A targeted drug delivery system capable of resisting drug-resistant tumors and its preparation method

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: 2021-07-02
SHANGHAI UNIV OF T C M
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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  • A targeted drug delivery system capable of resisting drug-resistant tumors and its preparation method
  • A targeted drug delivery system capable of resisting drug-resistant tumors and its preparation method
  • A targeted drug delivery system capable of resisting drug-resistant tumors and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] First, prepare polyethyleneimine-α-tocophenous succinate polymers (budget: Pei-TOS)

[0058] 1.0 g of polyethylene imine (MW: 25 kDa), add 20 ml of anhydrous DMSO to dissolve; other than 180 mgα-tocophenose succinate, appropriate amounts of NHS and DCC, add 20 ml of anhydrous DMSO, protected, at room temperature After stirring for 3 h, then the DMSO solution of the polyethyleneimine was added thereto, and the reaction was protected in a room temperature; filtered, the filtrate was placed in a dialysis bag (MW: 3.4 kDa), and the solution was separated from 50% ethanol solution, deionized water dialysis , Lyophilized (-80 ° C, 0.01Pa), i.e., the polyethyleneimine-α-tantenol succinate polymer, 1 h core magnetic hydrogen spectrum measurement results figure 1 Indicated.

[0059] by 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 peak of α-tocophen succinate is: 0.8 ppm (-CH (CH) 3 ) ...

Embodiment 2

[0095] Example 2 In vitro cell intake experiment

[0096] Calmicoxin 6 (C6) is a fat-soluble fluorescent dye, commonly used as a hydrophobic fluorescent probe to be contained in a nanometer, and conduct cell-proof or in vivo trace. The pharmaceutical micelle preparation method according to Example 1, which only replaced the PTX to C6 micelle solution to examine the intake of the in vitro cells of the pharmaceutical micelles.

[0097] Pharmaceutical formulation: 2 mg C6, add 0.1 ml of DMSO, vortex to dissolve; 10 μl of the solution, 2 mLDMEM, vortex mix, to obtain a DMEM solution (DMSO concentration of 0.5%) of the C6 concentration of 0.1 μg / ml. .

[0098] PEI-TOS (C6) / HA-QU drug micelle solution: Weigh 1 mg lyophilized PEI-TOS (C6) / HA-Q japonic micelle, add 0.65 ml of ultra-pure water, vortex 20 μL of the solution was taken, 2 ml of DMEM, vortex mixed, to give a PEI-TOS (C6) / HA-Q jam micelle solution having a C6 concentration of 0.1 μg / mL.

[0099] Take MDA-MB-231 / MDR1...

Embodiment 3

[0101] Example 3 In vivo distribution test

[0102] A coumarin C6 solution was prepared: 3 mg C6 was weighed, 1 ml of ethanol, vortexed to dissolve; 10 μl of the solution was added, 1 ml of syringe was added, and the vortex was mixed to give a solution of a C6 concentration of 30 μg / mL. Solution.

[0103] PEI-TOS (C6) / HA-QU drug micelle solution formulated: lyophilized PEI-TOS (C6) / HA-QU drug micelle 2mg, add 0.43 ml of syringe saline, vortex to dissolve, A PEI-TOS (C6) / HA-Q japral micelle solution having a C6 concentration of 30 μg / mL was obtained.

[0104] Nude mouse (tumor volume 200mm) 3 ), Randomly divided into two groups, respectively by tail intravenous injection, PEI-TOS (C6) / HA-Q japonic micelle solution, C6 administration dose of 150 μg / kg, 28 hours after administration, nude mice, take out The internal organs (heart, liver, spleen, lung, kidney) and tumors are placed in a living imagery and take pictures, and the emission wavelength is 466 nm, and the exci...

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Abstract

The invention discloses a targeted drug-loading system capable of resisting drug-resistant tumors and a preparation method thereof. The targeted drug-loaded system is composed of polyethyleneimine-α-tocopherol succinate polymer as the drug-loaded core , nanomicelles shelled by quercetin-modified hyaluronic acid polymers. Experiments have proved that the targeted drug delivery system of the present invention not only has certain acid sensitivity, but can be actively released under the tumor microenvironmental conditions, and will be rapidly diluted by blood after entering the blood, without causing severe hemolysis, and is safe. It is suitable for intravenous administration, and can reverse the drug resistance of drug-resistant tumor cells to a certain extent, can significantly improve the sensitivity of drug-resistant tumor cells to chemotherapeutic drugs, and can increase the accumulation of chemotherapeutic drugs in tumor sites , significantly improve the therapeutic effect of chemotherapeutic drugs on drug-resistant tumors, have good tumor targeting effect, and have no obvious toxic and side effects; in addition, the preparation method of the present invention is easy to implement, simple to operate and good in repeatability.

Description

Technical field [0001] The present invention relates to a targeting drug system capable of resisting drug resistance and a preparation method thereof, belonging to the field of targeting administration. Background technique [0002] At present, chemotherapy has been treated with surgery, and radiotherapy is an important treatment for malignant tumors. During the clinical chemotherapy, the phenomenon of malignant tumor chemotherapy failure is uncommon, and the main reason is the phenomenon of Multidrug Resistance, MDR, formed after a long-term use of anti-tumor drugs. The so-called Multidrug RESITANCE, MDR means that after the tumor cell has long contact with a chemotherapeutic drug, this tumor has a variety of anti-tumor drugs that have different anti-tumor drugs that have different anti-tumor drugs. Drug resistance. It is currently known that chemotherapy drugs related to MDR include doxorubicin, phosphoric, gelatin, Bolemycin, mitohymmycin, chlorine, oroproposin, paclitaxel, ci...

Claims

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Application Information

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Patent Type & Authority Patents(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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