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Targeting drug delivery system capable of resisting drug-resistant tumor and preparation method of targeting drug delivery system

A drug-carrying system and targeting technology, which is applied in the direction of anti-tumor drugs, pharmaceutical formulations, medical preparations of non-active ingredients, etc., can solve the problems of carrier toxicity, metabolism, poor excretion, weak drug efficacy, etc., and achieve simple operation, Increased accumulation, high safety effect

Active Publication Date: 2020-02-07
SHANGHAI UNIV OF T C M
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AI Technical Summary

Problems solved by technology

However, the research on the drug-loading system is faced with: 1. The toxicity of the carrier itself, because it can be used as a material for efficient delivery carrier, often shows the problem of poor metabolism and excretion, so there is a potential carrier toxicity problem; 2. Suitable The choice of carrier construction components, the composition and volume of the carrier and other factors will directly affect the type and amount of the drug loaded, the drug load is too small, the drug effect is too weak, if the drug load required by the constructed carrier is too large If it is large, it is likely that the toxicity of the antineoplastic drug itself will cause unacceptable side effects in practical applications; 3. Stability issues, how to ensure the stability of the carrier itself and the drug-loaded delivery system is also a matter of carrier design and The thorny problem that builders often have to face; 4. The problem of targeting. If it is sensitive to the tumor microenvironment, it will reduce the toxic and side effects on normal organs and improve the efficacy of anti-tumor; 5. The problem of hemolysis, if it is sensitive to the tumor microenvironment After injection into the blood, it will be rapidly diluted by the blood without causing severe hemolysis, and will be suitable for intravenous administration; 6. The problem of drug resistance, how to reverse the drug resistance of drug-resistant tumor cells, and enhance drug-resistant tumor cells Sensitivity to chemotherapy drugs will be of great value in improving the effect of chemotherapy

Method used

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  • Targeting drug delivery system capable of resisting drug-resistant tumor and preparation method of targeting drug delivery system
  • Targeting drug delivery system capable of resisting drug-resistant tumor and preparation method of targeting drug delivery system
  • Targeting drug delivery system capable of resisting drug-resistant tumor and preparation method of targeting drug delivery system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] 1. Preparation of polyethyleneimine-α-tocopheryl succinate polymer (abbreviated as: PEI-TOS)

[0058] Weigh 1.0g of polyethyleneimine (Mw: 25KDa), add 20mL of anhydrous DMSO to dissolve; another weigh 180mg of α-tocopheryl succinate, appropriate amount of NHS and DCC, add 20mL of anhydrous DMSO, avoid light, and store at room temperature Stir for 3 hours, then add the DMSO solution of polyethyleneimine above, and react in the dark for 24 hours at room temperature; filter, put the filtrate in a dialysis bag (Mw: 3.4KDa), and dialyze with 50% ethanol solution and deionized water to remove mixed, and then lyophilized (-80°C, 0.01Pa), the polyethylenimine-α-tocopherol succinate polymer was obtained, and the 1H NMR results were as follows: figure 1 shown.

[0059] Depend on figure 1 It can be seen that the characteristic peak of polyethyleneimine is: 1.7ppm (-NH 3 ,-NH 2 -), 2.5-3.0ppm (-CH 2 -), the characteristic peaks of α-tocopheryl succinate are: 0.8ppm (-CH(CH 3 ...

Embodiment 2

[0095] Example 2 In vitro cell uptake experiment

[0096] Coumarin 6 (C6) is a fat-soluble fluorescent dye, which is usually used as a hydrophobic fluorescent probe entrapped in nanocarriers for cell uptake or in vivo tracking. According to the preparation method of the drug-loaded micelles in Example 1, except that PTX was replaced by C6, a C6-loaded micelles solution was prepared to investigate the in vitro cell uptake of the drug-loaded micelles.

