Amphipathic conjugate anti-tumor nano-drug with function of reversing multidrug resistance of tumors and preparation method and application thereof

A multi-drug resistance and anti-tumor drug technology, applied in the field of anti-tumor drugs, can solve problems such as multi-drug resistance and inflammation of kidneys and other organs, so as to increase drug concentration, reverse multi-drug resistance of tumors, reduce Toxic effects

Active Publication Date: 2017-05-10
SHANGHAI JIAO TONG UNIV
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  • Abstract
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  • Claims
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Problems solved by technology

[0005] The first purpose of the present invention is to provide an amphiphilic conjugate anti-tumor nano drug with the function of reversing tumor multidrug resistance, so as to solve the problem of multidrug resistance common in most anti-tumor small molecule drugs, At the same time, it is necessary to use nanometer-sized substances as carriers to solve the reversal of tumor multidrug resistance in the prior art. After these nanocarriers deliver drugs into tumor cells, they themselves need to be excreted through kidneys and other organs, which may cause kidney and other diseases. Technical problems such as inflammation of an organ or causing some other condition
[0006] The second purpose of the present invention is to provide a preparation method of amphiphilic conjugate anti-tumor nano-drugs with the function of reversing tumor multi-drug resistance, so as to solve the ubiquitous multi-drug resistance of most anti-tumor small molecule drugs At the same time, it is necessary to use nanometer-sized substances as carriers to solve the reversal of tumor multidrug resistance in the prior art. After these nanocarriers deliver drugs into tumor cells, they themselves need to be excreted through organs such as the kidneys. Inflammation of kidneys and other organs or technical problems such as some other diseases
[0007] The third object of the present invention is that the above-mentioned amphiphilic conjugate anti-tumor nano-drugs are applied to the treatment of tumors and drug-resistant tumors, so as to solve the problem of multi-drug resistance that is common in most anti-tumor small molecule drugs, and at the same time To solve the reversal of tumor multidrug resistance in the prior art, it is necessary to use nano-sized substances as carriers, and after these nano-carriers deliver drugs into cancer cells, they themselves need to be excreted through kidneys and other organs, which may cause kidney and other diseases. Technical problems such as inflammation of an organ or causing some other condition

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  • Amphipathic conjugate anti-tumor nano-drug with function of reversing multidrug resistance of tumors and preparation method and application thereof
  • Amphipathic conjugate anti-tumor nano-drug with function of reversing multidrug resistance of tumors and preparation method and application thereof
  • Amphipathic conjugate anti-tumor nano-drug with function of reversing multidrug resistance of tumors and preparation method and application thereof

Examples

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Effect test

Embodiment 1

[0039] Embodiment 1: A kind of amphiphilic conjugate Ir-ss-Qu antitumor nano drug prepared by quinine Qu (formula 1) and irinotecan Ir (formula 2) of the present invention

[0040]

[0041] 1. The preparation method of the amphiphilic conjugate Ir-ss-Qu anti-tumor nano-drug specifically comprises the following steps:

[0042] (1) Synthesis of intermediate Qu-ss-COOH

[0043] Such as figure 1 As shown, at room temperature, respectively, in 250mL dry and clean round bottom flasks, add 4,4'-dithiodibutyric acid (4.77g, 20mmol), dicyclohexylcarbodiimide (2.27g, 11mmol) , 4-methylaminopyridine (1.22g, 10mmol) and 100mL of anhydrous tetrahydrofuran, after stirring and reacting for 30min, then 50mL of tetrahydrofuran solution dissolved with quinine (Qu, 3.24g, 10mmol) was added dropwise to the above reaction system, The reaction was continued for 24h, and after the reaction was finished, the organic solvent was removed by rotary evaporation to obtain the crude product, which was...

Embodiment 2

[0065] Embodiment 2: A kind of amphiphilic conjugate antitumor nano drug prepared by quinine Qu (formula 1) and irinotecan Ir (formula 2) of the present invention

[0066] 1. Another preparation method of the amphiphilic conjugate Ir-cc-Qu anti-tumor nanomedicine, which specifically includes the following steps: Example 2 is the same as Example 1 except for the following steps.

