CN109512825A - A kind of composition and its application of platinum-like compounds and Sodium Hyaluronate - Google Patents
A kind of composition and its application of platinum-like compounds and Sodium Hyaluronate Download PDFInfo
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- CN109512825A CN109512825A CN201811654035.1A CN201811654035A CN109512825A CN 109512825 A CN109512825 A CN 109512825A CN 201811654035 A CN201811654035 A CN 201811654035A CN 109512825 A CN109512825 A CN 109512825A
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- composition
- sodium hyaluronate
- platinum class
- derivative compound
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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
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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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 and its application of platinum class derivative compound and Sodium Hyaluronate.Platinum class derivative compound and Sodium Hyaluronate disclosed by the invention 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: platinum class derivative compound and the united composition of Sodium Hyaluronate of the invention has apparent antitumor action, and antitumous effect is related to the type of platinum class derivative compound, there are its dosage ranges for two kinds of drug combinations；Brought toxic side effect when platinum class drug derivative is administered alone can be effectively relieved in drug combination composition；Drug combination 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.Wherein, oxaliplatin, lobaplatin are respectively the derivative of cis-platinum: difficult to understand
Pt atom and 1 in husky benefit platinum, 2 diamino hexamethylenes (DACH) and an oxalate base combine；Lobaplatin chemical name is 1,2 diamino first
Base-cyclobutane-lactic acid closes platinum, all contains organic acid.
Composition in the present invention is to be combined platinum class derivative compound and Sodium Hyaluronate, and measure it to different
The tumor killing effect of cancer cell.The composition can reduce the dosage of platinum medicine, 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 platinum class derivative compound and Sodium Hyaluronate, and it is applied in the preparation of anti-tumor drug.Wherein,
Platinum class derivative compound is divided into lobaplatin and two kinds of oxaliplatin.
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
Lobaplatin and oxaliplatin list medicine are separately added into tumour cell, and (present invention has also attempted its in addition to this two kinds of platinum-like compounds
His platinum class derivative compound: it is derivative to have chosen the best platinum class of two kinds of effects for such as carboplatin, Nedaplatin, Miboplatin, Lobaplatin and Eptaplatin
Compound carries out follow-up study), the final concentration of lobaplatin, oxaliplatin is obtained, the IC50 concentration of two kinds of drugs is learnt with this.Add
The Sodium Hyaluronate for entering various concentration is administered in combination.Then start following Collaborative experiment.Test component list medicine group and connection
Share medicine 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, often
3 parallel holes of a dosage.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, is destained overnight to MTT and is completely dissolved, and each hole is measured at Yu Zidong elisa reading instrument 570nm and 630nm
Absorbance (A) counts inhibiting rate and IC50.
Preferably, lobaplatin, final concentration of the 5 of oxaliplatin, 50,500,5000,50000ng/mL in step (1).
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 composition of the composition of platinum class derivative compound and Sodium Hyaluronate, Sodium Hyaluronate and lobaplatin
Molar ratio range is 0.0002~0.09；The molar ratio range of the composition of Sodium Hyaluronate and oxaliplatin be 0.0004~
0.33。
The invention has the benefit that
Platinum class derivative compound and Sodium Hyaluronate combination evaluate display, this hair to the Q value of the inhibiting effect of cancer cell line
Bright composition shows good tumor killing effect to cancer cell line, and the type of two in composition kind drug is different, to cancer
The inhibiting effect of cell strain is also different.Composition is combined the inhibiting effect and platinum class derivative 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 has also been attempted lobaplatin and oxaliplatin compound and the polysaccharide Type of Collective other than Sodium Hyaluronate
Object is combined, and composition also produces good tumor killing effect, but the present invention has chosen the relatively good Sodium Hyaluronate of effect
It is combined the research of administration.
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.Lobaplatin and oxaliplatin list medicine are first separately added into tumour cell before experiment, so that lobaplatin, oxaliplatin is final concentration of
5,50,500,5000,50000ng/mL, the IC50 concentration of two kinds of drugs is learnt with this, the Sodium Hyaluronate of various concentration is added
It is administered in combination.Then start following Collaborative experiment.Test component list medicine group and drug combination group.Reagent controls group adds
Culture medium is measured, tumour cell control group adds the culture medium of the identical not drug containing of equivalent, 3 parallel holes of each dosage.In CO2Incubator
After middle culture for 24 hours, every 10 μ L of Kong Zhongjia 0.5%MTT continues to cultivate 4h, and 100 μ L, tri- lysate is added, is destained overnight to MTT
It is completely dissolved, each hole absorbance (A) is measured at Yu Zidong elisa reading instrument 570nm and 630nm, count inhibiting rate and IC50.
Interpretation of result:
(1) lobaplatin and Sodium Hyaluronate are administered in combination
Lobaplatin and Sodium Hyaluronate are administered in combination, as a result such as table 1.By analyzing as it can be seen that for liver cancer cells
BxPc-3 increases the inhibiting rate of tumour when the molar ratio of Sodium Hyaluronate in composition and lobaplatin is 0.001
116%；For pancreatic cancer cell Panc-1, when the molar ratio of Sodium Hyaluronate in composition and lobaplatin is 0.017, to swollen
The inhibiting rate of tumor increases 136%；For lung carcinoma cell A427, when the molar ratio of Sodium Hyaluronate in composition and lobaplatin is
When 0.0002~0.0064,132%~145% is increased to the inhibiting rate of tumour；For lung carcinoma cell NCI-H460, work as group
When the molar ratio of Sodium Hyaluronate and lobaplatin is 0.0064 in conjunction object, 111% is increased to the inhibiting rate of tumour；For mammary gland
Cancer cell MCF-7, the inhibition when the molar ratio of Sodium Hyaluronate in composition and lobaplatin is 0.004~0.017, to tumour
Rate increases 118%~154%；For breast cancer cell MM231, when the molar ratio of Sodium Hyaluronate in composition and lobaplatin is
When 0.028~0.057,174% is increased to the inhibiting rate of tumour；For breast cancer cell MM436, when transparent in composition
When the molar ratio of matter acid sodium and lobaplatin is 0.057,125% is increased to the inhibiting rate of tumour.
