiate and stir for 6 h under ultraviolet wavelength 365 nm. The reacted solution was concentrated to 1 / 10 of the original volume, then added to 10 mL of acetonitrile for recrystalliz...

Embodiment 3

[0083] This embodiment provides a doxorubicin complex modified by a zwitterionic polypeptide, and nanomicelles formed by its self-assembly, specifically including:

[0084] (1) Use zwitterionic polypeptide (EK) composed of glutamic acid (E) and lysine (K) 14 -C, add 3mg (EK) per 1mL methanol 14 -C peptide configuration 3mg / mL (EK) 14 -C methanol solution. According to the thiol-containing zwitterionic polypeptide (EK) 14 -C and 2-methacrylohydrazide hydrogen bromide molar ratio is 1:4, dissolve 3.3mg of 2-methacrylohydrazide hydrogen bromide in 2mL methanol solution, add 8.2mL 3mg / mL(EK) 14 -C methanol solution, add 1 mg of 4-dimethylaminopyridine (DMAP) catalyst and stir for 10 min with nitrogen gas, remove the nitrogen gas, isolate the oxygen, seal it, place it at room temperature and irradiate and stir for 12 h under ultraviolet wavelength 365nm. Concentrate the reacted solution to 1 / 10 of the original volume, then add it to 10 mL of acetonitrile for recrystallization...

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Abstract

The invention provides a sulfydryl-containing zwitterionic polypeptide modified doxorubicin derivative, a nano-micelle and a preparation method of the nano-micelle, and belongs to the field of biological medicines. The doxorubicin derivative has a structure as shown in a general formula (I). The preparation method of the doxorubicin derivative comprises the following steps of in a polar solvent, mixing sulfydryl-containing zwitterionic polypeptide with acryloylhydrazine to react, and performing crystallizing to obtain a polypeptide derivative; and dissolving the polypeptide derivative and doxorubicin hydrochloride in the polar solvent according to a molar ratio of 1: (0.2-5), adding a trifluoroacetic acid catalyst, and carrying out a stirring reaction to obtain the doxorubicin derivative.The nano-micelle prepared from the doxorubicin derivative is long in in-vivo blood circulation time, high in drug loading capacity, small in toxic and side effects, good in pH value response and goodin tumor inhibition effect.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a doxorubicin derivative modified based on a thiol-containing zwitterionic polypeptide, a nano-micelle and a preparation method thereof. Background technique [0002] Doxorubicin (Doxorubicin, DOX) is also known as doxorubicin, 14-hydroxydaunorubicin, 14-hydroxydaunomycin, 14-hydroxydaunomycin, 14-hydroxydaunorubicin, doxorubicin , Hydroxyrubicin, Hydroxydaunorubicin, etc. It is an antitumor antibiotic that can be used to inhibit the synthesis of RNA and DNA, especially the strongest inhibitory effect on RNA. Both have effects, are cycle non-specific drugs, and have killing effects on tumor cells in various growth cycles. Mainly applicable to acute leukemia, malignant lymphoma, breast cancer, ovarian cancer, bladder cancer, thyroid cancer, prostate cancer, testicular cancer, gastric cancer, liver cancer, etc. Although doxorubicin has a wide range of applications in the field of anti-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/64A61K31/704A61P35/00B82Y5/00B82Y40/00
CPCA61K31/704A61K47/64A61K47/6907B82Y5/00B82Y40/00A61P35/00
Inventor 王龙刚崔天明
Owner YANSHAN UNIV
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