CN109528763A - The composition of cis-platinum and Sodium Hyaluronate - Google Patents
The composition of cis-platinum and Sodium Hyaluronate Download PDFInfo
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- CN109528763A CN109528763A CN201811653517.5A CN201811653517A CN109528763A CN 109528763 A CN109528763 A CN 109528763A CN 201811653517 A CN201811653517 A CN 201811653517A CN 109528763 A CN109528763 A CN 109528763A
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- platinum
- cis
- composition
- sodium hyaluronate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention relates to organic syntheses and field of medicinal chemistry, and in particular to a kind of composition of cis-platinum and Sodium Hyaluronate.Cis-platinum disclosed by the invention and Sodium Hyaluronate are combined combination administration, it can be applied to prepare in anti-tumor drug, pharmacological experiment shows, it has apparent tumor killing effect to different cancer cells, specifically include: cis-platinum and the united composition of Sodium Hyaluronate of the invention has apparent antitumor action, and there are its dosage ranges for two kinds of compound combinations；Brought toxic side effect when platinum medicine is administered alone can be effectively relieved in combination composition；Being combined composition has potential Development volue for the anti-tumor drug of new and effective, less toxic side effect, anti-drug resistance.
Description
Technical field
The present invention relates to organic syntheses and field of medicinal chemistry, and in particular to composition, preparation method and applications.
Background technique
Cancer is a kind of common frdquently encountered disease for seriously endangering human health, captures the heat that cancer cell is always studied both at home and abroad
Point problem.Chemotherapy is a kind of method of main anti-malignant tumor for systemic therapy, but it is resisting tumour cell
While, it can also damage other cells.Therefore, seek a kind of efficient anti-tumor drug of low toxicity is for antitumor treatment
Extremely urgent.
Platinum antineoplastic compound has become the most wide drug of the indispensable and application range in cancer chemotherapy.From 1978
Year cis-platinum as first generation anti-tumor drug, ratify for the first time through U.S. Food and Drug Administration (FDA) on
Behind city, platinum series antineoplastic medicament initially enters the visual field of people and is worked as by the clinical treatment promptly applied to various malignant tumours
In, successively there is the platinum antineoplastics compound such as carboplatin, Nedaplatin, oxaliplatin, Lobaplatin, Eptaplatin, lobaplatin, Miboplatin in various countries
City.Studies at home and abroad show that after platinum-like compounds enter the cell of human body, it is most to be generated in conjunction with intracellular matter
Conjugate can have cytotoxicity, to play antineoplastic action.The effect of platinum antineoplastic compound and cancer cell
Mechanism can be summarized by following steps: platinum antineoplastic compound hydrolyzes in cytoplasm after injecting and entering cell,
It reacts to form positively charged hydrate with water, enters nucleus under electrostatic attraction effect, form complex, resistance with DNA
Hinder the duplication and transcription of DNA, so as to cause the apoptosis of cell.
Composition in the present invention is to be combined cis-platinum and Sodium Hyaluronate, and measure it to different cancer cells
Tumor killing effect.The composition can reduce the dosage of cis-platinum, and the antitumous effect after combination is more preferable.
Summary of the invention
Toxic side effect to solve the problems, such as existing anti-tumor drug platinum class compound is big, it is an object of the present invention to mention
For the composition of a kind of cis-platinum and Sodium Hyaluronate, and it is applied in the preparation of anti-tumor drug.
The present invention is realized by following technical method:
Cell Proliferation detects (mtt assay):
(1) cancer cell of logarithmic growth phase is made 2 × 10496 holes are added in the suspension of a cell/mL, every 100 μ L of hole
In culture plate.
(2) reagent controls group, the experimental group of tumour cell control group and various various concentration compositions are set.First exist before experiment
Cis-platinum list medicine is added in tumour cell, and (present invention has also attempted other platinum-like compounds in addition to this cis-platinum: such as carboplatin, Nai Da
Platinum, Miboplatin, Lobaplatin and Eptaplatin etc. have chosen cis-platinum and carry out follow-up study), the final concentration of cis-platinum is obtained, composition is learnt with this
IC50 concentration.The Sodium Hyaluronate that various concentration is added is administered in combination.Then start following Collaborative experiment.Experimental group
Divide single medicine group and drug combination group.
(3) reagent controls group adds equivalent culture medium, and tumour cell control group adds the culture medium of the identical not drug containing of equivalent.First
In CO2It is cultivated in incubator, then every 10 μ L of Kong Zhongjia 0.5%MTT continues to cultivate, and is eventually adding 100 μ L, tri- lysate, mistake
Night decolourizes to MTT to be completely dissolved, and each hole absorbance (A) is measured at Yu Zidong elisa reading instrument 570nm and 630nm, counts inhibiting rate
And IC50.
