CN108542905A - Antitumor medicine composition and application thereof - Google Patents
Antitumor medicine composition and application thereof Download PDFInfo
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- CN108542905A CN108542905A CN201810226419.7A CN201810226419A CN108542905A CN 108542905 A CN108542905 A CN 108542905A CN 201810226419 A CN201810226419 A CN 201810226419A CN 108542905 A CN108542905 A CN 108542905A
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- 239000003814 drug Substances 0.000 title claims abstract description 47
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 27
- 239000000203 mixture Substances 0.000 title claims abstract description 26
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 94
- 229910052742 iron Inorganic materials 0.000 claims abstract description 45
- 238000002360 preparation method Methods 0.000 claims abstract description 41
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims abstract description 37
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims abstract description 35
- 229960003787 sorafenib Drugs 0.000 claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims description 19
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 229940041181 antineoplastic drug Drugs 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 208000018084 Bone neoplasm Diseases 0.000 claims description 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- FRHBOQMZUOWXQL-UHFFFAOYSA-L ammonium ferric citrate Chemical compound [NH4+].[Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FRHBOQMZUOWXQL-UHFFFAOYSA-L 0.000 claims description 3
- 229960004642 ferric ammonium citrate Drugs 0.000 claims description 3
- 235000002332 ferrous fumarate Nutrition 0.000 claims description 3
- 239000011773 ferrous fumarate Substances 0.000 claims description 3
- 229960000225 ferrous fumarate Drugs 0.000 claims description 3
- 235000013924 ferrous gluconate Nutrition 0.000 claims description 3
- 239000004222 ferrous gluconate Substances 0.000 claims description 3
- 229960001645 ferrous gluconate Drugs 0.000 claims description 3
- 235000000011 iron ammonium citrate Nutrition 0.000 claims description 3
- 239000004313 iron ammonium citrate Substances 0.000 claims description 3
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 3
- VRIVJOXICYMTAG-IYEMJOQQSA-L iron(ii) gluconate Chemical compound [Fe+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O VRIVJOXICYMTAG-IYEMJOQQSA-L 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims 1
- 239000004375 Dextrin Substances 0.000 claims 1
- 235000003891 ferrous sulphate Nutrition 0.000 claims 1
- 239000011790 ferrous sulphate Substances 0.000 claims 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 35
- 210000004881 tumor cell Anatomy 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 13
- 150000002632 lipids Chemical class 0.000 abstract description 9
- 238000006243 chemical reaction Methods 0.000 abstract description 7
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- 230000005778 DNA damage Effects 0.000 abstract description 3
- 231100000277 DNA damage Toxicity 0.000 abstract description 3
- 108090000623 proteins and genes Proteins 0.000 abstract description 3
- 102000004169 proteins and genes Human genes 0.000 abstract description 3
- 230000003617 peroxidasic effect Effects 0.000 abstract description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 22
- 241000036848 Porzana carolina Species 0.000 description 18
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 14
- 229960003180 glutathione Drugs 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 9
- 229960003067 cystine Drugs 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 8
- 201000008968 osteosarcoma Diseases 0.000 description 8
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 7
- 229910002092 carbon dioxide Inorganic materials 0.000 description 7
- 239000001569 carbon dioxide Substances 0.000 description 7
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 7
- 235000018417 cysteine Nutrition 0.000 description 7
- VZUNGTLZRAYYDE-UHFFFAOYSA-N N-methyl-N'-nitro-N-nitrosoguanidine Chemical compound O=NN(C)C(=N)N[N+]([O-])=O VZUNGTLZRAYYDE-UHFFFAOYSA-N 0.000 description 6
- 230000031700 light absorption Effects 0.000 description 6
- 230000010261 cell growth Effects 0.000 description 5
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 5
- 108010087230 Sincalide Proteins 0.000 description 4
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- 238000000034 method Methods 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 108010024636 Glutathione Proteins 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
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- 235000013922 glutamic acid Nutrition 0.000 description 3
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- 210000005170 neoplastic cell Anatomy 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- ZLXPLDLEBORRPT-UHFFFAOYSA-M [NH4+].[Fe+].[O-]S([O-])(=O)=O Chemical compound [NH4+].[Fe+].[O-]S([O-])(=O)=O ZLXPLDLEBORRPT-UHFFFAOYSA-M 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
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- 230000000052 comparative effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 101100074336 Xenopus laevis ripply2.1 gene Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
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- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
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- 235000008434 ginseng Nutrition 0.000 description 1
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- 231100000001 growth retardation Toxicity 0.000 description 1
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- 235000009566 rice Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
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- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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Classifications
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of antitumor medicine composition, described pharmaceutical composition includes Sorafenib and at least one iron preparation.Antitumor medicine composition provided by the invention inhibits SystemXc activity in Sorafenib, reduces intracellular GSH contents, under the premise of reducing cell reduced level, the iron preparation is added, because tumour cell has thermophilic iron characteristic, then can dramatically increase the Fe in tumour cell body2+Content, Fe2+Fenton's reaction is participated in, ROS is further generated, ROS can occur peroxidatic reaction of lipid with lipid and generate lipid ROS, can also cause protein and DNA damage, lead to the death of cell.
