CN109453164A - A kind of antitumor combination medicine - Google Patents
A kind of antitumor combination medicine Download PDFInfo
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- CN109453164A CN109453164A CN201811237698.3A CN201811237698A CN109453164A CN 109453164 A CN109453164 A CN 109453164A CN 201811237698 A CN201811237698 A CN 201811237698A CN 109453164 A CN109453164 A CN 109453164A
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- dephnetin
- tumor drug
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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
- A61K31/335—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
- A61K31/37—Coumarins, e.g. psoralen
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The present invention provides a kind of antitumor medicine composition and combination medicines, it is made of by a certain percentage dephnetin and anti-tumor drug.The results show, dephnetin and other anti-tumor drugs have significant antitumor action after being used in combination.
Description
Technical field
The invention belongs to drug fields, and in particular to a kind of antitumor combination medicine.
Background technique
Malignant tumour is the primary killers of current mankind health, be seriously threaten human life most important disease it
One.Combined therapy of tumour is mainly surgical operation, radiotherapy and chemotherapy of tumors.Drug plays in malignant tumor chemotherapy focuses on
It acts on.In recent years, the research and development work of anti-tumor drug makes chemotherapy of tumors make much progress, last century carboplatin, purple
The application of the drugs such as China fir alcohol makes certain specific tumors have very high cure rate.But since anti-tumor drug is there are poor selectivity,
The defects of toxic side effect is big, drug resistance still has tumor patients more than half to eventually lead to reactionless or drug resistance is treated at present
The treatment for the treatment of failure, especially entity tumor.
Dephnetin (daphnetin), chemical name Daphnelin (7,8-dihydroxycoumarin), also known as
Daphnetin is the representative monomers ingredient of coumarin kind compound, be China's independent research one of natural drug, be compared with
Early one of the traditional Chinese medicine ingredients for being used for antitumor research.
It yet there are no and use dephnetin and chemotherapy drugs in combination come the relevant report for the treatment of tumour.
Summary of the invention
In order to solve the above-mentioned technical problem, present invention firstly provides dephnetins to prepare the purposes in IDO1 inhibitor.
The present invention also provides a kind of antitumor medicine compositions, it is made of dephnetin and anti-tumor drug.
Further, the dosage of the dephnetin and anti-tumor drug ratio is 1:(0.033~5)；Wherein, described anti-
Tumour medicine is cyclophosphamide, Doxorubicin, cis-platinum, taxol；Preferably, the anti-tumor drug is taxol.
The present invention also provides the preparation methods of pharmaceutical composition above-mentioned, it is characterised in that: it is the following steps are included: press
Dephnetin and anti-tumor drug are taken according to ratio, solution is made, is mixed.
The present invention also provides a kind of anti-tumor medicinal preparation, it be using pharmaceutical composition above-mentioned as active constituent, in addition
The preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared.
The present invention also provides a kind of antitumor combination medicine, while it contains same or different specification or
The dephnetin and anti-tumor drug and pharmaceutically acceptable carrier being administered respectively.
Further, the dosage of the dephnetin and anti-tumor drug ratio is 1:(0.033~5)；Wherein, described anti-
Tumour medicine is cyclophosphamide, Doxorubicin, cis-platinum, taxol；Preferably, the anti-tumor drug is taxol.
The present invention also provides the purposes of dephnetin and anti-tumor drug combination in the preparation of antitumor drugs.
Further, the dosage of the dephnetin and anti-tumor drug ratio is 1:(0.033~5)；Wherein, described anti-
Tumour medicine is cyclophosphamide, Doxorubicin, cis-platinum, taxol；Preferably, the anti-tumor drug is taxol.
Further, the tumour is selected from breast cancer, liver cancer, lung cancer, melanoma；Preferably, the tumour is selected from cream
Gland cancer.
The results show, dephnetin and other anti-tumor drugs have significant antitumor action after being used in combination.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
Fig. 1 is IC50 of the dephnetin to IDO1 enzyme.
Fig. 2 is that dephnetin inhibits the IDO1 being overexpressed.
Fig. 3 is that dephnetin lowers IDO1 expression.
Fig. 4 is proliferation function of the dephnetin to HeLa cell.
Fig. 5 is influence of the dephnetin of various concentration to MCF-7 cell Proliferation.
Fig. 6 is the influence of dephnetin and chemotherapeutics combination to tumour cell.