Preferably, in step (1) cis-platinum final concentration of 5,50,500,5000,50000ng/mL.
Preferably, in CO in step (2)2Incubation time is 12~36h in incubator, continues the time cultivated after adding MTT
For 2~6h.
Preferably, the molar ratio range of the composition of the composition of cis-platinum and Sodium Hyaluronate, Sodium Hyaluronate and cis-platinum
It is 0.0001~0.1250.
The invention has the benefit that
Cis-platinum and Sodium Hyaluronate combination evaluate display, the present composition pair to the Q value of the inhibiting effect of cancer cell line
Cancer cell line shows good tumor killing effect, and composition is combined the inhibiting effect and cis-platinum and Sodium Hyaluronate of cancer cell line
Dosage range it is related.The usage amount that composition is administered in combination is significantly lower than clinical use dosage, and safety is good.It can be used for preparing
Anti-tumor drug is treated, the present invention can provide the new application of the present composition in medicine, concretely relate to this hair
Bright composition is preparing the application in antineoplastic new drug.
The present invention is described in further detail by the following examples, but protection scope of the present invention is not by specific reality
Any restrictions of example are applied, but are defined in the claims.
Specific embodiment
This patent, which has also been attempted, is combined cis-platinum and the polysaccharide polymer other than Sodium Hyaluronate, composition
Also good tumor killing effect is produced, but the present invention has chosen the relatively good Sodium Hyaluronate of effect and is combined grinding for administration
Study carefully.
Embodiment 1
Cell line and culture: 2 plants of liver cancer cells (BEL-7402, Hep-G2), pancreatic cancer cell 5 plants of (BxPC-3, Capan-
1, Colo357, Miapaca-2, Panc-1), lung carcinoma cell 6 plants of (A427, A549, NCI-H1299, NCI-H2170, NCI-
H358, NCI-H460), 3 plants of colorectal cancer cell (Colo205, Lovo, RKO), breast cancer cell 6 plants of (HCC-1806, MCF-
7, MDA-MB-231, MDA-MB-361, MDA-MB-436, TD-47), 1 plant of cervical cancer cell (Hela), these cells are by Nanjing
University give, with contain 10% fetal calf serum DMEM/RPMI1640/McCoy ' 5a culture medium, in 37 DEG C, 5%CO2In incubator
Culture, changes the liquid once for 2~3 days, and logarithmic growth phase cell is for testing.
Cell Proliferation detects (mtt assay): the cancer cell of logarithmic growth phase is made 2 × 104The suspension of a cell/mL,
Every 100 μ L of hole is added in 96 well culture plates.If reagent controls group, the experiment of tumour cell control group and various various concentration drugs
Group.Experiment before first cis-platinum list medicine is separately added into tumour cell so that final concentration of the 5 of cis-platinum, 50,500,5000,
50000ng/mL, the IC50 concentration of composition is learnt with this, and the Sodium Hyaluronate that various concentration is added is administered in combination.Then
Start following Collaborative experiment.Test component list medicine group and drug combination group.Reagent controls group adds equivalent culture medium, tumour cell
Control group adds the culture medium of the identical not drug containing of equivalent.In CO2After being cultivated for 24 hours in incubator, every Kong Zhongjia 0.5%MTT10 μ L after
Continuous culture 4h, is added 100 μ L, tri- lysate, is destained overnight to MTT and is completely dissolved, Yu Zidong elisa reading instrument 570nm and
Each hole absorbance (A) is measured at 630nm, counts inhibiting rate and IC50.
Interpretation of result:
(1) cis-platinum and Sodium Hyaluronate are administered in combination:
Cis-platinum and Sodium Hyaluronate are administered in combination, as a result such as table 1.By analyzing as it can be seen that for lung carcinoma cell
NCI-H129, the inhibition when the molar ratio of Sodium Hyaluronate in composition and cis-platinum is 0.0026~0.0053, to tumour
Rate increases 138%~157%；For cervical cancer cell Hela, when the molar ratio of Sodium Hyaluronate in composition and cis-platinum is
When 0.125,118% is increased to the inhibiting rate of tumour；For colorectal cancer cell HF29, when Sodium Hyaluronate in composition
When molar ratio with cis-platinum is 0.0001~0.0063,164%~214% is increased to the inhibiting rate of tumour.In measurement
In concentration range, Sodium Hyaluronate does not almost all show cytotoxicity to all tumour cells.
Table 1
This patent is investigated cis-platinum and is administered alone pair in addition to the inhibiting rate for investigating cis-platinum and Sodium Hyaluronate drug combination
The inhibiting rate and Sodium Hyaluronate of tumour are administered alone the inhibiting rate to tumour.Significantly it is not so good as due to being administered alone inhibiting rate
Drug combination, so, excessive description is not done to the inhibiting rate being administered alone in the method for the present invention.