Description
Technical field
The invention belongs to field of medicinal compositions more particularly to a kind of medical composition and its uses of antitumor drug.
Background technology
SorafenibIt is a kind of oral drugs of the treatment tumour of more targetings, is only one quilt
Standard care drug of the U.S. FDA approval for advanced liver cancer patient.Sorafenib has dual antitumor action, a side
Face, by inhibiting RAF/MEK/ERK signal transduction pathway directly to inhibit tumour growth；On the other hand, by inhibiting VEGF and blood
Platelet derivative growth factor (PDGF) receptor and block tumor neovasculature formation, indirectly inhibit tumour cell growth.
Cysteine is necessary to protein synthesis, for maintaining the level of glutathione (GSH) to play an important roll.
Glutathione is a kind of three peptide thiols, is made of glutamic acid, cysteine and glycine.GSH has shorter half-life period, life
Object synthesis rate is limited by cysteine content.Cell can lead to intracellular to the reduction of extracellular cystine/cysteine intake
The horizontal reductions of GSH and subsequent growth retardation.Cell mainly obtains cystine/cysteine by two approach.On the one hand,
Cell can pass through cystine/glutamic acid transportor (System XC -) extracellular cystine is directly absorbed, or close on activation
Macrophage, dendritic cells, fibroblast etc. are reduced to half after absorbing cystine by cystine/glutamic acid transportor
Cystine is simultaneously secreted into microenvironment, and cell is then easily from extracellular intake cysteine.It therefore, can be with cystine/paddy
Propylhomoserin transhipment is target spot, by inhibiting its function, causes intracellular cystine/cysteine hungry, causes GSH horizontal not
Foot.Currently, System X can be inhibited by having document report SorafenibC -, tumor cell of liver Glutathione peptide level is reduced, is increased
The generation of active oxygen in ledger line plastochondria.When individually using Sorafenib as antineoplastic component, the dosage of Sorafenib
It is higher.
Invention content
The purpose of the present invention is to provide a kind of medical composition and its uses of antitumor drug, it is intended to solve existing skill
When art individually uses Sorafenib as antineoplastic component, the higher problem of dosage of Sorafenib.
For achieving the above object, the technical solution adopted by the present invention is as follows：
One aspect of the present invention provides a kind of antitumor medicine composition, and described pharmaceutical composition includes Sorafenib and extremely
A kind of few iron preparation.
Preferably, the iron preparation is selected from iron ammonium sulfate, ferrous fumarate, ferrous gluconate, Ferric Ammonium Citrate, the right side
The sugared acid anhydride iron of rotation, ferric oxide nanometer particle.
Preferably, the mole of the iron preparation accounts for the 50-90% of Sorafenib and iron preparation integral molar quantity.
It is furthermore preferred that the mole of the iron preparation accounts for the 65-80% of Sorafenib and iron preparation integral molar quantity.
Preferably, the iron preparation is superparamagnetic nano iron particles.
Preferably, further include pharmaceutically acceptable auxiliary material.
Preferably, described pharmaceutical composition is by Sorafenib, at least one iron preparation and pharmaceutically acceptable auxiliary material
It is made.
And the antitumor medicine composition is as the purposes for preparing antitumor drug.
Preferably, described pharmaceutical composition is preparing resisting bone tumor drug, anti-brain tumor drug, anti-breast cancer medicines, is resisting
The purposes of gastric cancer medicament, anti-lung-cancer medicament, medicines resistant to liver cancer.