Specific embodiment
The influence of embodiment 1, dephnetin to IDO1 enzymatic activity
1 experimental material
1.1 cells and plasmid
Human cervical carcinoma cell HeLa, human embryonic kidney cells HEK-293A are provided purchased from Chinese Academy of Sciences Shanghai school of life and health sciences cell
Source center is saved by natural products central laboratory, Chengdu Inst. of Biology, Chinese Academy of Sciences；IDO cDNA is stuck up purchased from Beijing justice
Divine Land Science and Technology Ltd..
1.2 reagent
Dephnetin (Daphnetin) is purchased from Shanghai Yuan Ye Biotechnology Co., Ltd；Epacadostat is purchased from upper sea blue wood
Chemical Co., Ltd.；Human interferon IFN-γ is purchased from Nanjing Genscript Biotechnology Co., Ltd.；Anti-, GAPDH rabbit more than IDO1 rabbit
It is how anti-purchased from Wuhan Sanying Bio-Technology Co., Ltd.；Transfection reagent LIPOFECTAMINE 2000 is purchased from the silent winged generation that science and technology of match
Company；EasySee Western Blot Kit luminescent solution is purchased from Beijing Quanshijin Biotechnology Co., Ltd；Enhanced CCK-8
Kit is purchased from the green skies Bioisystech Co., Ltd in Shanghai.
1.3 instrument
The multi-functional readout instrument of Verioskan Flash (Thermo Fisher)；500 one chemical conversion of ImageQuant LAS
As instrument (GE Healthcare).
2 experimental methods
2.1 cell culture
Human cervical carcinoma cell HeLa, human embryonic kidney cells HEK-293A are in DMEM- high glucose medium (10% newborn ox blood
Clearly, 100U/mL ampicillin and 100mg/mL streptomysin), 5%CO2, cultivate in 37 DEG C of cell incubators.
2.2 IDO1 inhibitor screenings
HeLa cell presses 1.0 × 105A/hole is seeded to 48 orifice plates, 37 DEG C of overnight incubations.Appropriate reagent to be measured is added in every hole
Object, Epacadostat is as positive control drug, and culture is for 24 hours.The culture of 50ng/mL IFN-γ is added for 24 hours with inducing cell in every hole
Interior IDO is generated.It takes 100 μ L cell culture fluids into centrifuge tube, TCA, the 50 DEG C of water-bath 30min of 25 μ L 30% is added,
10000gpm is centrifuged 10min, takes 100 μ L supernatants into 96 orifice plates, and the paradime thylaminobenzaldehyde of 100 μ L 2% is added in every hole
(PDAB), 10min is stored at room temperature after mixing, multi-functional readout instrument detects A492.
2.3 immunoblotting assay
HeLa cell presses 1.0 × 106A/hole is seeded to 6 orifice plates, 37 DEG C of overnight incubations.Various concentration winter daphne is added in every hole
Element, Epacadostat is as positive control drug, and culture is for 24 hours.The culture of 50ng/mL IFN-γ is added for 24 hours with inducing cell in every hole
Interior IDO is generated.Suck culture medium, PBS is rinsed cell 3 times, is added appropriate RIPA lysate, ice bath 30min lytic cell, with thin
For born of the same parents' scraper by under cell scraper, 12000gpm centrifugation, collection supernatant is protein extract.5 × loading buffer boiling is added
Protein sample is made in water-bath 5min.Albumen is separated by electrophoresis in 12%SDS-PAGE, and albumen is transferred to NC film with semidry method.Transferring film
After, it is put into the 5%BSA of TBST configuration and closes 2h.Caudacoria and primary antibody (1:1000 dilution) 4 DEG C of overnight incubations are closed, is used
TBST is rinsed 3 times, and the secondary antibody (1:5000 dilution) with HRP label is after being incubated at room temperature 2h, and TBST is rinsed 3 times, according to EasySee
Western Blot Kit luminescent solution specification develops the color, and is imaged by GE Health imaging system.