(2) platinum-like compounds are administered alone:
Table 2
(3) Sodium Hyaluronate is administered alone:
Table 3
Cis-platinum and Sodium Hyaluronate are combined by the present invention, and are applied to and are prepared in anti-tumor drug.The two, which is combined, to be made
Antitumous effect with the dosage that can reduce cis-platinum, and after being combined is more preferable；Tumour cell can be improved to suitable in the two combination
The sensibility of platinum；There are certain dose relationships for the combination of both cis-platinum and Sodium Hyaluronate.
The present invention has also been attempted except hepatoma cell strain noted in the disclosure, pancreas cancer cell strain, lung cancer cell line, knot
Rectum cancer cell strain, breast carcinoma cell strain, outside cervical cancer cell lines, the classification of other cell strains and specific type also all generate
The effect of certain inhibition tumour；The platinum-like compounds in addition to cis-platinum have also been attempted in the present invention, carry out with Sodium Hyaluronate
Combination combination produces the effect that certain enhancing inhibits tumour；The present invention has also been attempted will be more in addition to Sodium Hyaluronate
Sugar compounds are administered in combination with cis-platinum, can enhance antitumous effect；The present invention is also attempted cis-platinum and Sodium Hyaluronate
Composition and conventional anticancer compound be combined, antitumous effect can be further increased.
Particular embodiments described above has carried out further in detail the purpose of the present invention, technical scheme and beneficial effects
It describes in detail bright, it should be understood that the above is only a specific embodiment of the present invention, is not intended to restrict the invention, it is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in guarantor of the invention
Within the scope of shield.
Claims (8)
1. the composition of cis-platinum and Sodium Hyaluronate, which is characterized in that the composition is made of cis-platinum and Sodium Hyaluronate.Its
In, the molar ratio range of the composition of Sodium Hyaluronate and cis-platinum is 0.0001~0.1250.
2. the composition application in preparation of anti-tumor drugs of cis-platinum as described in claim 1 and Sodium Hyaluronate.
3. the application of the composition of cis-platinum as described in claim 1 and Sodium Hyaluronate, which is characterized in that in preparation anti-liver cancer and anti-
Application in drug.
4. the application of the composition of cis-platinum as described in claim 1 and Sodium Hyaluronate, which is characterized in that preparing anti-pancreas
Application in cancer drug.
5. the application of the composition of cis-platinum as described in claim 1 and Sodium Hyaluronate, which is characterized in that in preparation anti-lung cancer
Application in drug.
6. the application of the composition of cis-platinum as described in claim 1 and Sodium Hyaluronate, which is characterized in that straight preparing resistive connection
Application in bowelcancer medicine.
7. the application of the composition of cis-platinum as described in claim 1 and Sodium Hyaluronate, which is characterized in that preparing anti-mammary gland
Application in cancer drug.
8. the application of the composition of cis-platinum as described in claim 1 and Sodium Hyaluronate, which is characterized in that in preparation and routine
Application in the anti-tumor drug of anti-tumor drug conjunctive use.
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Citations (7)
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|---|---|---|---|---|
| CN1388760A (en) * | 2000-07-14 | 2003-01-01 | 美迪泰克研究有限公司 | Hyaluronan as a cytotoxic agent, drug pre-sensitizer and chemo-sensitizer in the treatment of disease |
| CN101287474A (en) * | 2005-07-27 | 2008-10-15 | 阿尔卡米亚肿瘤学股份有限公司 | Therapeutic protocols using hyaluronan |
| CN101965201A (en) * | 2008-01-30 | 2011-02-02 | 堪萨斯大学 | Intralymphatic chemotherapy drug carriers |
| CN102014966A (en) * | 2008-04-22 | 2011-04-13 | 费迪亚医药股份公司 | Therapeutic use of new pharmaceutical preparations containing antitumoral drugs bound to hyaluronic acid in the treatment of neoplasias |
| CN105125522A (en) * | 2015-09-05 | 2015-12-09 | 四川大学 | Hyaluronic acid-cationic drug ion pair particle |
| US20160022824A1 (en) * | 2014-07-24 | 2016-01-28 | University-Industry Foundation, Yonsei University | Nanoparticle comprising hydrophobic drug conjugated to cationic polymer and hydrophilic drug conjugated to anionic polymer |
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2018
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| US20160022824A1 (en) * | 2014-07-24 | 2016-01-28 | University-Industry Foundation, Yonsei University | Nanoparticle comprising hydrophobic drug conjugated to cationic polymer and hydrophilic drug conjugated to anionic polymer |
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Application publication date: 20190329 |