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Multifunctional nano-carrier with drug resistance and hypoxia/glutathione dual responsiveness and preparation method and application thereof

A technology of nanocarriers and drug resistance, applied in the field of multifunctional nanocarriers and its preparation, can solve problems such as poor water solubility, lack of tumor targeting, poor stability, etc., and achieve good dispersion, good biocompatibility, The effect of uniform particle size

Pending Publication Date: 2021-12-03
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the development of polymer micellar nanocarriers with integrated intelligent functions and the encapsulation of alkylating agents in nanomicelles can not only overcome the problems of poor water solubility and poor stability of drugs, but also effectively solve the problem of their lack of tumor targeting. defects, thereby improving its efficacy and reducing its toxic side effects

Method used

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  • Multifunctional nano-carrier with drug resistance and hypoxia/glutathione dual responsiveness and preparation method and application thereof
  • Multifunctional nano-carrier with drug resistance and hypoxia/glutathione dual responsiveness and preparation method and application thereof
  • Multifunctional nano-carrier with drug resistance and hypoxia/glutathione dual responsiveness and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Preparation of a multifunctional nanocarrier (NI-TMG-PLGA-SS-PEG NPs) with dual responses to drug resistance and hypoxia / GSH:

[0042] (1) Synthesis of NI-TMG-PLGA-SS-PEG

[0043] Weigh 0.12g (0.5mmol) O 6 -TMG was dissolved in 10 mL of dichloromethane to give a concentration of 12 mg / mL of O 6 -TMG dichloromethane solution, then weighed 0.15g (0.5mmol) triphosgene, under the condition of 0-10 ℃, the O 6 -TMG solution was added dropwise to triphosgene, and after the addition was completed, the 2 Under the conditions of protection and 0.25mL (3mmol) pyridine as a catalyst, react at 25°C for 4h. Then add 0.17g (1 mmol) (1-(aminoethyl)-2-nitro-1H-imidazol-5-yl)methanol, and continue the reaction at 25°C for 6h. After removing the solvent by rotary evaporation under reduced pressure at 35°C, the above reaction solution was separated and purified by column chromatography. The stationary phase was silica gel, and the mobile phase was petroleum ether and ethyl ac...

Embodiment 2

[0049] Example 2 Preparation of a multifunctional nanocarrier (NI-TMG-PLGA-SS-PEG NPs) with dual responses to drug resistance and hypoxia / GSH:

[0050] (1) Synthesis of NI-TMG-PLGA-SS-PEG

[0051] Weigh 0.2g (0.8mmol) O 6 -TMG was dissolved in 15 mL of dichloromethane to give a concentration of 13 mg / mL O 6 -TMG dichloromethane solution, then weighed 0.3g (1mmol) triphosgene, under the condition of 0-10 ℃, O 6 -TMG solution was added dropwise to triphosgene, and after the addition was completed, the 2 Under the conditions of protection and 0.72mL (5.6mmol) triethylamine as a catalyst, react at 25°C for 6h. Add 0.3g (1.8 mmol) (1-(aminoethyl)-2-nitro-1H-imidazol-5-yl)methanol, and continue the reaction at 25°C for 8h. After removing the solvent by rotary evaporation under reduced pressure at 35°C, the above reaction solution was separated and purified by column chromatography. The stationary phase was silica gel, and the mobile phase was petroleum ether and ethyl acetate. ...

Embodiment 3

[0057] Example 3 Preparation of a multifunctional nanocarrier (NI-TMG-PLGA-SS-PEG / BCNU NPs) loaded with carmustine that has both anti-drug resistance and hypoxia / GSH dual responses

[0058] (1) Synthesis of NI-TMG-PLGA-SS-PEG

[0059] Weigh 0.25g (1mmol) O 6 -TMG was dissolved in 18 mL of dichloromethane to give a concentration of 13 mg / mL O 6 -TMG dichloromethane solution, then weighed 0.45g (1.5mmol) triphosgene, under the condition of 0-10 ℃, the O 6 -TMG solution was added dropwise to triphosgene, and after the addition was completed, the 2 Under the conditions of protection and 0.7mL (8 mmol) pyridine as a catalyst, react at 25°C for 8h. Then 0.43 g (2.5 mmol) (1-(aminoethyl)-2-nitro-1H-imidazol-5-yl)methanol was added, and the reaction was continued at 25° C. for 6 h. After removing the solvent by rotary evaporation under reduced pressure at 35°C, the above reaction solution was separated and purified by column chromatography. The stationary phase was silica gel, and...

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Abstract

The invention provides a multifunctional nano-carrier with drug resistance and hypoxia / glutathione dual responsiveness and a preparation method and application thereof, and belongs to the technical field of biomedical polymer materials. A nano delivery system carrier is an amphiphilic block copolymer, and can encapsulate hydrophobic chemotherapeutic drugs through intermolecular force to form nano-micelles. In hypoxia and GSH high-expression tumor tissues, nitro groups on the nano-carrier can be reduced, so that coupling between nitroimidazole and O6-thienylmethylguanine (O6-TMG) is broken, and at the same time, disulfide bonds are reduced by glutathione and also broken, thereby causing the nano-micelles to be broken. After the micelles are broken, an internally encapsulated alkylating agent and O6-TMG capable of inhibiting AGT activity are released, thereby exerting a targeted anti-tumor effect, and at the same time, the sensitivity of tumor cells to the alkylating agent is specifically improved.

Description

technical field [0001] The invention belongs to the technical field of biomedical polymer materials, and relates to a multifunctional nanocarrier and its preparation method and application. Specifically, it is a multifunctional nano-carrier with anti-drug resistance and hypoxia / glutathione dual responsiveness, its preparation method and its application as a pharmaceutical carrier. Background technique [0002] Since nitrogen mustard was used to treat malignant lymphoma, the basic research and clinical application of alkylating agents have developed rapidly, and alkylating agents have become an important class of drugs in cancer chemotherapy. Alkylating agents can produce positively charged carbon ion intermediates, form covalent bonds with DNA in cells, cause DNA damage, and then interfere with the normal replication of DNA or cause base mismatches during DNA replication, resulting in the structure and function of DNA damage, eventually leading to cell death. However, most...

Claims

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Application Information

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IPC IPC(8): A61K47/60A61K47/69A61K31/522A61K45/06A61K31/17A61K31/4188A61K31/18A61P35/00A61P35/02C08G63/91
CPCA61K47/60A61K47/6935A61K31/522A61K45/06A61K31/17A61K31/4188A61K31/18A61P35/00A61P35/02C08G63/912A61K2300/00
Inventor 赵丽娇王娇娇李多孙国辉张娜钟儒刚
Owner BEIJING UNIV OF TECH
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