CN108635581A - A kind of composition and its application in the drug for preparing treatment tumour - Google Patents
A kind of composition and its application in the drug for preparing treatment tumour Download PDFInfo
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- CN108635581A CN108635581A CN201810500604.0A CN201810500604A CN108635581A CN 108635581 A CN108635581 A CN 108635581A CN 201810500604 A CN201810500604 A CN 201810500604A CN 108635581 A CN108635581 A CN 108635581A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
A kind of application the present invention relates to pharmaceutical technology field more particularly to composition and its in the drug for preparing treatment tumour.A kind of application the present invention provides composition and its in the drug for preparing treatment tumour, the composition are made of photosensitizer and sweet wormwood Sesquiterpene lactones compound.Studies have shown that derivatives of porphyrin or aminolevulinic acid class compound can dramatically increase the active anticancer of sweet wormwood Sesquiterpene lactones compound with sweet wormwood Sesquiterpene lactones compound combination.Wherein MAL (methylamino ketone valeric acid) close even better than anticarcinogen Temozolomides with the activity of the composition of Artesunate.
Description
Technical field
The present invention relates to pharmaceutical technology field more particularly to a kind of composition and its in the drug for preparing treatment tumour
Using.
Background technology
Tumour (tumour) refers to body under the effect of the various tumorigenesis factors, and local organization hyperplasia is formed by new life
Object (neogrowth), because this neoformation is in occupancy block-like protrusions, also referred to as neoplasm (neoplasm) more.According to new life
The cell characteristics of object and harmfulness degree to body, and tumour is divided into benign tumour and malignant tumour two major classes, cancer is
The general name of malignant tumour.Malignant tumour originating from epithelial tissue is known as cancer (cancer), such as：It is formed by colorectal mucosa epithelium
Malignant tumour be known as colorectal mucosa epithelioma, abbreviation colorectal cancer.Malignant tumour originating from mesenchymal tissue is known as sarcoma, multiple
It is born in skin, subcutaneous, periosteum and long bone both ends.Also a small number of malignant tumours are not pressed mentioned above principle and are named, and such as the nephroblastoma is disliked
Property teratoma etc..
There are many kinds of malignant tumours, and property type is different, the tissue that involves is different with organ, stadium is different, to various
The reaction for the treatment of is also different, therefore most of patient needs to carry out complex treatment.So-called complex treatment is exactly the body according to patient
Body situation, is invaded situations such as range the histological type of tumour, comprehensive using operation, chemotherapy, radiotherapy, immunization therapy, traditional Chinese medicine
The means such as treatment, interventional treatment, micro-wave therapeutic to greatly improve cure rate, and improve the quality of life of patient.
Photodynamic therapy (Photodynamic therapy, PDT) has relative selectivity and tissue to tumour cell
The advantages of specificity, toxicity is low, safe Small side effects.Photosensitizer in PDT can absorb the energy and biography of the light of specific wavelength
The oxygen molecule of surrounding is passed, the very active singlet oxygen of chemical property is generated, singlet oxygen can be made with large biological molecule
With destroying the structure domain-functionalities of cell and crganelle, to killing tumor cell, achieve the purpose that treat tumour.In addition, photosensitive
Agent can also generate fluorescence, and normal structure and lesion can be effectively distinguished with intake by detecting the distribution of photosensitizer in the tissue
Tissue, to carry out diagnostic analysis to cancer.
It is current research hotspot that photosensitizer and antitumor drug, which are used in combination, qinghaosu also known as Arteannuin, be from
A kind of isolated common sweet wormwood of Sesquiterpene lactones compound with peroxide bridge structure is extracted in feverfew artemisia annua
Plain derivative is the effective monomer for treating malaria, has become control at present such as dihydroartemisinine, Artesunate and Artemether
Treat the first-line drug of malaria.With deepening continuously to qinghaosu and its derivative pharmacological research, it is found that it also has and resist
Immense value in terms of tumor promotion.Recent research confirms, the antitumor activity of the level and qinghaosu of ferroheme in cancer cell
It is closely related.Artemisine compounds and photosensitizer are combined to obtain better antitumous effect.