[0067] (1) Synthesis of intermediate Qu-cc-COOH

[0068] Take 100mL reaction flask, add quinine (324mg, 1mmol), succinic anhydride (500mg, 5mmol), DMAP (122mg, 1mmol) and 50mL anhydrous CH 2 Cl 2 , under the protection of nitrogen, react in the dark at 75°C for 48 hours, after the reaction, remove the solvent CH with a rotary evaporator 2 Cl2, then the crude product was purified through a silica gel column (CH 2 Cl 2 :CH 3 OH=20:1, v / v), after collection, the organic solvent was removed by rotary evaporation to obtain a light yellow solid Qu-COOH (237 mg, yield: 51.1%).

[0069] (2) Synthesis of...

Embodiment 3

[0072] Example 3: An amphiphilic conjugate Ir-ss-Qu anti-tumor nano drug prepared by quinine Qu (formula 1) and irinotecan Ir (formula 2) of the present invention

[0073] 1. Another preparation method of the amphiphilic conjugate Ir-ss-Qu anti-tumor nano-medicine, which specifically includes the following steps: In Example 3, except for the following steps, other steps are the same as in Example 1

[0074] (1) Synthesis of intermediate Qu-ss-OH

[0075] Take a 240mL reaction bottle, add quinine (972mg, 3mmol), triphosgene (311.6mg, 1.05mmol), DMAP (1.22mg, 10mmol) and 120mL anhydrous CH 2 Cl 2 , under the protection of nitrogen, after reacting for 1 hour at room temperature in the dark, add 2,2′-dithiodiethanol (2.26 g, 3.85 mmol) in 50 mL of CH 2 Cl 2 Solution, continue to react for 24h, after the end of the reaction, wash 3 times with 1N HCl, then wash with 10% saturated NaHCO 3 Solution was washed 3 times, saturated brine once, deionized water twice, and anhydrous Na ...

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Abstract

The invention discloses an amphipathic conjugate anti-tumor nano-drug with the function of reversing multidrug resistance of tumors. An anti-tumor drug is in covalent linkage with a P-gp protein inhibitor quinine by a coupling agent to form amphipathic conjugate, and the amphipathic conjugate is self-assembled under water, so as to obtain the amphipathic conjugate anti-tumor nano-drug. The invention also discloses a preparation method and application of the amphipathic conjugate anti-tumor nano-drug. Compared with the prior art, the amphipathic conjugate disclosed by the invention can be self-assembled in water to form the anti-tumor nano-drug, and does not need any drug carrier, thereby realizing common delivery of the P-gp protein inhibitor and the anti-tumor drug; after the anti-tumor nano-drug enters multidrug resistance tumor cells, linking groups are fractured under a microenvironment condition in tumor cells, and the anti-tumor drug and the P-gp protein inhibitor are released out and generate the synergistic effect, thereby effectively killing the tumor cells and the multidrug resistance tumor cells and hopefully improving the treatment effect of the tumors and multidrug resistance tumors.

Description

technical field [0001] The invention belongs to the technical field of anti-tumor drugs, and in particular relates to an amphiphilic conjugate anti-tumor nano-medicine capable of reversing multi-drug resistance of tumors and its preparation method and application. Background technique [0002] Multidrug resistance (MDR) is the main cause of failure of clinical tumor chemotherapy, and drug efflux regulated by adenosine triphosphate (ATP) binding cassette (ABC) membrane transporter is the most common mechanism of MDR. P-gp glycoprotein is one of the most important members of membrane transport proteins. P-gp protein can obtain energy from ATP hydrolysis, thereby excluding small molecule drugs such as doxorubicin and paclitaxel from tumor cells, resulting in small The enrichment concentration of molecular drugs is greatly reduced, leading to the failure of tumor chemotherapy (Nano Today 2011, 6, 176-185; Curr. Opin. Struct. Biol. 2000, 10, 649-655). In order to solve the above...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/54A61K45/06A61K31/59A61P35/00
CPCA61K31/49A61K45/06A61K2300/00
Inventor 黄平颜德岳黄卫朱新远周永丰
Owner SHANGHAI JIAO TONG UNIV
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