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Immune checkpoint blocking polypeptide prodrug nano-micelle, preparation method and application

A technology of immune checkpoints and nanomicelles, which is applied in the fields of pharmaceutical formulations, antineoplastic drugs, drug combinations, etc., can solve problems such as the inability to guarantee the dosage of tumor drugs, avoid systemic immune-related adverse reactions, and enhance immune checkpoint resistance. effect of treatment and inhibition of tumor growth

Inactive Publication Date: 2020-11-20
INST OF BIOMEDICAL ENG CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Immunotherapy drugs have an "on-target but off-tumor" effect, and often have a recognition effect on related receptors expressed in normal tissues, which not only cannot guarantee the local effective drug dose of the tumor, but also easily lead to inevitable immune-related adverse reactions, serious limit its clinical application

Method used

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  • Immune checkpoint blocking polypeptide prodrug nano-micelle, preparation method and application
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  • Immune checkpoint blocking polypeptide prodrug nano-micelle, preparation method and application

Examples

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Embodiment 1

[0046] A method for preparing immune checkpoint blocking polypeptide prodrug nanomicelles, comprising the steps of:

[0047] (1) 1 mole of methoxypolyethylene glycol succinimidyl acetate and 2 moles of matrix metalloproteinase-sensitive linking peptide were dissolved in N,N-dimethylformamide and reacted at room temperature for 8 hours, After dialysis, purification, and freeze-drying, a polyethylene glycol-matrix metalloproteinase-sensitive linking peptide conjugate referred to as intermediate product 1 was obtained; 1 mole of intermediate product 1 was mixed with 2 moles of doxorubicin and 2 moles of N,N-bicyclic Hexylcarbodiimide was mixed, dissolved in N,N-dimethylformamide, reacted at room temperature for 8 hours, dialyzed, purified, and freeze-dried to obtain polyethylene glycol-matrix metalloproteinase-sensitive Connected peptide-doxorubicin prodrug;

[0048] (2) 1 mole of matrix metalloproteinase-sensitive linking peptide and 2 moles of Sulfo-SMCC were dissolved in N,N-...

Embodiment 2

[0060] A method for preparing immune checkpoint blocking polypeptide prodrug nanomicelles, comprising the steps of:

[0061] (1) 1 mole of methoxypolyethylene glycol succinimidyl acetate and 1 mole of matrix metalloproteinase-sensitive linking peptide were dissolved in dimethyl sulfoxide, reacted at room temperature for 24 hours, dialyzed and purified, After freeze-drying, obtain the conjugate of polyethylene glycol-matrix metalloproteinase-sensitive linking peptide referred to as intermediate product 1 for short; mix 1 mole of intermediate product 1 with 1 mole of docetaxel, 1 mole of 1-(3-dimethylaminopropyl base)-3-ethylcarbodiimide, dissolved in dimethyl sulfoxide, reacted at room temperature for 24 hours, dialyzed, purified, and freeze-dried to obtain polyethylene glycol-matrix metal Protease-sensitive linker peptide-docetaxel prodrug;

[0062] (2) 1 mole of matrix metalloproteinase-sensitive linking peptide and 1 mole of SMCC were dissolved in dimethyl sulfoxide and mix...

Embodiment 3

[0070] A method for preparing immune checkpoint blocking polypeptide prodrug nanomicelles, comprising the steps of:

[0071] (1) Dissolve 1 mole of methoxypolyethylene glycol succinimidyl acetate and 5 moles of matrix metalloproteinase-sensitive linking peptide in tetrahydrofuran, react at room temperature for 6 hours, dialyze, purify, and freeze-dry to obtain A polyethylene glycol-matrix metalloproteinase-sensitive linker peptide conjugate referred to as intermediate product 1 for short; mix 1 mole of intermediate product 1 with 5 moles of paclitaxel and 5 moles of diisopropylcarbodiimide, dissolve in tetrahydrofuran, and Reaction at room temperature for 6 hours, dialysis, purification, and freeze-drying to obtain a polyethylene glycol-matrix metalloproteinase-sensitive linking peptide-paclitaxel prodrug referred to as intermediate product 2;

[0072] (2) Dissolving 1 mole of matrix metalloproteinase-sensitive connecting peptide and 5 moles of SPDP in tetrahydrofuran and mixi...

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Abstract

The invention discloses an immune checkpoint blocking polypeptide prodrug nano-micelle, a preparation method and application. The nano-micelle takes a hydrophobic anti-tumor drug as a core, and the core is independently connected with immune checkpoint blocking polypeptide and polyethylene glycol through a matrix metalloproteinase sensitive connection peptide, wherein the immune checkpoint blocking polypeptide and the polyethylene glycol form a shell layer. The nano-micelle disclosed by the invention has a tumor microenvironment enzyme response, and can responsively release the immune checkpoint blocking polypeptide under a function of matrix metalloproteinase under a tumor microenvironment, and avoids systemic immunity related adverse reaction caused by tumor off-target releasing of an immune checkpoint blocking drug. Through a chemotherapy killing function of an anti-tumor drug and a blocking function of the immune checkpoint, while nano-micelle blood circulation time is prolonged, the accumulation of the anti-tumor drug in a tumor focus can be enhanced, drug bioavailability is improved, the systemic immunity related adverse reaction caused by the tumor off-target releasing of the immune checkpoint blocking drug can be avoided, and a synergetic anti-tumor function of chemotherapy killing and the immune checkpoint blocking is realized.

Description

technical field [0001] The invention relates to an immune checkpoint blocking polypeptide prodrug nano-micelle, a preparation method and application thereof. Background technique [0002] Malignant tumors are still one of the main causes of human death. Traditional tumor treatment methods include surgical resection, chemotherapy, and radiotherapy. The emergence of tumor immunotherapy has brought an innovation to the treatment of tumors. Among the many strategies for activating therapeutic anti-tumor immunity, blocking immune checkpoints in the T cell activation inhibitory pathway is one of the current research hotspots in tumor immunotherapy, and its effectiveness has been gradually confirmed by clinical trials. Among them, the blockade of the immune checkpoint signaling pathway mediated by programmed cell-death protein 1 (PD-1) and its ligand (programmed cell-death 1ligand1, PD-L1) is clinically A major breakthrough has been made. However, clinical treatment results have ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K31/337A61K31/704A61K47/60A61K47/64A61P35/00
CPCA61K9/1075A61K31/337A61K31/704A61K47/60A61K47/64A61P35/00
Inventor 马桂蕾朱相慧陆妍
Owner INST OF BIOMEDICAL ENG CHINESE ACAD OF MEDICAL SCI
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