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Double-targeting polypeptide-antibody-drug conjugate, and prepared method and antineoplastic application thereof

A technology of drug conjugates and targeting peptides, used in antitumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of low drug accumulation, non-specific drug uptake by tumor cells, etc., to achieve no toxic side effects, good tumors Inhibitory effect, the effect of overcoming drug resistance and killing tumor cells

Inactive Publication Date: 2018-09-28
INST OF CHEM CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still some challenges in anti-tumor strategies targeting mitochondria, such as low accumulation of drugs in mitochondria, non-specific drug uptake by tumor cells and normal cells, etc.

Method used

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  • Double-targeting polypeptide-antibody-drug conjugate, and prepared method and antineoplastic application thereof
  • Double-targeting polypeptide-antibody-drug conjugate, and prepared method and antineoplastic application thereof
  • Double-targeting polypeptide-antibody-drug conjugate, and prepared method and antineoplastic application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1, Synthesis of Dual Targeting Polypeptide-Drug Conjugate PDC

[0075] according to figure 1 The reaction scheme for the preparation.

[0076] Synthesis of AP2H-hydrazide

[0077]

[0078] Synthesized manually using FMOC solid-phase synthesis strategy. FMOC-Gly-Wang resin (0.698mmol / g glycine bonded amount) was used as starting material, 20% hexahydropyridine / DMF was used as deprotection reagent, and N-methylmorpholine and HBTU were used as activation reagent.

[0079] The specific synthesis steps of the AP2H polypeptide sequence are as follows: put the weighed FMOC-Gly-Wang resin into a sand core funnel, swell with DMF for 30 minutes, and then wash with DMF three times. Add 20% hexahydropyridine / DMF solution at a ratio of 30mL / g resin, stir for 5 minutes with a magnet and then drain, repeat twice to remove the FMOC protecting group. The resin was washed six times with DMF, agitated for 1 min each, and vacuumed for 10 s. Dissolve the mixture of FMOC-AA-O...

Embodiment 2

[0085] Example 2. Performance investigation of dual-targeting polypeptide-drug conjugate PDC

[0086] 1. Fluorescence detection

[0087] DOX, TPP-DOX and PDC were respectively dissolved in DMSO to make a mother solution with a concentration of 2mM. Take 10μL of the mother solution and dilute it to 1mL with PBS, and perform fluorescence spectrum detection on a Hitachi F-4600 fluorescence instrument. The excitation wavelength is 498nm, and the record is 510-900nm range of fluorescence emission spectra.

[0088] 2. pH-sensitive drug release kinetics

[0089] In order to investigate the pH-sensitive drug release process of PDC in the solution state, the PDC mother solution was diluted to 10 μM with three different pH PBS of pH 7.4, pH 5.0 and pH 6.0, and incubated at 37°C in the dark, at different times Points (0,1,2,3,4,9,12,24,36 and 48h) to take out 100μL solution, using liquid chromatography to monitor the drug release process.

[0090] Phosphate buffered salt with pH 7.4 w...

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Abstract

The invention discloses a double-targeting polypeptide-antibody-drug conjugate, and a prepared method and antineoplastic application thereof. The double-targeting polypeptide-antibody-drug conjugate structurally includes four components of (A), tumor specificity targeting polypeptide; (B), an antineoplastic drug; (C), a mitochondria target functional group; and (D), hydrazone bonds used for connecting the polypeptide and the antineoplastic drug. The tumor specificity targeting polypeptide is connected with the antineoplastic drug by a connecting arm comprising the hydrazone bonds; the antineoplastic drug is connected with the mitochondria target functional group by chemical bonds; and the tumor specificity targeting polypeptide is suitable for targeting the conjugate to a tumour cell and marker protein LAPTM4B carried on the surface of the tumour cell is used as a specificity target. A molecular target is combined with an organelle target, selective uptake of the drug in the tumour cell can be increased, an acting site of a DOX drug can be transferred form cell nucleus to mitochondria, and therefore the condition that the tumour cell is killed by drug resistance is avoided.

Description

technical field [0001] The invention relates to a dual-targeting polypeptide-drug conjugate, its preparation method and anti-tumor application. Background technique [0002] Chemotherapy, as a systemic treatment, is widely used in the treatment of cancer, especially in the process of cancer metastasis. However, due to various reasons, traditional antineoplastic drugs are often difficult to cure cancer. Among them, systemic side effects and drug resistance are two key factors for the failure of chemotherapy. Due to the lack of selectivity and tumor specificity, the use of traditional anticancer drugs is often accompanied by severe side effects and low absorption at the tumor site. In order to reduce systemic toxicity, the optimal dose is usually not administered, which makes clinical treatment The effect is very limited. Multidrug resistance is another major obstacle encountered by chemotherapy. It can make chemotherapy drugs lose their efficacy through a variety of differe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K47/54A61K31/704A61P35/00
CPCA61K31/704A61K47/548A61K47/64A61P35/00
Inventor 黄嫣嫣朱媛媛金钰龙桂诗浪赵睿
Owner INST OF CHEM CHINESE ACAD OF SCI
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