Antitumor medicine composition provided by the invention contains Sorafenib and at least one iron preparation.The rope is drawn
Fei Ni can inhibit the also original systems of the GSH in tumour cell, prevents the ROS generated into the cell from effectively being removed, causes ROS's
Accumulation, finally causes death of neoplastic cells.Inhibit System Xc- activity in Sorafenib, under the premise of reducing reduced level,
After the iron preparation enters in vivo, the thermophilic iron characteristic of tumour cell can dramatically increase the Fe in tumour cell body2+Content, Fe2+Ginseng
With Fenton's reaction, ROS is further generated, ROS can not only be damaged with lipid generation peroxidatic reaction of lipid generation lipid ROS, ROS
Lipid and protein, but also DNA damage can be caused, lead to the death of cell.Therefore, it Sorafenib and is being improved with iron preparation
It shows to act synergistically in terms of tumour cell oxidative stress.The Sorafenib and the iron preparation are used simultaneously, it can
With significantly synergistic treatment tumour.Provided by the present invention for the pharmaceutical composition for the treatment of tumour, it can both enhance antitumor drug effect,
The dosage of Sorafenib is reduced, and toxicity of the Sorafenib to cell can be reduced again.
Antitumor drug is prepared using the antitumor medicine composition, can be used for inhibiting the life of tumour cell
It is long, and inhibit the transfer of tumour.
Description of the drawings
Fig. 1 is the pharmaceutical composition of various concentration Sora and SPIO provided in an embodiment of the present invention, Sora to MG-63 cells
Effect of vigor result figure；
Fig. 2 is the pharmaceutical composition of various concentration Sora and SPIO provided in an embodiment of the present invention, Sora to MNNG/HOS
Cell viability influences result figure；
Fig. 3 is the pharmaceutical composition of various concentration Sora and SPIO provided in an embodiment of the present invention, Sora to U2OS cells
Effect of vigor result figure.
Specific implementation mode
In order to make technical problems, technical solutions and advantageous effects to be solved by the present invention be more clearly understood, below in conjunction with
Embodiment, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only used to explain
The present invention is not intended to limit the present invention.
In the description of the present invention, it is to be understood that, term " first ", " second " are used for description purposes only, and cannot
It is interpreted as indicating or implies relative importance or implicitly indicate the quantity of indicated technical characteristic.Define as a result, " the
One ", the feature of " second " can explicitly or implicitly include one or more this feature.In the description of the present invention,
The meaning of " plurality " is two or more, unless otherwise specifically defined.
An embodiment of the present invention provides a kind of antitumor medicine composition, described pharmaceutical composition include Sorafenib and
At least one iron preparation.
Antitumor medicine composition provided in an embodiment of the present invention contains Sorafenib and at least one iron preparation.Institute
It states Sorafenib and can inhibit GSH antioxidant systems in tumour cell, prevent the ROS generated into the cell from effectively being removed,
The accumulation for causing ROS, finally causes death of neoplastic cells.After rope is pulled through inhibition System Xc- activity, reduce intracellular
GSH contents, under the premise of improving oxidation level, after the iron preparation enters in vivo, the thermophilic iron characteristic of tumour cell can significantly increase
Add the Fe in tumour cell body2+Content, Fe2+Fenton's reaction is participated in, ROS is further generated, with lipid lipid mistake can occur for ROS
Oxidation reaction generates lipid ROS, and ROS not only damages lipid and protein, but also can cause DNA damage, promotes the dead of cell
It dies.Therefore, Sorafenib shows to act synergistically with iron preparation in terms of improving tumour cell oxidative stress.By the rope
La Feini and the iron preparation use simultaneously, can significantly synergistic treatment tumour.Provided by the present invention for treatment tumour
Pharmaceutical composition can both enhance antitumor drug effect, reduce the dosage of Sorafenib, and can reduce Sorafenib again to thin
The toxicity of born of the same parents.
Specifically, in the embodiment of the present invention, described iron preparation itself can increase in vivo without antitumor activity
Fe2+Level, Fe2+The generation that Fenton's reaction promotes ROS is participated in, and then by inhibiting intracellular GSH antioxidant systems, breaks original
The Redox homeostasis that some Sorafenibs are formed, maintains higher level, to promote the dead of cell by intracellular ROS
It dies.For the embodiment of the present invention by supplementing iron preparation, making can Fe in tumour cell2+Content increases, and is generated by Fenton's reaction a large amount of
Active oxygen radical；Meanwhile the Sorafenib can inhibit the also original systems of the GSH in tumour cell, make the ROS generated into the cell
It cannot effectively be removed, the accumulation of ROS, the two synergistic effect is caused finally to promote death of neoplastic cells.
