Chemotherapy-sensitizing polypeptide aggregate and its preparation method and application

A technology of aggregates and polypeptides, applied in the field of medicine, can solve the problems of low intracellular effective drug concentration, increase the specificity of cancer cells, etc., and achieve the effects of chemotherapy sensitization and increased permeability

Active Publication Date: 2021-02-23
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to overcome the problem of low intracellular effective drug concentration caused by insufficient intracellular drug uptake of cancer cells, especially drug-resistant cancer cells, during chemotherapy, and proposes a cancer cell-specific drug that can increase the uptake of chemotherapeutic drugs. Polypeptide aggregate and preparation method thereof

Method used

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  • Chemotherapy-sensitizing polypeptide aggregate and its preparation method and application
  • Chemotherapy-sensitizing polypeptide aggregate and its preparation method and application
  • Chemotherapy-sensitizing polypeptide aggregate and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: the design of polypeptide

[0037] 1. Synthesis and covalent coupling of peptides:

[0038] Targeting polypeptide: synthesize a polypeptide capable of targeting and recognizing CAIX, the sequence is YNTNHVPLSPKY;

[0039] Effector peptide: synthesize a peptide with assembly behavior, the sequence is APIAQKDELEKLVFFAEC;

[0040]Experimental instruments and materials: dimethylformamide (DMF), piperidine, resin, dichloromethane (DCM), ninhydrin reaction reagent (ninhydrin, vitamin C, phenol), tetramethyluronium hexafluorophosphate (HBTU), hexahydropyridine, triisopropylsilane TIS, ethanedithiol (EDT), anhydrous ether, trifluoroacetic acid (TFA), N-methylmorpholine (NMM), methanol, various amino acids, Fmoc-e-Acp-OH, FITC, peptide solid-phase synthesis tubes, etc.

[0041] Solution preparation: deprotection solvent - hexahydropyridine: DMF = 1:4; reaction solution - NMM:DMF = 1:24; lysate - TFA (92.5%) TIS (2.5%) EDT (2.5%); Ninhydrin test solution—one dro...

Embodiment 2

[0047] Example 2: The targeting polypeptide 1-FITC can specifically bind to renal cancer cells

[0048] Human kidney cancer tissue samples were obtained from the Tumor Specimen Bank of the Urology Department of the Fourth Affiliated Hospital of Harbin Medical University. The specimens were human renal normal tissue and renal clear cell carcinoma tissue. CAIX is highly expressed in more than 95% of renal clear cell carcinomas, while normal renal tissues hardly express this protein. In order to verify the specificity of the targeting polypeptide 1-FITC, we selected 5 cases (n=5) of each tumor and normal tissue for tissue paraffin-fixed sectioning and co-localization of the targeting polypeptide. The specific operation method:

[0049] 1. Fixation: tissue block, the size of a soybean grain, soaked in 4% paraformaldehyde (cell cryopreservation tube, add more fixative), fixation time > 2 days, rinse with tap water for 2 hours.

[0050] 2. Dehydrated and transparent

[0051] 3. M...

Embodiment 3

[0068] Example 3: After the polypeptide reacts (1+2), it can remain in the cell level and animal level for a long time

[0069] The cells selected for the experiment were the kidney cancer cell line SK-RC-52 with high expression of CAIX, and the cells were treated with 1-FITC, 2-FITC and 1+2-FITC respectively. Observing the cells under a confocal microscope found that the fluorescence retention time of 1+2-FITC was significantly longer than that of 1-FITC and 2-FITC alone ( Figure 5 ). Subsequently, kidney cancer cells were used to establish mouse xenograft tumors, and 1x10 6 The cells were subcutaneously injected into the right leg of the mouse, and the tumor formed after 2 weeks (n=3). Peptide 1-Cy, polypeptide 2, and polypeptide 1+2 were injected into the rat tail vein respectively, and imaged with IVIS small animal imager. The results showed that the tumor retention ability of polypeptide 1+2 was stronger than that of other groups ( Image 6 ). Then the mice were kill...

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Abstract

The invention discloses a chemotherapy-sensitizing polypeptide aggregate and its preparation method and application. The polypeptide combination is composed of two polypeptide fragments with different functions, one of which has a target recognition function, and the other contains an assembly unit and has an assembly function. Driving function, the two polypeptides can self-assemble through efficient click reaction to form polypeptide aggregates with chemosensitizing effect. The method disclosed in the present invention can aggregate the polypeptide at the target site through specific design, improve the retention capacity of the polypeptide through the aggregation behavior at the target site, and at the same time, the aggregation of the polypeptide can disturb the cell membrane to promote the uptake of chemotherapy drugs by cancer cells. Through the design of the polypeptide aggregate and the selection of indications, the present invention provides a new idea for the transformation and development of the polypeptide aggregate, and also provides a new treatment method for the chemotherapy of cancer cells, especially drug-resistant cancer cells.

Description

technical field [0001] The invention relates to a chemotherapy-sensitizing polypeptide aggregate and a preparation method thereof. The invention belongs to the technical field of medicine. Background technique [0002] Chemotherapy is the abbreviation of chemical drug therapy, which can achieve the purpose of treating cancer by killing cancer cells. Chemotherapy is currently one of the most effective means of treating cancer, together with surgery and radiotherapy, it is also known as the three major cancer treatment methods. Surgery and radiotherapy are local treatments, which are only effective on cancer cells at the treatment site, and it is difficult to exert an effective therapeutic effect on potential metastatic lesions and cancer cells that have already undergone clinical metastasis. Chemotherapy is a systemic treatment method, which will be treated with blood circulation under various routes of administration (oral, intravenous, and body cavity administration, etc....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/10A61K47/42A61P35/00A61K31/704A61K31/337A61K31/7068A61K33/243
CPCA61K9/0019A61K31/337A61K31/704A61K31/7068A61K33/24A61K38/10A61K47/42A61P35/00A61K2300/00
Inventor 徐万海王浩王子琦安红维侯大勇
Owner HARBIN MEDICAL UNIVERSITY
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