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Anti-tumor polypeptide nano-drug carrier targeting PD-L1 and application thereof

A nano-drug carrier, PD-L1 technology, applied in the field of bio-nano materials and biomedicine, can solve the problems of immune-related side effects, poor stability in vitro, acquired drug resistance, etc., and achieve the elimination of immunosuppression, small molecular weight, and adverse reactions and weak effects of toxic and side effects

Active Publication Date: 2021-02-26
FUJIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the results of multiple clinical trials suggest that less than 30% of patients respond positively to immune checkpoint therapy, and most patients naturally do not respond to these drugs, and there are also drug-related adverse reactions, including skin itching, loss of appetite, fatigue, etc.
[0006] Although monoclonal antibodies show good clinical activity, on the other hand they have serious immune-related side effects
In addition, due to the cumbersome preparation of antibody drugs, poor in vitro stability, acquired drug resistance, high molecular weight, weak penetration and high cost, their application is limited.

Method used

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  • Anti-tumor polypeptide nano-drug carrier targeting PD-L1 and application thereof
  • Anti-tumor polypeptide nano-drug carrier targeting PD-L1 and application thereof
  • Anti-tumor polypeptide nano-drug carrier targeting PD-L1 and application thereof

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preparation example Construction

[0037] The present invention provides a polypeptide nanoassembly for tumor immunotherapy and its preparation method and application, especially a polypeptide that can bind to PD-L1 protein and a product derived from the polypeptide that can bind to PD-L1 protein and Use of the above-mentioned polypeptide or its derived products in the preparation of anticancer drug preparations.

[0038] The present invention adopts following technical scheme:

[0039] In the first aspect, the present invention provides an anti-tumor polypeptide nano-assembly (anti-tumor polypeptide nano-drug carrier), and the anti-tumor polypeptide nano-assembly includes a hydrophilic anti-tumor polypeptide, an enzyme-responsive polypeptide and a hydrophobic functional molecule.

[0040] The anti-tumor polypeptide nanomedicine provided by the present invention overcomes the shortcoming of the short half-life of ordinary linear polypeptide drugs, and the amino acid residues constituting the polypeptide can be ...

Embodiment 1

[0056] Example 1 Synthesis and Characterization of PD-L1 Polypeptide Nanoassembly PCP

[0057] 1. Experimental instruments and materials

[0058] N-methylmorpholine (NMM), piperidine, trifluoroacetic acid (TFA), dichloromethane (DCM), ninhydrin, vitamin C, phenol, tetramethyluronium hexafluorophosphate (HBTU), hexahydro Pyridine, triisopropylsilane (TIS), ethanedithiol (EDT), and human colon cancer cells (MC38) were purchased from ATCC. CO 2 Cell incubator, fluorescence microscope, small centrifuge, digital constant temperature water bath.

[0059] Synthesize the amphiphilic polypeptide PCP according to the solid-phase synthesis method. The amino group of the lysine side chain used for coupling C18 functional molecules is protected by benzyloxycarbonyl. After all the synthesis is completed, the peptide chain is cleaved from the resin with high-concentration trifluoroacetic acid. Next, the amphipathic anti-tumor polypeptide PCP is obtained after purification: CNYSKPTDRQYHFK ...

Embodiment 2

[0063] Example 2 Immunosuppression of PCP assembly in vitro and regulation of macrophage polarization to M1

[0064] In order to study the targeting effect of peptide nano-assembly on tumor cell MC38, macrophage Raw264.7 and dendritic cell DC2.4. Three kinds of cells in 1×10 5 The density was seeded into a confocal microscope petri dish. After the cells were incubated at 37°C for 24 hours, they were treated with 100 μg / mL Cy5.5-labeled polypeptide assembly PCP for 4 hours (FAP-α enzyme was pretreated for 1 hour), then the cells were washed with cold PBS, and finally Hoechst 33342 Incubate for 10 min to stain nuclei. Laser confocal imaging (LSM710 CLSM) was used for analysis. Such as Figure 4 As shown, PCP@R848 / DOX(Cy5.5) was significantly accumulated in the three types of cells and co-localized by lysozyme, indicating that R848 was efficiently delivered into endosomes.

[0065] Raw264.7 (1×10 6 / well) were cultured overnight in a 6-well plate, and the cells were polariz...

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Abstract

The invention provides an anti-tumor polypeptide nano-drug carrier targeting PD-L1 and application thereof. The anti-tumor polypeptide nano-drug carrier targeting PD-L1 can block a PD-L1 / PD-1 signal channel and activate the immune response of T cells, and a PD-L1 polypeptide nano-assembly comprises amphiphilic anti-tumor polypeptide, stearic acid coupled with a polypeptide side chain and enzyme responsive functional polypeptide. Specifically, the invention relates to a method for improving polypeptide stability through C18 modification and application thereof in activating immunotherapy. The nano-drug carrier is simple in preparation method, low in cost and high in practicability, shows a higher tumor inhibition effect compared with a single polypeptide, and is a tumor immunotherapy polypeptide nano-assembly with tumor site protease responsiveness, good biocompatibility, high stability and good stability. Important theoretical and clinical reference bases are provided for treatment research of various tumor immune checkpoints.

Description

technical field [0001] The present invention relates to the fields of biomedicine and bionanomaterials, in particular, anti-tumor polypeptide nano-drug carriers targeting PD-L1 and applications thereof. Background technique [0002] At present, with the continuous deepening of research on the mechanism of tumor immune escape, inhibitors targeting immune checkpoints have shown good clinical effects in the treatment of various solid tumors, becoming a milestone event in the history of cancer treatment, making people understand Immunotherapy can truly play an important role in the treatment of malignant tumors. Immune checkpoint inhibitors release the tolerance / shielding effect of tumors on immunity, allowing immune cells to re-recognize tumor cells and attack tumor cells. Among them, the PD-L1 / PD-1 pathway, as an important cell cycle checkpoint, plays a specific antigen-dependent negative regulatory role. Their combination can inhibit the immune activity of T cells and play a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K47/54A61K38/08A61K38/10A61K38/16A61K31/704A61K31/4745A61K9/51A61K47/42A61P35/00
CPCA61K47/64A61K47/542A61K38/08A61K38/10A61K38/16A61K31/704A61K31/4745A61K9/5169A61P35/00A61K2300/00
Inventor 王子华胡志远
Owner FUJIAN MEDICAL UNIV
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