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1,2-dicarboxylic acid mono-amide taken as chemotherapy synergist

A dicarboxylic acid monoamide and polymer technology, which is applied in the direction of drug combination, drug delivery, medical preparations of non-active ingredients, etc., can solve the problem of insufficient dosage, little application value, and influence on the particle distribution of macromolecular drug carriers and penetration issues

Inactive Publication Date: 2018-12-07
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the past ten years, a lot of research has been done on the nano-drug carrier system, and many scientific papers have been published. However, there are only a handful of nano-drugs that have entered clinical application based on the nano-carrier drug-loading system, and even several nano-drugs that have been clinically used are not as good as Compared with traditional chemotherapy drugs, the side effects are only slightly reduced, and the efficacy has not been significantly increased
The reason is that the drug delivery efficiency of this system is too low, and the amount of drug reaching the tumor site is less than 1% of the dose (Wilhelm S, etal. Analysis of nanoparticle delivery to tumors, Nature Reviews Materials, 2016, 1 :16014)
The reason for the low efficiency of drug delivery is mainly caused by any one or even multiple factors in the following factors: (1) low drug loading of the carrier; (2) short blood circulation time of nanoparticles; (3) loaded (4) The loaded drug cannot be released quickly and completely after entering the tumor tissue or cancer cells
The second is due to the low permeability of nanoparticles in the tumor site, the presence of dense extracellular matrix in tumor tissue and the high intratumoral osmotic pressure caused by the lack of lymphatic drainage, resulting in the fluid pressure in the tumor tissue space is usually 10-40 times that of normal tissue , resulting in gradient difference and heterogeneous flow affecting the distribution and penetration of macromolecular drug carrier particles (Swartz M A, Lund A W. Lymphatic and interstitial flow in the tumor microenvironment: linking mechanism with immunity, Nature Reviews Cancer, 2012, 12(3) : 210-219), so it is difficult for nanoparticles reaching the tumor site through blood circulation to penetrate deep into the tumor tissue to kill tumor cells
However, this accelerator that promotes the entry of chemotherapeutic drugs into cells needs to work at a high concentration, so it has little practical value.

Method used

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  • 1,2-dicarboxylic acid mono-amide taken as chemotherapy synergist

Examples

Experimental program
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Effect test

Embodiment 1

[0027] 24 mg of 1,1,1-trimethylolpropane was weighed and added to 0.02 mL of 25% methanol solution of potassium methoxide, and excess methanol was distilled off under reduced pressure. Under the protection of nitrogen, slowly add 10ml of glycidol to the trimethylolpropane, the addition is completed in 10-12 hours, and the reaction is carried out at 95 degrees Celsius. After the reaction, the product was dissolved in methanol, potassium ions were removed by cation exchange resin, and then precipitated twice in ether to obtain hyperbranched polyglycerol, which was detected by gel permeation chromatography with a weight average molecular weight of 49,200. Dissolve 1 g of hyperbranched polyglycerol in 15 mL of tetrahydrofuran, add 4.3 g of p-toluenesulfonyl chloride and 4.5 mL of triethylamine, react at room temperature for 12 hours, remove the triethylamine salt by filtration, and then precipitate in ether to obtain p- Tosyl-modified hyperbranched polyglycerols. Dissolve it in 1...

Embodiment 2

[0029] The dendritic polyamide-amine (G8 PAMAM) of 0.6g 8 generations was weighed and dissolved in 10mL water, stirred and dispersed evenly in an ice-water bath, then adding 0.4g 2,3-dimethylmaleic anhydride ( DMA), the pH of the system dropped significantly after the addition of DMA, and sodium hydroxide solution was added to keep the pH of the reaction solution between 8-9. After the addition of DMA, the reaction was continued at room temperature for 24 hours. After the reaction, the reaction solution was added to the dialysis bag, and the pH was 10 in the sodium hydroxide solution for 72 hours, and freeze-dried to obtain 8 generations of dendritic polyamide-amine-2,3-dimethylmaleic anhydride Modifier (G8 PAMAM-DMA).

Embodiment 3

[0031] Weigh 0.6g of linear polyethyleneimine (LPEI) with a molecular weight of 10,000 10K ) was dissolved in 15mL water, stirred and dispersed evenly in an ice-water bath, and then 1.8g cyclohexene-1,2-dicarboxylic anhydride (TPA) was added in several times thereafter, the pH of the system dropped significantly after TPA was added, and sodium hydroxide was added The solution kept the pH of the reaction solution between 8-9, and continued the reaction at room temperature for 24 hours after adding TPA. After the reaction, the reaction solution was added to a dialysis bag, dialyzed in a sodium hydroxide solution with a pH of 10 for 72 hours, and freeze-dried to obtain a linear polyethylenimine-cyclohexene-1,2-dicarboxylate with a molecular weight of 10,000. acid modifier (LPEI 10K -TPA).

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Abstract

The invention discloses an application of a polymer as a synergist of a chemotherapy drug. The polymer contains a 1,2-dicarboxylic acid mono-amide structure. After the polymer, a chemotherapy drug, and cancer cells are co-cultured in a slightly acidic environment of simulated tumor tissues, the survival rate of cancer cells is lower than the survival rate of cancer cells that are not subjected toco-culture under same conditions; and after the polymer and the chemotherapy drug are injected into cancer bearing animals, the effect on inhibiting tumor growth is better, compared with the situationthat only the chemotherapy drug with a same dose is injected.

Description

technical field [0001] The invention relates to the field of antitumor drug synergists, in particular to a charge-switchable polymer with a 1,2-dicarboxylic acid monoamide structure to increase the intake of chemotherapeutic drugs by tumor cells to achieve antitumor effects enhance and overcome drug resistance of tumor cells. Background technique [0002] Chemotherapy (chemotherapy) is the treatment of cancer cells by using chemical drugs to kill cancer cells. As one of the most effective means of treating cancer at present, chemotherapy is not only a palliative therapy for cancer relief or as an adjuvant method for surgery and radiotherapy, but also treats some cancers sensitive to chemotherapy drugs such as leukemia, lymphoma, chorionic Malignant tumors such as epithelial cancer are cured. However, chemotherapeutic drugs are usually highly toxic and have strong side effects. While killing cancer cells, they can also cause damage to normal tissue cells, resulting in adver...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/795A61K31/785A61P35/00
CPCA61K31/785A61K31/795A61K9/0019A61K31/704A61K47/32A61K47/34A61P35/00
Inventor 阎虎生曹君
Owner NANKAI UNIV
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