[0097] Preparation of drug solution: weigh 2mg C6, add 0.1mL DMSO, vortex until dissolved; take 10μL of the above solution, add 2mL DMEM, vortex mix to obtain a DMEM solution with a C6 concentration of 0.1μg / mL (DMSO concentration is 0.5%) .

[0098] Preparation of PEI-TOS(C6) / HA-QU drug-loaded micelles solution: Weigh 1mg of lyophilized PEI-TOS(C6) / HA-QU drug-loaded micelles, add 0.65mL ultrapure water, vortex to dissolve ; Take 20 μL of the above solution, add 2 mL DMEM, vortex and mix to obtain a PEI-TOS(C6) / HA-QU drug-loade...

Embodiment 3

[0101] Embodiment 3 in vivo distribution test

[0102] Preparation of coumarin C6 solution: Weigh 3 mg of C6, add 1 mL of ethanol, vortex until dissolved; take 10 μL of the above solution, add 1 mL of normal saline for injection, vortex and mix to obtain a solution with a C6 concentration of 30 μg / mL.

[0103] Preparation of PEI-TOS(C6) / HA-QU drug-loaded micelles solution: Take 2mg of lyophilized PEI-TOS(C6) / HA-QU drug-loaded micelles, add 0.43mL normal saline for injection, vortex until dissolved, A PEI-TOS(C6) / HA-QU drug-loaded micelle solution with a C6 concentration of 30 μg / mL was obtained.

[0104] Six nude mice (tumor volume 200mm 3 ), were randomly divided into two groups, and were injected with C6 solution and PEI-TOS(C6) / HA-QU drug-loaded micelles solution respectively through the tail vein, and the dose of C6 was 150 μg / kg. Viscera (heart, liver, spleen, lung, kidney) and tumors were observed and photographed in an in vivo imager with an emission wavelength of 466...

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Abstract

The invention discloses a targeting drug delivery system capable of resisting drug-resistant tumor and a preparation method of the targeting drug delivery system. The targeting drug delivery system isa nano-micelle taking a polyethylenimine-alpha-tocopheryl succinate polymer as a drug delivery core and a quercetin-modified hyaluronic acid polymer as a shell. Experiments prove that the targeting drug delivery system has certain acid sensitivity, can be actively released in a tumor microenvironment, is quickly diluted by blood after entering blood, cannot cause severe hemolysis, has higher safety, is applicable to intravenous injection administration, can reverse drug resistance of drug-resistant tumor cells to a certain degree, can significantly improve sensitivity of drug-resistant tumorcells to chemotherapy drugs, can increase accumulation of chemotherapy drugs at tumor parts, can remarkably improve treatment effects of the chemotherapy drugs on drug-resistant tumor, has good tumortargeting functions and has no obvious toxic or side effects; and besides, the preparation is easy to realize, simple to operate and good in repeatability.

Description

technical field [0001] The invention relates to a targeted drug delivery system capable of resisting drug-resistant tumors and a preparation method thereof, belonging to the technical field of targeted drug delivery. Background technique [0002] At present, chemotherapy has become an indispensable and important treatment method for malignant tumors along with surgical treatment and radiotherapy. In the course of clinical chemotherapy, the failure of chemotherapy for malignant tumors is common, and the main reason is the multidrug resistance (MDR) phenomenon formed after long-term use of anticancer drugs. The so-called tumor multidrug resistance (MDR) refers to that after long-term exposure of tumor cells to a chemotherapeutic drug to produce drug resistance, the tumor will cross over to a variety of anti-tumor drugs that have not been exposed to, have nothing to do with structure, and have different mechanisms. drug resistance. Chemotherapy drugs currently known to be ass...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K47/34A61K47/36A61K31/337A61P35/00
CPCA61K9/1075A61K31/337A61K47/34A61K47/36A61P35/00
Inventor 谢燕钱进阳天舒孙嘉彬刘烁赵娟娟田瑞叶泰玮
Owner SHANGHAI UNIV OF T C M
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