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Targeting nano carrier bearing nucleoside anti-tumor drugs and preparation method and application thereof

An anti-tumor drug and nanocarrier technology, applied in the field of medicine, can solve the problems of serious side reactions, poor biocompatibility and degradability, and unsatisfactory drug effect.

Inactive Publication Date: 2019-01-18
HEBEI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] One of the objectives of the present invention is to provide a targeted nanocarrier loaded with nucleoside anti-tumor drugs, so as to solve the problems of difficult control of drug loading, poor biocompatibility and degradation, and serious side effects in existing anti-tumor drug carrier systems. and the problem of unsatisfactory drug efficacy

Method used

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  • Targeting nano carrier bearing nucleoside anti-tumor drugs and preparation method and application thereof
  • Targeting nano carrier bearing nucleoside anti-tumor drugs and preparation method and application thereof
  • Targeting nano carrier bearing nucleoside anti-tumor drugs and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0080] Example 1 Synthesis of nucleoside antineoplastic drug phosphoramidite intermediates

[0081] In order to integrate nucleoside antineoplastic drugs into DNA single strands, nucleoside antineoplastic drugs must first be converted into corresponding phosphoramidite intermediates through chemical synthesis. Take deoxyfluridine as an example below, and carry out the synthesis of phosphoramidite intermediates according to the following synthetic route.

[0082] First, weigh 4,4-dimethoxytrityl chloride (DMT-Cl) (1.860g, 5.5mmol) and deoxyfluridine (1.231g, 5mmol), add 50mL of anhydrous pyridine, stir well, The reaction was stirred at room temperature for 4h. Then add 5mL of methanol, continue to stir the reaction for 30min. The solvent was removed by rotary evaporation under reduced pressure, and the product was separated by column chromatography to obtain a white powder (compound 2) with a yield of 80%. 1H NMR (400MHz, DMSO-d6) δ (ppm): 11.86 (1H, br s, NH), 7.88 (1H, d, ...

Embodiment 2

[0089] Example 2 Synthesis of DNA single strands supporting oligonucleoside antineoplastic drugs

[0090] The oligodeoxyfluorouridine (n=10) sequence was connected to the 5' ends of the four DNA single strands of the DNA tetrahedron through DNA solid-phase synthesis technology (F represents deoxyfluridine), and one of the DNA single strands 3' modified NH2. The nucleotide sequence of each DNA single strand is as follows:

[0091] A13F-NH2:

[0092] 5’-FFFFFFFFFFACACTACGTCAGAACAGCTTGCATCACTGGTCACCAGAGTA-NH 2 -3';

[0093] B13F: 5'-FFFFFFFFFFACGAGCGAGTTGATGTGATGCAAGCTGAATGCGAGGGTCCT-3';

[0094]C13F:5'-FFFFFFFFFFCAACTCGCTCGTAACTACACTGTGCAATACTCTGGTGACC-3';

[0095] D13F: 5'-FFFFFFFFFFCTGACGTAGTGTATGCACAGTGTAGTAAGGACCCTCGCAT-3'.

[0096] Freeze-dried powders of four DNA single strands were obtained through DNA synthesis and stored at -20°C for later use.

[0097] The oligomeric gemcitabine (n=16) sequence was connected to the 5' end of the four DNA single strands of the DN...

Embodiment 3

[0107] Example 3 Fermentative production and purification of affibody molecules

[0108] The sequence of the affibody molecule used in this example is:

[0109] MIHHHHHHLQVDNKFNKEMRNAYWEIALLPNLNNQQKRAFIRSLYDDPSQSANLLAEAKKLNDAQAPKVDC.

[0110] Affibody was expressed and produced in Escherichia coli BL21(DE3) cells. The seed liquid culture conditions are: 37° C., 200 rpm shaking, 80 mL of LB medium (100 μg / mL ampicillin) in the culture liquid for 10 hours. The culture condition of the 5L fermenter is: 10% (v / v) inoculum amount, inoculated into a 5L fermenter filled with 2.0L LB medium (100 μg / mL ampicillin). At the same time, 0.5 mM final concentration of IPTG was added to the medium and the temperature was lowered to 30 °C. During the entire fermentation process, the pH of the culture solution was maintained at 7.0 by automatically adding ammonia solution. After the fermentation was completed, Escherichia coli containing affibody was obtained by centrifugation, and the Esch...

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Abstract

The invention provides a targeting nano carrier bearing nucleoside anti-tumor drugs and preparation method and application thereof. The targeting nano carrier comprises DNA tetrahedron, Affibody molecule and nucleoside anti-tumor drugs. The preparation method comprises the following steps: a, the nucleoside anti-tumor drugs are modified with phosphoramidite; B, synthesizing four DNA single strandsby DNA solid phase synthesis technology, integrating the nucleoside anti-tumor drugs into the 5 'ends of the four DNA single strands, and modifying NH2 at the 3' ends of one of the DNA single strands; C, linking the affibody molecule to the 3 'end of the NH2-modified DNA single strand through a linker; (d) mix and assembling that four DNA single strand in a molar ratio of 1: 1: 1: 1 to obtain DNAtetrahedron; and (d) assembling the four DNA single strands in a molar ratio of 1: 1: 1 to obtain DNA tetrahedron; Affibody targeting nanoparticles. The targeting nano carrier of the invention can precisely control the combined quantity of drugs, has faster tumor targeting ability and higher cell, tissue penetration ability, good pharmaceutical effect, and is suitable for popularization and application.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a targeted nanocarrier loaded with nucleoside anti-tumor drugs and its preparation method and application. Background technique [0002] Nucleoside analogs are clinically very important antitumor drugs, including a variety of purine and pyrimidine nucleoside derivatives, which are mainly used in the treatment of hematological malignancies and some solid tumors. They belong to anti-metabolite drugs, compete with physiological nucleosides, and inhibit protein synthesis by interfering with the DNA synthesis of tumor cells or affecting the transcription process of nucleic acids, so as to achieve the effect of treating tumors. [0003] So far, at least 15 FDA-approved nucleoside analogs have been used to treat various cancers, accounting for nearly 20% of current cancer chemotherapy drugs, such as 5-fluorouracil, cytarabine, gemcitabine, and decitabine. As a typical nucleoside analo...

Claims

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Application Information

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IPC IPC(8): A61K47/54A61K47/62A61K47/69A61K31/7072A61K31/7076A61K31/7056A61P35/00
CPCA61K31/7056A61K31/7072A61K31/7076A61K47/543A61K47/549A61K47/62A61K47/6929A61P35/00
Inventor 李玮张超张红蕾韩孟楠周婷婷杜洁
Owner HEBEI UNIVERSITY
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