Invention content
In view of this, the technical problem to be solved in the present invention is to provide a kind of composition and its is preparing treatment tumour
Application in drug.
Composition provided by the invention is made of photosensitizer and sweet wormwood Sesquiterpene lactones compound；
The photosensitizer is derivatives of porphyrin or aminolevulinic acid class compound.
In the present invention, the sweet wormwood Sesquiterpene lactones compound is selected from qinghaosu, dihydroartemisinine, Artesunate or wormwood artemisia
At least one of methyl ether.
In the present invention, the derivatives of porphyrin is protoporphyrin IX；The aminolevulinic acid class compound is methylamino ketone
Valeric acid.
In the present invention, the molar ratio of the photosensitizer and sweet wormwood Sesquiterpene lactones compound is (12~120)：1.
In the embodiment of the present invention, the molar ratio of the qinghaosu Sesquiterpene lactones compound and porphyrins is 1:
(12~120)；The molar ratio of the qinghaosu Sesquiterpene lactones compound and aminolevulinic acid class compound is 1:(20~
50)。
In some embodiments, the molar ratio of the qinghaosu Sesquiterpene lactones compound and porphyrins is 1:
(30~120)；The molar ratio of the qinghaosu Sesquiterpene lactones compound and aminolevulinic acid class compound is 1:(25~
50)。
In some specific embodiments, the composition：
It is 12 by molar ratio:1 protoporphyrin IX is formed with qinghaosu；
Or by molar ratio be 30:1 protoporphyrin IX is formed with qinghaosu；
Or by molar ratio be 75:1 protoporphyrin IX is formed with qinghaosu；
Or by molar ratio be 30:1 protoporphyrin IX is formed with dihydroartemisinine；
Or by molar ratio be 60:1 protoporphyrin IX is formed with dihydroartemisinine；
Or by molar ratio be 120:1 protoporphyrin IX is formed with dihydroartemisinine；
Or by molar ratio be 30:1 protoporphyrin IX is formed with artesunate；
Or by molar ratio be 60:1 protoporphyrin IX is formed with artesunate；
Or by molar ratio be 120:1 protoporphyrin IX is formed with artesunate；
Or by molar ratio be 12:1 protoporphyrin IX is formed with Artemether；
Or by molar ratio be 30:1 protoporphyrin IX is formed with Artemether；
Or by molar ratio be 75:1 protoporphyrin IX is formed with Artemether；
Or by molar ratio be 20:1 MAL is formed with qinghaosu；
Or by molar ratio be 25:1 MAL is formed with qinghaosu；
Or by molar ratio be 31.25:1 MAL is formed with qinghaosu；
Or by molar ratio be 50:1 MAL is formed with dihydroartemisinine；
Or by molar ratio be 50:1 MAL is formed with artesunate；
Or by molar ratio be 20:1 MAL is formed with Artemether；
Or by molar ratio be 25:1 MAL is formed with Artemether；
Or by molar ratio be 31.25:1 MAL is formed with Artemether.
Application of the composition provided by the invention in preparing the drug for inhibiting growth of tumour cell.
In the embodiment of the present invention, the tumour cell be human lymphoma cell, brain glioblastoma cell, embryonal-cell lipoma cell,
Pancreatic cancer cell or lung adenocarcinoma cell.
Molar ratio is 12:The composition that 1 protoporphyrin IX is formed with qinghaosu protoporphyrin in inhibiting growth of tumour cell
A concentration of 600 μm of ol/L of IX；A concentration of 50 μm of ol/L of qinghaosu.
Molar ratio is 30:The composition that 1 protoporphyrin IX is formed with qinghaosu protoporphyrin in inhibiting growth of tumour cell
A concentration of 300 μm of ol/L of IX；A concentration of 10 μm of ol/L of qinghaosu.