In the embodiment of the present invention, the iron preparation be clinically used in treatment iron-deficient mass formed by blood stasis iron supplementary and its
His chalybeate.Preferably, the iron preparation is selected from iron ammonium sulfate, ferrous fumarate, ferrous gluconate, Ferric Ammonium Citrate, the right side
The sugared acid anhydride iron of rotation, ferric oxide nanometer particle.The preferred iron preparation, not only has preferable biological safety, will not increase people
Other security risks of body, and the preferred iron preparation has preferable bio-dissipative in human body, can effectively carry
High internal Fe2+Content.
It is further preferred that the mole of the iron preparation accounts for the 50-90% of Sorafenib and iron preparation integral molar quantity.If
The molar content of the iron preparation is too low, then is difficult to effectively improve intracellular ROS contents, to cannot obviously break original
The Redox homeostasis that some Sorafenibs are formed, to the antitumor without apparent facilitation of Sorafenib.If the iron
The molar content of preparation is excessively high, can normal tissue cell generation iron toxicity.It is furthermore preferred that the mole of the iron preparation
Account for the 65-80% of Sorafenib and iron preparation integral molar quantity.
As a kind of particular preferred embodiment, the preparation is superparamagnetic nano iron particles.Sorafenib and superparamagnetic are received
The collaboration of both rice iron particles, can advantageously promote the antitumor activity of Sorafenib, reduce the dosage of Sorafenib, and
And reduce the cytotoxic activity of Sorafenib.
Pharmaceutically acceptable dosage form can be made in antitumor medicine composition described in the embodiment of the present invention.In view of
This, further, on the basis of the above embodiments, antitumor medicine composition described in the embodiment of the present invention further includes pharmacy
Upper acceptable auxiliary material.Pharmaceutically acceptable auxiliary material does not limit strictly described in the embodiment of the present invention, can be according to being made
Different dosage forms be adjusted.Specific preferred, described pharmaceutical composition is by Sorafenib, at least one iron preparation and pharmacy
Upper acceptable auxiliary material is made.
And an embodiment of the present invention provides the antitumor medicine compositions as the use for preparing antitumor drug
On the way.Antitumor drug is prepared using the antitumor medicine composition, can be used for inhibiting the growth of tumour cell, and is pressed down
The transfer of tumour processed.
Wherein, described pharmaceutical composition is preparing resisting bone tumor drug, anti-brain tumor drug, anti-breast cancer medicines, anti-stomach
The purposes of cancer drug, anti-lung-cancer medicament, medicines resistant to liver cancer.
It is illustrated with reference to specific embodiment.
Embodiment 1
Inhibition of the pharmaceutical composition of Sorafenib (Sora) and superparamagnetic nano iron particles (SPIO) to osteosarcoma cell
Effect
Cell strain and cell culture：Experiment cell used includes osteosarcoma cell MG-63, MNNG/HOS and U2OS.It is all
The condition of culture of cell is：37 DEG C in carbon dioxide incubator, saturated humidity, carbon dioxide content 5%, it is grown on and contains
10% fetal calf serum, containing in 1% dual anti-DMEM culture mediums, MG-63 and MNNG/HOS passages in every two days are primary, and U2OS is every
Passage in four days is primary, and centre changes the liquid once.
The cell in logarithmic phase growth is collected, is prepared into 5 × 104The single cell suspension of a/mL.Cell suspension is pressed per hole
100uL is inoculated in 96 well culture plates, after being cultivated for 24 hours in carbon dioxide incubator, discards original fluid.It is added containing difference
Culture medium concentration Sora (2uM, 5uM, 10uM, 20uM, 50uM) and be used in combination with 30ug/mLSPIO, each concentration are set
Five holes are set, for 24 hours, observation drug is to cell growth effect for culture.Non- dosing cell blank control group is separately set in experiment.Use CCK-
8 methods detect half-inhibition concentration of the drug to cell growth.
Comparative example 1
Growth inhibition effects of the SPIO to tumour cell
Cell strain and cell culture are same as Example 1：Experiment cell used includes osteosarcoma cell MG-63, MNNG/
HOS and U2OS.The condition of culture of all cells is：37 DEG C in carbon dioxide incubator, saturated humidity, carbon dioxide content be
5%, it is grown on containing 10% fetal calf serum, containing in 1% dual anti-DMEM culture mediums, MG-63 and MNNG/HOS are passed for every two days
In generation, is primary, and U2OS passages in every four days are primary, and centre changes the liquid once.