2.4 HEK-293A are overexpressed IDO
HEK-293A cell presses 1.0 × 106A/hole is seeded to 6 orifice plates, 37 DEG C of overnight incubations.2h will be cultivated before transfection
Fluid exchange is serum-free culture solution without double antibody.2.5 μ g IDO cDNA, another 125 μ L Opti- are diluted with 125 μ L Opti-MEM
MEM dilutes 5 μ L LIPOFECTAMINE 2000, mixes gently, is stored at room temperature 5min.Plasmid dilution is added dropwise to and is diluted
Transfection reagent in, be stored at room temperature 20min, mixed liquor be added dropwise in 6 orifice plates, 37 DEG C of culture 6h are changed to complete medium,
37 DEG C are continued culture and are overexpressed IDO for 24 hours.
2.5 HeLa cell Proliferations
HeLa cell is seeded to 96 orifice plates, 37 DEG C of overnight incubations by 5000/hole.Various concentration dephnetin, culture is added
For 24 hours, 10% enhanced CCK-8 solution is added in every hole, continues to cultivate 0.5-1h at 37 DEG C.When culture solution color turns yellow, more function
It can readout instrument detection 450nm absorbance.
2.6 data statistics and processing
It is all experiment repeat three times, be as a result expressed as mean+SD, with GraphPad Prism software into
Row one-way analysis of variance (One way-ANOVA), P < 0.05 are with significant difference.
3 experimental results
3.1 IDO1 inhibitor screenings
It will be seen from figure 1 that expressing IDO1 enzyme to the HeLa cell that IFN-γ induces with the dephnetin detection of various concentration
Inhibiting effect calculates IC50 value using GraphPad Prism software.Wherein the IC50 value of dephnetin be 16.50 ±
0.33 μM, illustrating dephnetin in vitro has good IDO1 enzyme inhibition.
3.2 HEK-293A are overexpressed IDO1
IDO1 high expression in tumour cell, and silence state is among most cells.Table is crossed in HEK-293A
Up to IDO1, dephnetin is detected to the inhibiting effect of IDO1 enzyme.PCMV3-IDO1 plasmid transfection to HEK-293A cell for 24 hours after, add
Enter the dephnetin processing 6h of various concentration, cell supernatant detects IDO1 activity, as a result as shown in Fig. 2, dephnetin can press down
The IDO1 enzymatic activity being overexpressed is made, and is reinforced as concentration increases the inhibiting effect.The above result shows that dephnetin can be straight
Connect the activity for inhibiting IDO1.
The immunoblotting of 3.3 IDO1
The dephnetin of various concentration handles HeLa cell, and Western blot detects the expression of IDO1 albumen, as a result
As shown in Figure 3.The IFN-γ of 50ng/mL can promote IDO1 albumen significantly to express, and dephnetin can significantly inhibit IFN-
γ raises the effect of IDO1, and with the increase of compound concentration, inhibiting effect is more obvious, the above result shows that, dephnetin
Inhibiting IDO1 activity is likely to be the expression by lowering IDO1.
3.4 HeLa cell Proliferations
Respectively for 24 hours with the dephnetin processing HeLa cell of various concentration, CCK-8 detection compound is to HeLa cell Proliferation
It influences, as a result as shown in Figure 4.At low concentrations, dephnetin does not have apparent cytotoxicity to HeLa cell, shows low dense
Under conditions of degree, the expression that compound lowers the IDO1 of HeLa cell is not because of caused by the toxic effect to cell.
The experiment that embodiment 2, dephnetin and anti-tumor drug are used in combination
1 experimental material
1.1 cells and animal
MCF-7 cell strainHJ2mm, MDA-MB-231 are presented by National Cancer Institute doctor Cowan, in
Chengdu biological study natural products central laboratory, institute, the academy of sciences, state saves；SPF grades of ICR Healthy female mouse, weight 18-22g,
Company of Animals Ltd. is tested up to rich fruit purchased from Chengdu, credit number: SYXK (river) 2018-189.
1.2 drugs and reagent
Enhanced CCK-8 kit is purchased from the green skies Bioisystech Co., Ltd in Shanghai；Dephnetin (Daphnetin) is purchased from
Shanghai Yuan Ye Biotechnology Co., Ltd；Human interferon IFN-γ is purchased from Nanjing Genscript Biotechnology Co., Ltd.；Ring phosphinylidyne
Amine (cyclophosphamide, CTX) is purchased from Sigma Co., USA；Doxorubicin (Doxorubicin, Dox) injection is purchased from
Shanghai Xudong Hipu Medicine Co., Ltd；Cis-platinum (cisplatin, DDP) injection is purchased from the limited public affairs of Jiangsu Hao Sen medicine company group
Department；Taxol (paclitaxel, PTX) is purchased from Beijing Shuanglu Pharmaceutical Co., Ltd.；Bleocin HC1 vial
(bleomycin, BLM) is purchased from the pfizer inc Hai Zheng；1640 culture medium of RMPI is purchased from U.S. Hyclone company；It is excellent
Matter fetal calf serum (fetal bovine serum, FBS) is purchased from Shanghai Sheng Gong bioengineering limited liability company.