Molar ratio is 75:The composition that 1 protoporphyrin IX is formed with qinghaosu protoporphyrin in inhibiting growth of tumour cell
A concentration of 150 μm of ol/L of IX；A concentration of 2 μm of ol/L of qinghaosu.
Molar ratio is 30:The composition of 1 protoporphyrin IX and dihydroartemisinine composition is inhibiting growth of tumour cell Central Plains
A concentration of 600 μm of ol/L of porphyrin IX；A concentration of 20 μm of ol/L of dihydroartemisinine.
Molar ratio is 60:The composition of 1 protoporphyrin IX and dihydroartemisinine composition is inhibiting growth of tumour cell Central Plains
A concentration of 300 μm of ol/L of porphyrin IX；A concentration of 5 μm of ol/L of dihydroartemisinine.
Molar ratio is 120:The composition of 1 protoporphyrin IX and dihydroartemisinine composition is inhibiting growth of tumour cell Central Plains
A concentration of 150 μm of ol/L of porphyrin IX；A concentration of 1.25 μm of ol/L of dihydroartemisinine.
Molar ratio is 30:The composition of 1 protoporphyrin IX and Artesunate composition is inhibiting growth of tumour cell Central Plains porphin
A concentration of 600 μm of ol/L of quinoline IX；A concentration of 20 μm of ol/L of Artesunate.
Molar ratio is 60:The composition of 1 protoporphyrin IX and Artesunate composition is inhibiting growth of tumour cell Central Plains porphin
A concentration of 300 μm of ol/L of quinoline IX；A concentration of 5 μm of ol/L of Artesunate.
Molar ratio is 120:The composition of 1 protoporphyrin IX and Artesunate composition is inhibiting growth of tumour cell Central Plains porphin
A concentration of 150 μm of ol/L of quinoline IX；A concentration of 1.25 μm of ol/L of Artesunate.
Molar ratio is 12:The composition that 1 protoporphyrin IX is formed with Artemether protoporphyrin in inhibiting growth of tumour cell
A concentration of 600 μm of ol/L of IX；A concentration of 50 μm of ol/L of Artemether.
Molar ratio is 30:The composition that 1 protoporphyrin IX is formed with Artemether protoporphyrin in inhibiting growth of tumour cell
A concentration of 300 μm of ol/L of IX；A concentration of 10 μm of ol/L of Artemether.
Molar ratio is 75:The composition that 1 protoporphyrin IX is formed with Artemether protoporphyrin in inhibiting growth of tumour cell
A concentration of 150 μm of ol/L of IX；A concentration of 2 μm of ol/L of Artemether.
Molar ratio is 20:The composition that 1 MAL and qinghaosu form in inhibiting growth of tumour cell MAL it is a concentration of
1000μmol/L；A concentration of 50 μm of ol/L of qinghaosu.
Molar ratio is 25:The composition that 1 MAL and qinghaosu form in inhibiting growth of tumour cell MAL it is a concentration of
250μmol/L；A concentration of 10 μm of ol/L of qinghaosu.
Molar ratio is 31.25:The concentration of 1 MAL and composition MAL in inhibiting growth of tumour cell of qinghaosu composition
For 62.5 μm of ol/L；A concentration of 2 μm of ol/L of qinghaosu.
Molar ratio is 50:The composition that 1 MAL and dihydroartemisinine form in inhibiting growth of tumour cell MAL it is dense
Degree is 1000 μm of ol/L；A concentration of 20 μm of ol/L of dihydroartemisinine.
Molar ratio is 50:The composition that 1 MAL and dihydroartemisinine form in inhibiting growth of tumour cell MAL it is dense
Degree is 250 μm of ol/L；A concentration of 5 μm of ol/L of dihydroartemisinine.
Molar ratio is 50:The composition that 1 MAL and dihydroartemisinine form in inhibiting growth of tumour cell MAL it is dense
Degree is 62.5 μm of ol/L；A concentration of 1.25 μm of ol/L of dihydroartemisinine.
