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Liver-targeting drug-loaded microspheres with pH and reduction responsiveness, and preparation method and application thereof

A drug-loaded microsphere, stimuli-responsive technology, applied in the fields of polymer materials and biomedical engineering, can solve problems such as no active targeting function and inability to achieve targeted delivery of anti-tumor drugs

Inactive Publication Date: 2016-06-08
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In 2013, PolymerChemistry (Issue4, pp1199-1207) reported the synthesis of monomethoxy polyethylene glycol-poly N, N'-diethylaminoethyl acrylate copolymer (mPEG-b -PDEA), the mPEG-b-PDEA hydrogel was prepared after quaternization cross-linking reaction, and this hydrogel was used as the carrier of the antineoplastic drug doxorubicin to maintain a stable core-shell structure under physiological conditions , and can quickly release drugs in acidic and reducing tumor tissues and cells, so as to realize the intelligence of drug release, but the carrier material does not have active targeting function, and cannot realize the targeted delivery of anti-tumor drugs

Method used

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  • Liver-targeting drug-loaded microspheres with pH and reduction responsiveness, and preparation method and application thereof
  • Liver-targeting drug-loaded microspheres with pH and reduction responsiveness, and preparation method and application thereof
  • Liver-targeting drug-loaded microspheres with pH and reduction responsiveness, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] (1) Preparation of galactose modified gelatin (II)

[0055] Preparation of 1-bromo-2,3,4,6-tetraacetoxy-β-D-galactose (IIb): Add 0.08ml HClO to 16ml acetic anhydride with stirring at 0°C 4 , and then slowly add 4 g of β-D-galactose (IIa) within 30 minutes, and raise the temperature to 35-40° C. for 30 minutes. Add 1.2g of red phosphorus and 2.3ml of Br successively under ice cooling 2 With 1.5ml of water, raise the temperature to 18-20°C and react for 2h. Add 20ml of chloroform, stir and pour into ice water. Filtration and liquid separation, the aqueous phase was extracted twice with 20ml chloroform, the chloroform was combined, and saturated NaHCO 3 , Wash with distilled water until the water phase is neutral. Add anhydrous MgSO 4 After drying overnight, the chloroform was removed by rotary evaporation under reduced pressure to obtain a yellow syrup sample. Dissolve it with ether and add petroleum ether until the white precipitate is just no longer dissolved, and...

Embodiment 2

[0073] Galactose-modified gelatin was prepared according to the method of Example 1.

[0074] According to the method of Example 1, replace N, N'-dimethylethylenediamine with 69.6mg N, N'-dimethylbutylene diamine, prepare the linear poly( β-amino esters).

[0075] Preparation of empty microspheres:

[0076] Dissolve 45 mg of galactose-modified gelatin and poly-β-amino ester at a mass ratio of 2:1 in 1 ml of distilled water. with saturated Na 2 CO 3 The pH of the solution was adjusted to 9 to obtain an aqueous phase.

[0077] Add 0.25ml of span80 into 50ml of liquid paraffin, stir at 85°C and 550rpm for 30min to obtain an oil phase.

[0078] At a stirring speed of 550 rpm, the water phase was added dropwise to the oil phase. After continuing to stir for 20 minutes, cool to -5°C, add 0.1g of 25% glutaraldehyde, and react at -5°C in the dark for 2h. Then add 15ml of ethanol, continue to stir for 30 minutes, filter, and wash the solid matter with ethanol and petroleum ether f...

Embodiment 3

[0084] Galactose-modified gelatin was prepared according to the method of Example 1.

[0085] According to the method of Example 1, 86.4 mg N, N'-dimethylhexamethylenediamine is used to replace N, N'-dimethylethylenediamine to prepare a linear poly( β-amino esters).

[0086] Preparation of empty microspheres:

[0087] Dissolve 50 mg of galactose-modified gelatin and poly-β-amino ester at a mass ratio of 1:2 in 2 ml of distilled water. with saturated Na 2 CO 3 The pH of the solution was adjusted to 9 to obtain an aqueous phase.

[0088] Add 0.5ml of span80 into 10ml of liquid paraffin, stir at 25°C and 50rpm for 30min to obtain an oil phase.

[0089] At a stirring speed of 50 rpm, the water phase was slowly added dropwise to the oil phase. After continuing to stir for 20 minutes, cool to 5°C, add 62.5 mg of 40% glyoxal, and react at 5°C in the dark for 2 hours. Then add 15ml of methanol, continue to stir for 30min, filter, and wash the solid matter with methanol and petr...

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Abstract

The invention relates to microspheres with a liver active targeting function and pH and reduction stimulative responsiveness, a preparation method thereof, and an application of the microspheres in medicine. The microspheres are characterized in that: (1) a carrier is composed of galactose modified gelatin and poly(beta-amino ester), and the microspheres are prepared through an emulsion cross-linking method with galactose modified gelatin and linear poly(beta-amino ester) containing a disulfide bond as monomers, and dialdehyde as a crosslinking agent, wherein a terminal group of the linear poly(beta-amino ester) is a secondary amino group; (2) the drug-loaded microspheres are prepared through the following steps: with an antineoplastic drug, the galactose modified gelatin and the poly(beta-amino ester) as components, dispersing doxorubicin hydrochloride as a model drug of the antineoplastic drug into the monomers, i.e., the galactose modified gelatin and the linear poly(beta-amino ester), then adding the crosslinking agent, and subjecting the two monomers to a crosslinking reaction so as to form the microspheres; and (3) the prepared microspheres have good recognition properties to liver cells and good pH and reduction stimulative release properties to model drugs, and can be further researched and developed into a novel targeting preparation used for treatment of liver cancer.

Description

technical field [0001] The invention relates to a new type of microsphere, in particular to the microsphere with liver active targeting function and pH and reduction stimulus responsiveness, its preparation method and medical application, belonging to the fields of polymer materials and biomedical engineering. technical background [0002] Liver cancer has ranked the second cause of death from tumors in my country. Chemotherapy is an important treatment method when liver transplantation and hepatectomy are not available for advanced liver cancer. Antineoplastic drugs often have poor therapeutic effects and severe side effects due to poor physical and chemical properties, short half-life and no choice of action. By embedding, aggregating or adsorbing drugs in the carrier responsive to specific environmental stimuli, avoiding the direct interaction between chemotherapy drugs and normal tissues, so that the drugs are only released at the site of action, which can improve the se...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08J3/24C08J3/12C08L89/00C08L79/00C08K5/07A61K9/16A61K47/42A61K45/00A61K31/704A61P35/00
Inventor 蒋玉仁詹国平曾维霖邓友超杜阳森
Owner CENT SOUTH UNIV
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