2 experimental methods
2.1 cell culture
Human breast carcinoma MCF-7 and MDA-MB-231 cell are with 1640 complete medium of RMPI containing 10%FBS, in 37
In 5%CO under the conditions of DEG C2It is cultivated in cell incubator.
2.2 breast cancer in situ Establishment of mouse model and grouping
The MDA-MB-231 cell suspension for collecting logarithmic growth phase, mixes with Matrigel glue by 1: 1, aseptically
With 1 × 107/ 0.2mL is inoculated under the 4th pair of breast pad of ICR Healthy female right side of mice, continuously cultivates 16-20d.To modeling at
After function, mouse is randomly divided into blank control group, chemotherapeutics group and chemotherapeutic and dephnetin drug combination group.
Wherein, chemotherapeutics group and drug combination group chemotherapeutics administration mode and approach are as shown in table 1, drug combination group
For dephnetin using oral sustained release administration (10mg/kg/d), blank control group gives same amount of normal saline.
The different chemotherapeutics administration modes of table 1 and approach
Note: i.v.:intravenous injection, intravenous injection；Qd:quaque die, once a day.
The measurement of 2.3 cell viabilities
The MCF-7 cell inoculation of logarithmic growth phase is in 96 orifice plates (1.0 × 103/ hole), it is added after cell is adherent
25ng/mL IFN-γ is incubated for 10-12h, discards supernatant, and the drug that physiological saline or various concentration is added continues to cultivate, and every group sets
6 multiple holes.Wait cultivate 12h, for 24 hours, after 48h and 72h, every hole is added 20 μ l CCK-8 solution (5mg/ml), after Incubation in dark 4h
With microplate reader at 450nm densitometric value (Optical density, OD), experiment is repeated 3 times, calculate cell inhibitory rate
(inhibition rate,IR).IR=[(ODControl group-ODDosing group)/ODControl group] × 100%.
2.4 primary tumor stereometries
Administration is after three weeks, public by ellipsoid annular volume with the length (L) and width (W) of vernier caliper measurement groups of animals tumor tubercle
Formula (V=LW2/ 2) it calculates gross tumor volume and asks each cell mean, the volume tumour inhibiting rate of more each treatment group.Tumour inhibiting rate (%)=
(blank control group transplantable tumor volume-treatment group's transplantable tumor volume)/blank control group transplantable tumor volume × 100%.
2.5 statistical procedures
Statistical procedures are carried out using 15.0 software of SPSS, measurement data is indicated with mean ± SD, data ratio more than two
Compared with one-way analysis of variance (One-way ANOVA) is used, comparison among groups are examined using t, and P < 0.05 indicates that difference has statistics
Meaning.
3 experimental results
The determination of 3.1 dephnetin combined concentrations
MCF-7 cell 72h, CCK-8 detection compound is handled to the shadow of HeLa cell Proliferation with the dephnetin of various concentration
It rings.Fig. 5 shows: dephnetin (2.5~640 μm of olL-1) it can inhibit to concentration dependent the proliferation of MCF-7 cell.2.5μ
mol·L-1Dephnetin is selected as combined concentration and does subsequent reality for (8.73 ± 1.45) % to the IR of MCF cell less than 20%
It tests.
3.2 dephnetins can enhance the reactivity of Treated with Chemotherapeutic Drugs object
The different chemotherapeutics of table 2 are with dephnetin compatibility to the inhibiting effect of breast cancer orthotopic tumour
**: P < 0.05vs-Daphnetin groups.
After preparing breast cancer orthotopic model, surveyed after chemotherapy medicine, dephnetin and chemotherapy drugs in combination medication is respectively adopted
Determine primary tumor volume.Table 2 is shown, compared with chemotherapy drug-treated group, dephnetin and chemotherapy drugs in combination processing group are in situ
Knurl product is reduced, and tumour inhibiting rate apparent increase (P < 0.05), this shows that tumor tissues can be improved to the quick of anti-tumor drug in dephnetin
Perception.
3.3 dephnetins can enhance tumour cell to the sensibility of taxol
It is total with physiological saline, dephnetin, taxol and drug combination after inducing IDO1 protein expression with IFN-γ in advance
Same-action MCF-7 cell, and cell viability is detected with CCK-8.Fig. 6 shows that dephnetin only produces slight antitumor action；
And 2.5 μm of olL-1After dephnetin and paclitaxel plus application, taxol enhances (P < 0.05) to the cytotoxicity of MCF-7, this
Showing that IDO inhibitor is combined with chemotherapy may be the effective way for improving clinical treatment breast cancer.