Molar ratio is 50:The concentration of 1 MAL and composition MAL in inhibiting growth of tumour cell of Artesunate composition
For 1000 μm of ol/L；A concentration of 20 μm of ol/L of Artesunate.
Molar ratio is 50:The concentration of 1 MAL and composition MAL in inhibiting growth of tumour cell of Artesunate composition
For 250 μm of ol/L；A concentration of 5 μm of ol/L of Artesunate.
Molar ratio is 50:The concentration of 1 MAL and composition MAL in inhibiting growth of tumour cell of Artesunate composition
For 62.5 μm of ol/L；A concentration of 1.25 μm of ol/L of Artesunate.
Molar ratio is 20:The composition that 1 MAL and Artemether form in inhibiting growth of tumour cell MAL it is a concentration of
1000μmol/L；A concentration of 50 μm of ol/L of Artemether.
Molar ratio is 25:The composition that 1 MAL and Artemether form in inhibiting growth of tumour cell MAL it is a concentration of
250μmol/L；A concentration of 10 μm of ol/L of Artemether.
Molar ratio is 31.25:The concentration of 1 MAL and composition MAL in inhibiting growth of tumour cell of Artemether composition
For 62.5 μm of ol/L；A concentration of 2 μm of ol/L of Artemether.
Application of the composition provided by the invention in preparing the drug for inhibiting gross tumor volume to increase.
In the embodiment of the present invention, the tumour is glioma.
In the embodiment of the present invention, the composition for inhibiting gross tumor volume to increase is made of protoporphyrin IX and Artesunate.
In some specific embodiments, for inhibiting in the composition that gross tumor volume increases, the dosage of protoporphyrin IX is 25mg/
The dosage of kg, Artesunate are 50mg/kg.
The present invention also provides antitumor drugs, including composition of the present invention.
The present invention also provides a kind of methods for treating tumour, to give antitumor drug provided by the invention.
The method given is injection.
A kind of application the present invention provides composition and its in the drug for preparing treatment tumour, the composition is by photosensitive
Agent is formed with sweet wormwood Sesquiterpene lactones compound.Studies have shown that derivatives of porphyrin or aminolevulinic acid class compound and sweet wormwood
Sesquiterpene lactones compound combination can dramatically increase the active anticancer of sweet wormwood Sesquiterpene lactones compound.Wherein MAL (methyl
Aminolevulinic acid) the close even better than anticarcinogen Temozolomide with the activity of the composition of Artesunate.
Description of the drawings
Each administration group mice tumors grew situation after Fig. 1 mouse inoculation SNB19 cells；
Fig. 2 each group mice tumors grew situations.
Specific implementation mode
A kind of application the present invention provides composition and its in the drug for preparing treatment tumour, those skilled in the art
Present disclosure can be used for reference, technological parameter realization is suitably modified.In particular, it should be pointed out that all similar substitutions and modifications pair
It is it will be apparent that they are considered as being included in the present invention for those skilled in the art.The method of the present invention and application are
Be described through passing through preferred embodiment, related personnel obviously can not depart from the content of present invention, in spirit and scope to this
The methods and applications of text are modified or suitably change and combine, to realize and apply the technology of the present invention.
The examination material that the present invention uses is all common commercially available product, can all be bought in market.
With reference to embodiment, the present invention is further explained：
The external model of 1 composition of medicine active anticancer of embodiment is investigated
By human lymphoma cell (SU-DHL-4), brain glioblastoma cell (SNB19), embryonal-cell lipoma cell (SW872), pancreas
Cancer cell (PANC-1), lung adenocarcinoma cell (95D) are inoculated into respectively in 96 orifice plates, per 180 μ L cell suspensions of hole.Culture medium is
Cell culture medium containing 10%FBS.Qinghaosu, Artemether, Artesunate, dihydroartemisinine, former porphin are added in inoculation respectively afterwards for 24 hours
Quinoline IX, methylamino ketone valeric acid (MAL), protoporphyrin IX and qinghaosu, protoporphyrin IX and dihydroartemisinine, protoporphyrin IX and sweet wormwood
Amber ester, protoporphyrin IX and Artemether, MAL and qinghaosu, MAL and dihydroartemisinine, MAL and Artesunate, MAL and Artemether
The phosphate buffer of equivalent is added in composition, control medium.After adding compound 48h, cell survival rate is commented with mtt assay
Estimate.As a result as shown in following list.