Table 1
(2) oxaliplatin and Sodium Hyaluronate are administered in combination
Oxaliplatin and Sodium Hyaluronate are administered in combination, as a result such as table 2.By analyzing as it can be seen that for cancer of pancreas
Cell Capan-2 increases the inhibiting rate of tumour when the molar ratio of Sodium Hyaluronate in composition and oxaliplatin is 0.33
Grow 181%；By analysis as it can be seen that for breast cancer cell MCF-7, when rubbing for Sodium Hyaluronate in composition and oxaliplatin
When you are than being 0.083,126% is increased to the inhibiting rate of tumour；By analysis as it can be seen that for breast cancer cell TD-47, when
When the molar ratio of Sodium Hyaluronate and oxaliplatin is 0.165 in composition, 138% is increased to the inhibiting rate of tumour.?
In the concentration range of measurement, Sodium Hyaluronate does not almost all show cytotoxicity to all tumour cells.
Table 2
This patent is investigated platinum class in addition to investigating the inhibiting rate of platinum class derivative compound and Sodium Hyaluronate drug combination
Derivative compound is administered alone the inhibiting rate being administered alone to the inhibiting rate and Sodium Hyaluronate of tumour to tumour.Due to list
Solely administration inhibiting rate is significantly not so good as drug combination, so, excessive description is not done to the inhibiting rate being administered alone in the method for the present invention.
(4) platinum-like compounds are administered alone inhibiting rate:
Table 3
(5) Sodium Hyaluronate is administered alone
Table 4
Platinum class derivative compound and Sodium Hyaluronate are combined by the present invention, and are applied to and are prepared in anti-tumor drug.
The dosage that can reduce platinum medicine is used in combination in the two, and the antitumous effect after combination is more preferable；The two combination can mention
Sensibility of the high tumour cell to platinum medicine；Platinum class derivative compounds species are different, and the antitumous effect of composition is different；Platinum
There are certain dose relationships for the combination of both class derivative compound 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 class derivative compound in addition to cis-platinum and oxaliplatin has also been attempted in the present invention, with
Sodium Hyaluronate is combined combination, produces the effect that certain enhancing inhibits tumour；The present invention has also been attempted will be except transparent
Compound of polysaccharide except matter acid sodium is administered in combination from different platinum class derivative compounds, can enhance antitumous effect；
The present invention also attempts for the composition of platinum class derivative compound and Sodium Hyaluronate and conventional anticancer compound to be combined, Neng Goujin
One step improves antitumous effect.
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. a kind of composition of platinum class derivative compound and Sodium Hyaluronate, which is characterized in that the composition is by platinum class derivatization
Close object and Sodium Hyaluronate composition.Wherein, platinum class derivative compound refers to one of lobaplatin and oxaliplatin or a variety of.
2. a kind of composition of platinum class derivative compound and Sodium Hyaluronate as described in claim 1, which is characterized in that transparent
The molar ratio range of the composition of matter acid sodium and lobaplatin is 0.0002~0.09；The composition of Sodium Hyaluronate and oxaliplatin
Molar ratio range is 0.0004~0.33.
3. the composition of a kind of platinum class derivative compound as described in claim 1 and Sodium Hyaluronate is preparing anti-tumor drug
In application.
4. the application of the composition of a kind of platinum class derivative compound as described in claim 1 and Sodium Hyaluronate, feature exist
In preparing the application in medicines resistant to liver cancer.
5. the application of the composition of a kind of platinum class derivative compound as described in claim 1 and Sodium Hyaluronate, feature exist
In, preparation anti-pancreatic cancer medicament in application.
6. the application of the composition of a kind of platinum class derivative compound as described in claim 1 and Sodium Hyaluronate, feature exist
In preparing the application in anti-lung-cancer medicament.
7. the application of the composition of a kind of platinum class derivative compound as described in claim 1 and Sodium Hyaluronate, feature exist
In, preparation anti-colorectal cancer medicament in application.
8. the application of the composition of a kind of platinum class derivative compound as described in claim 1 and Sodium Hyaluronate, feature exist
In preparing the application in anti-breast cancer medicines.
A kind of application of the composition of platinum class derivative compound and Sodium Hyaluronate as described in claim 1, which is characterized in that
Application in the anti-tumor drug of preparation and conventional anticancer drugs conjunctive use.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112608398A (en) * | 2020-11-30 | 2021-04-06 | 西安交通大学 | reduction/pH sensitive polysaccharide-based nano prodrug carrying adriamycin and platinum drugs together, and preparation method and application thereof |
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2018
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| CN1051503A (en) * | 1989-09-21 | 1991-05-22 | 诺法米克公司 | Disease and treatment of diseases |
| 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 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112608398A (en) * | 2020-11-30 | 2021-04-06 | 西安交通大学 | reduction/pH sensitive polysaccharide-based nano prodrug carrying adriamycin and platinum drugs together, and preparation method and application thereof |
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