The cell in logarithmic phase growth is collected, is prepared into 5 × 104The single cell suspension of a/mL.Cell suspension is pressed per hole
100uL is inoculated in 96 well culture plates, after being cultivated for 24 hours in carbon dioxide incubator, discards original fluid.Addition contains
The culture medium of 30ug/mLSPIO, is arranged five holes, and culture for 24 hours, observes effect of the drug to osteosarcoma cell.It is examined with CCK-8 methods
Survey half-inhibition concentration of the drug to cell growth.
Half-inhibition concentration of the CCK-8 methods detection to cell growth is respectively adopted in embodiment 1, comparative example 1, specifically
CCK-8 methods are：Cell discards former culture medium after drug-treated setting time, and per hole, it is molten to contain 10%CCK-8 by addition 100uL
The culture medium of liquid, reacts 2h in carbon dioxide incubator.96 orifice plates are taken out, light absorption value is measured with microplate reader at 450nm.Often
The light absorption value in hole and living cells quantity are proportional, cell survival rate (%)=(drug-treated group light absorption value-blank control group
Light absorption value)/(cell controls group light absorption value-blank control group light absorption value) × 100%.
The pharmaceutical composition of Sora and SPIO, Sora to experimental result such as Fig. 1 of the growth inhibition effect of osteosarcoma cell,
2, shown in 3.Experimental result shows, Sora to three-type-person's osteosarcoma cell line MG63, MNNG/HOS, U2OS show concentration according to
Rely property inhibiting effect.And Sora and SPIO is combined, and can reduce the concentration that Sora plays inhibiting effect, reduces the dosage of Sora,
Enhance the effect of the anti-osteosarcoma of Sora.As it can be seen that SPIO can promote the effect of the anti-osteosarcoma of Sora, the two synergy can be with
The dosage of Sora is reduced, while enhancing the inhibition of Sora again.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
All any modification, equivalent and improvement etc., should all be included in the protection scope of the present invention made by within refreshing and principle.
Claims (9)
1. a kind of antitumor medicine composition, which is characterized in that described pharmaceutical composition includes Sorafenib and at least one
Iron preparation.
2. antitumor medicine composition as described in claim 1, which is characterized in that the iron preparation is selected from ferrous sulfate
Ammonium, ferrous fumarate, ferrous gluconate, Ferric Ammonium Citrate, iron-dextrin, ferric oxide nanometer particle.
3. antitumor medicine composition as described in claim 1, which is characterized in that the mole of the iron preparation accounts for Suo La
The 50-99% of Fei Ni and iron preparation integral molar quantity.
4. antitumor medicine composition as claimed in claim 3, which is characterized in that the mole of the iron preparation accounts for Suo La
The 65-80% of Fei Ni and iron preparation integral molar quantity.
5. antitumor medicine composition according to any one of claims 1-4, which is characterized in that the iron preparation is super suitable
Magnetic nano iron particles.
6. antitumor medicine composition according to any one of claims 1-4, which is characterized in that further include that can pharmaceutically connect
The auxiliary material received.
7. antitumor medicine composition according to any one of claims 1-4, which is characterized in that described pharmaceutical composition by
Sorafenib, at least one iron preparation and pharmaceutically acceptable auxiliary material are made.
8. antitumor medicine composition is as the purposes for preparing antitumor drug as described in claim any one of 1-7.
9. the purposes of antitumor medicine composition as claimed in claim 8, which is characterized in that described pharmaceutical composition is being made
The use of standby resisting bone tumor drug, anti-brain tumor drug, anti-breast cancer medicines, anti-gastric cancer medicament, anti-lung-cancer medicament, medicines resistant to liver cancer
On the way.
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| CN109908137A (en) * | 2019-03-11 | 2019-06-21 | 江苏省人民医院（南京医科大学第一附属医院） | Application of artemisinin in medicine for killing breast cancer stem cells |
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| CN109908137A (en) * | 2019-03-11 | 2019-06-21 | 江苏省人民医院（南京医科大学第一附属医院） | Application of artemisinin in medicine for killing breast cancer stem cells |
| CN109908137B (en) * | 2019-03-11 | 2022-02-18 | 江苏省人民医院（南京医科大学第一附属医院） | Application of artemisinin in medicine for killing breast cancer stem cells |
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Application publication date: 20180918 |