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Podophyllotoxin lipid derivative, nano carrier, preparation method thereof, and application of podophyllotoxin lipid derivative and nano carrier in tumor treatment

A technology of lipid nanocarriers and lipid derivatives, applied in the direction of nanotechnology, nanotechnology, nanomedicine, etc., can solve the problems of poor solubility, unsuccessful, toxic clinical applications, etc., to improve solubility, improve side effects, Effect of increasing cellular uptake content

Pending Publication Date: 2021-12-17
DALIAN NATIONALITIES UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the remarkable antitumor effects of PPT, its poor solubility and significant toxicity have made its clinical application in systemic cancer therapy unsuccessful

Method used

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  • Podophyllotoxin lipid derivative, nano carrier, preparation method thereof, and application of podophyllotoxin lipid derivative and nano carrier in tumor treatment
  • Podophyllotoxin lipid derivative, nano carrier, preparation method thereof, and application of podophyllotoxin lipid derivative and nano carrier in tumor treatment
  • Podophyllotoxin lipid derivative, nano carrier, preparation method thereof, and application of podophyllotoxin lipid derivative and nano carrier in tumor treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058]

[0059] Take N-4β-((4-methylpiperazine-1-methyl)benzamide)-4'-desmethyl epipodophyllotoxin 2a 1.0g (1eq) and 1-tetradecylcarbamate 3a Put 1.1g (2.8eq) in a 50mL round bottom flask, add 8mL tetrahydrofuran solvent, and then add 1.0g (1.2eq) of diethyl azodicarboxylate and 0.8g (1.2eq) of triphenylphosphine under the action of The reaction was stirred at room temperature for 1.5 h. After the reaction was complete as detected by TLC, the solution was evaporated to dryness under reduced pressure to obtain 1.73 mg of a yellow powder, namely compound 1a, with a yield of 48%.

Embodiment 2

[0061]

[0062] Take N-4β-((4-methylpiperazine-1-methyl)benzamide)-4'-desmethyl epipodophyllotoxin 2a 0.5g (1eq) and 1-tetradecylcarbamate 3a 2.5g (2.8eq) in a 50mL round bottom flask, add 5mL dimethylformamide solvent, then add N,N'-diisopropylcarbodiimide 5ml (1.0eq) and 1-hydroxybenzotri Azole (1.2eq) was reacted at 0°C for 2h under stirring. After the reaction was complete as detected by TLC, the solution was evaporated to dryness under reduced pressure to obtain 2.08mg of yellow powder, namely compound 1b, with a yield of 59%.

Embodiment 3

[0064] Take N-4β-((4-methylpiperazine-1-methyl)benzamide)-4'-desmethylepipodophyllotoxin 2a10 g (1eq) and 1-tetradecylcarbamate 3a10 g (1.8eq) in a 50mL round bottom flask, add 10mL dimethylformamide solvent, then add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl 17.8g (1.2eq) of urea hexafluorophosphate and 3ml (1.0eq) of N,N-diisopropylethylamine were stirred and reacted at 0°C for 1h. After the reaction was complete as detected by TLC, the solution was evaporated to dryness under reduced pressure to obtain yellow 13.23mg of the powder is compound 1b, and the yield is 87%.

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Abstract

The invention provides a podophyllotoxin lipid derivative, a nano-carrier, a preparation method thereof and an application of the podophyllotoxin lipid derivative and the nano-carrier in tumor treatment. The podophyllotoxin lipid derivative is prepared by adopting a podophyllotoxin drug mother nucleus as a hydrophobic nucleus, linking a micromolecular hydrophilic group on the podophyllotoxin drug mother nucleus to form the podophyllotoxin derivative, and introducing a highly hydrophobic long-chain fat-soluble substance to play a stabilizing role. The podophyllotoxin lipid nano-carriers with different structures can be synthesized by changing the types and sizes of the small molecules and the fat-soluble substances and the feeding ratio of the fat-soluble substances to the podophyllotoxin derivatives. The podophyllotoxin lipid derivative provided by the invention overcomes the limitations of low solubility and toxic and side effects of podophyllotoxin, and meanwhile, the podophyllotoxin lipid nano-carrier prepared by the invention has a lipid bilayer structure and an acid / enzyme sensitive connecting bond, and has the characteristic of regulating PD-L1 expression; therefore, the product has the application of tumor microenvironment response and immune escape prevention, and has a wide application prospect in the fields of chemotherapy and immunotherapy in tumor treatment.

Description

technical field [0001] The invention relates to a podophyllotoxin lipid derivative and a nano-carrier, in particular to an environment-responsive podophyllotoxin lipid nano-carrier and its preparation method and application in the fields of chemotherapy and immunotherapy for tumors. Background technique [0002] Malignant cells have been thought to develop multiple mechanisms to evade immune detection, and thus various therapeutic strategies to awaken exhausted immune cells in the immunosuppressive tumor microenvironment have emerged. Programmed cell death-1 (PD-1) is a well-known immune checkpoint receptor that can be expressed on activated T cells. Many solid tumors overexpress programmed cell death ligand 1 (PD-L1), which interacts with PD-1 to inhibit T cell proliferation and activity by inhibiting kinase signaling pathways. This mechanism has driven the development of monoclonal antibodies and therapeutic peptide antagonists against PD-1 / PD-L1. However, since both mon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04A61K31/365A61K47/54A61P35/00B82Y5/00B82Y30/00B82Y40/00
CPCC07D493/04A61K47/54A61K47/554A61K31/365A61P35/00B82Y5/00B82Y30/00B82Y40/00
Inventor 张树彪王瑞陈会英赵轶男支德福
Owner DALIAN NATIONALITIES UNIVERSITY
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