Inhibitory rate of cell growth=(control group-administration group) cell OD values/cellular control unit OD values
Index of cooperation CI=EA+B/(EA+EB-EA×EB),
Wherein EA+BFor drug combination inhibiting rate, EAAnd EBThe respectively inhibiting rate of A medicines and B medicines.
CI>0.85 is added for the effect of two medicines or enhances (collaboration).
Growth inhibition effect of the 1. each drug of table to human lymphoma cell (SU-DHL-4)
Growth inhibition effect of the 2. each drug of table to human glioma cell (SNB19)
Growth inhibition effect of the 3. each drug of table to people's embryonal-cell lipoma cell (SW872)
Growth inhibition effect of the 4. each drug of table to human pancreatic cancer cell (PANC-1)
Growth inhibition effect of the 5. each drug of table to human lung adenocarcinoma cell (95D)
From list above as can be seen that at human lymphoma cell (SU-DHL-4), human glioma cell (SNB19), people
Embryonal-cell lipoma cell (SW872), in human pancreatic cancer cell (PANC-1) and human lung adenocarcinoma cell (95D), qinghaosu, double hydrogen sweet wormwoods
Element, Artesunate and Artemether are used alone under high concentration and middle concentration has certain Inhibit proliferaton to make tumour cell
With；When above-mentioned artemisine compounds combine (combination) in use, its Proliferation Ability to tumour cell with protoporphyrin IX or MAL
Effect dramatically increases.Meanwhile two medicine joint (combination) medication index of cooperation (Combination Index, CI) be all higher than
0.85, illustrate artemisinin-based drug (including but not limited to qinghaosu, dihydroartemisinine, Artesunate, Artemether) and protoporphyrin
IX or MAL joints (combination) are in use, there is apparent synergistic function.
2. protoporphyrin IX of embodiment or MAL inhibit the zoopery of people's glioma to investigate with Artesunate composition
With the composition of protoporphyrin IX or MAL and Artesunate, Artesunate carry out zoopery, using Temozolomide as
Control drug.SNB19 cell culture is in the DMEM/F12 culture solutions containing 10% fetal calf serum.Collect exponential phase of growth
SNB19 cells, PBS be resuspended to suitable concentration and with matrigel 1:It is inoculated with for mouse subcutaneous tumor after 1 mixing.BALB/c females
Right side of mice inoculates 8 × 106SNB19 cells, cell are resuspended in 1：In 1 PBS and matrigel (0.1ml/ is only).Wait for tumour
Average external volume reaches 162mm3When, it is grouped at random according to tumor size：Physiological saline group, protoporphyrin IX 25mg/kg+ Artesunates
50mg/kg, MAL50mg/kg+ Artesunate 50mg/kg, Artesunate 50mg/kg, Temozolomide 50mg/kg, all administration groups
It is to be injected intraperitoneally in addition to Temozolomide group gavage, weekly administration stops 2 days for 5 days, and successive administration calculates tumour inhibiting rate in 2 weeks.As a result it shows
Show, protoporphyrin IX or the composition of MAL and Artesunate can significantly inhibit the growth of transplantable tumor, and therapeutic effect is substantially better than blueness
Group is applied alone in artemisic succinate, and suitable with Temozolomide group.
It the above is only the preferred embodiment of the present invention, it is noted that those skilled in the art are come
It says, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should be regarded as
Protection scope of the present invention.