To sum up, there is significant antitumor action after dephnetin and other anti-tumor drugs are used in combination, tumour can be improved
The sensibility to anti-tumor drug is organized, application prospect is excellent.
Claims (10)
1. dephnetin is preparing the purposes in IDO1 inhibitor.
2. a kind of antitumor medicine composition, it is characterised in that: it is made of dephnetin and anti-tumor drug.
3. pharmaceutical composition according to claim 2, it is characterised in that: the use agent of the dephnetin and anti-tumor drug
Amount is than being 1:(0.033~5)；Wherein, the anti-tumor drug is cyclophosphamide, Doxorubicin, cis-platinum, taxol；Preferably,
The anti-tumor drug is taxol.
4. the preparation method of pharmaceutical composition described in claims 1 to 3 any one, it is characterised in that: it includes following step
It is rapid: proportionally to take dephnetin and anti-tumor drug, solution is made, mix.
5. a kind of anti-tumor medicinal preparation, it is characterised in that: it is with pharmaceutical composition described in claims 1 to 3 any one
Object is active constituent, in addition the preparation that pharmaceutically acceptable auxiliary material or complementary ingredient are prepared.
6. a kind of antitumor combination medicine, it is characterised in that: while it contains same or different specification or difference
The dephnetin and anti-tumor drug and pharmaceutically acceptable carrier of administration.
7. combination medicine according to claim 6, it is characterised in that: the use agent of the dephnetin and anti-tumor drug
Amount is than being 1:(0.033~5)；Wherein, the anti-tumor drug is cyclophosphamide, Doxorubicin, cis-platinum, taxol；Preferably,
The anti-tumor drug is taxol.
8. the purposes of dephnetin and anti-tumor drug combination in the preparation of antitumor drugs.
9. purposes according to claim 8, it is characterised in that: the dosage of the dephnetin and anti-tumor drug ratio is
1:(0.033~5)；Wherein, the anti-tumor drug is cyclophosphamide, Doxorubicin, cis-platinum, taxol；Preferably, described anti-
Tumour medicine is taxol.
10. purposes according to claim 8 or claim 9, it is characterised in that: the tumour is selected from breast cancer, liver cancer, lung cancer, black
Melanoma；Preferably, the tumour is selected from breast cancer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112206228A (en) * | 2020-11-24 | 2021-01-12 | 烟台大学 | Paclitaxel and IDO1 small molecule inhibitor compound pharmaceutical composition and application thereof |
| CN113712959A (en) * | 2021-09-27 | 2021-11-30 | 中山大学附属第一医院 | Application of daphnetin in preparation of medicine for preventing and treating intervertebral disc degeneration |
| CN115040548A (en) * | 2022-03-11 | 2022-09-13 | 中国海洋大学 | Halocynthia Roretzi antitumor extract and preparation method and application thereof |
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| CN102617632A (en) * | 2012-03-08 | 2012-08-01 | 暨南大学 | Organic germanium complex, and preparation method and application thereof |
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| CN102617632A (en) * | 2012-03-08 | 2012-08-01 | 暨南大学 | Organic germanium complex, and preparation method and application thereof |
Non-Patent Citations (2)
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| FAUSTO ALEJANDRO JIMÉNEZ-OROZCO等: "Differential effects of esculetin and daphnetin on in vitro cell proliferation and in vivo estrogenicity", 《EUROPEAN JOURNAL OF PHARMACOLOGY》 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112206228A (en) * | 2020-11-24 | 2021-01-12 | 烟台大学 | Paclitaxel and IDO1 small molecule inhibitor compound pharmaceutical composition and application thereof |
| CN113712959A (en) * | 2021-09-27 | 2021-11-30 | 中山大学附属第一医院 | Application of daphnetin in preparation of medicine for preventing and treating intervertebral disc degeneration |
| CN115040548A (en) * | 2022-03-11 | 2022-09-13 | 中国海洋大学 | Halocynthia Roretzi antitumor extract and preparation method and application thereof |
| CN115040548B (en) * | 2022-03-11 | 2023-11-14 | 中国海洋大学 | Anti-tumor extract of sea squirt and preparation method and application thereof |
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| CN109453164B (en) | 2021-08-06 |
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