Claims (10)
1. a kind of composition, which is characterized in that be made of photosensitizer and sweet wormwood Sesquiterpene lactones compound；
The photosensitizer is derivatives of porphyrin or aminolevulinic acid class compound.
2. composition according to claim 1, which is characterized in that the sweet wormwood Sesquiterpene lactones compound is selected from sweet wormwood
At least one of element, dihydroartemisinine, Artesunate or Artemether.
3. composition according to claim 1, which is characterized in that the derivatives of porphyrin is protoporphyrin IX；The amino
Penta acid compounds of ketone are methylamino ketone valeric acid.
4. composition according to claim 1, which is characterized in that the photosensitizer and sweet wormwood Sesquiterpene lactones compound
Molar ratio be (12~120)：1.
5. composition according to claim 1, which is characterized in that the composition：
It is 12 by molar ratio:1 protoporphyrin IX is formed with qinghaosu；
Or by molar ratio be 30:1 protoporphyrin IX is formed with qinghaosu；
Or by molar ratio be 75:1 protoporphyrin IX is formed with qinghaosu；
Or by molar ratio be 30:1 protoporphyrin IX is formed with dihydroartemisinine；
Or by molar ratio be 60:1 protoporphyrin IX is formed with dihydroartemisinine；
Or by molar ratio be 120:1 protoporphyrin IX is formed with dihydroartemisinine；
Or by molar ratio be 30:1 protoporphyrin IX is formed with artesunate；
Or by molar ratio be 60:1 protoporphyrin IX is formed with artesunate；
Or by molar ratio be 120:1 protoporphyrin IX is formed with artesunate；
Or by molar ratio be 12:1 protoporphyrin IX is formed with Artemether；
Or by molar ratio be 30:1 protoporphyrin IX is formed with Artemether；
Or by molar ratio be 75:1 protoporphyrin IX is formed with Artemether；
Or by molar ratio be 20:1 MAL is formed with qinghaosu；
Or by molar ratio be 25:1 MAL is formed with qinghaosu；
Or by molar ratio be 31.25:1 MAL is formed with qinghaosu；
Or by molar ratio be 50:1 MAL is formed with dihydroartemisinine；
Or by molar ratio be 50:1 MAL is formed with artesunate；
Or by molar ratio be 20:1 MAL is formed with Artemether；
Or by molar ratio be 25:1 MAL is formed with Artemether；
Or by molar ratio be 31.25:1 MAL is formed with Artemether.
6. application of Claims 1 to 5 any one of them composition in preparing the drug for inhibiting growth of tumour cell.
7. application according to claim 6, which is characterized in that the tumour cell is human lymphoma cell, glioma
Cell, embryonal-cell lipoma cell, pancreatic cancer cell or lung adenocarcinoma cell.
8. application of Claims 1 to 5 any one of them composition in preparing the drug for inhibiting gross tumor volume to increase.
9. application according to claim 6, which is characterized in that the tumour is glioma.
10. a kind of antitumor drug, which is characterized in that including Claims 1 to 5 any one of them composition.
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|---|---|---|---|---|
| EP3868372A1 (en) * | 2020-02-19 | 2021-08-25 | JLP Health GmbH | A pharmaceutical combination of an artemisinin compound and a heme synthesis modulator for treating cancer |
| WO2021165405A1 (en) * | 2020-02-19 | 2021-08-26 | Jlp Health Gmbh | A pharmaceutical combination of an artemisinin compound, 5-aminolevulinic acid or methyl-5-aminolevulinic acid and a chemotherapeutic agent |
| CN114786661A (en) * | 2020-02-19 | 2022-07-22 | Jlp健康有限公司 | Pharmaceutical combination of an artemisinin compound, 5-aminolevulinic acid or methyl-5-aminolevulinic acid and a chemotherapeutic agent |
| CN111744014A (en) * | 2020-05-29 | 2020-10-09 | 新疆医科大学 | Photodynamic combined medicine composition and preparation method and application thereof |
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