CN108853507A - A kind of antitumor synergism medicine composition and its preparation method and application - Google Patents

A kind of antitumor synergism medicine composition and its preparation method and application Download PDF

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CN108853507A
CN108853507A CN201710330477.XA CN201710330477A CN108853507A CN 108853507 A CN108853507 A CN 108853507A CN 201710330477 A CN201710330477 A CN 201710330477A CN 108853507 A CN108853507 A CN 108853507A
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medicine composition
inhibitor
cell
antitumor
composition according
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鞠佃文
范佳君
章旭耀
王绍飞
王辰
王一辰
陈伟
栾静韵
梁嫣煦
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Fudan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine

Abstract

The present invention relates to medicine, field of biotechnology, are related to antitumor drug synergism drug, and in particular to a kind of pharmaceutical composition and its preparation method and application being made of Hedgehog signal pathway inhibitor and cell autophagy inhibitor.Pharmaceutical composition or compound medicine of the invention can promote tumour cell for the sensibility of Hedgehog signal pathway inhibitor, for the treatment of lung cancer, liver cancer, gastric cancer, the carcinoma of the rectum, melanoma, leukaemia and lymthoma, stronger antitumor curative effect can be generated.Described pharmaceutical composition preparation process is simple, is suitble to large-scale production and preparation.

Description

A kind of antitumor synergism medicine composition and its preparation method and application
Technical field
The present invention relates to medicine, field of biotechnology, are related to antitumor drug synergism drug, and in particular to Yi Zhongyou The pharmaceutical composition and its preparation method and application of Hedgehog signal pathway inhibitor and cell autophagy inhibitor composition.
Background technique
It is that disease incidence highest, the death rate are highest swollen in the world at present prior art discloses lung cancer (Lung Cancer) One of tumor, disease incidence accounts for the 17% of tumor incidence, and the death rate accounts for 21%, it is difficult to cure, wherein non-small cell lung cancer (non-small-cell lung cancer, NSCLC) morbidity sum then accounts for the 70%~75% of lung cancer morbidity number；The illness Have the characteristics that patient numbers are numerous and is difficult to cure.
Currently, the treatment method of non-small cell lung cancer mainly includes：Surgical resection, chemotherapy and tyrosine kinase inhibit Agent treatment.Practice display, the case that can be performed a surgical operation due to non-small cell lung cancer is simultaneously few, so about 85% case need to be according to The anti-tumor drug treatment for relying chemotherapy or tyrosine kinase inhibitor to rely on, however, clinical practice is shown, no matter which kind of, which is intervened, is controlled The cure rate for the treatment of method is very low, and therefore, leading to 5 years survival rates of Patients with Non-small-cell Lung is only 10%~15% [DeNicola GM,Chen PH,Mullarky E,et al.NRF2regulates serine biosynthesis in non-small cell lung cancer.Nature Genetics.2016；48:473.]；So researching and developing completely new be directed to The intervention stratege and drug of non-small cell lung cancer have necessary clinical meaning.
It is a kind of to evolve upper highly conserved and respectively organizing and organ in human body that data, which discloses Hedgehog signal path, Access [Hu L, Lin X, Lu H, the et al.An overview of hedgehog signaling in of middle constructive expression fibrosis.Molecular pharmacology.2015；87:174-82.], it can be transduceed by various types of signal, as Wnt, P53, G-repector etc. regulate and control [1. Scales SJ, the de such as embryonic development, cell Proliferation, regeneration and Apoptosis Sauvage FJ.Mechanisms of Hedgehog pathway activation in cancer and implications for therapy.Trends in pharmacological sciences.2009；30:303-12.； ②Kimura S,Ando T,Kojima K.Ever-advancing chronic myeloid leukemia treatment.International journal of clinical oncology.2014；19:3-9.].Hh signal path Mainly by signaling molecule Hh aglucon, transmembrane protein receptor Patched (PTCH1), transmembrane protein Smoothened (SMO), fusion The composition such as repressor protein SUFU and zinc finger transcription factor GLI；Wherein PTCH1 can inhibit SMO, so that Hh signal path is closed, when After Hh is in conjunction with ligand PTCH1, PTCH1 then loses the inhibiting effect to SMO, thus activate Hh signal path, prevent GLI2 and The shearing of GLI3, the GLI2 of activation in conjunction with endonuclear GLI promoter, stimulate GLI1, PTCH1, HHIP, Bcl-2 and Isogenic transcription [Dereck A, Zainab J, the Marion D.Unraveling the therapeutic of Cyclin potential of the Hedgehog pathway in cancer.Nature Medicine 2013,19(11):1410- 1422.]。
Some researches show that Hedgehog signal path high expression in multiple tumours, such as basal-cell carcinoma (BCC) [Basset-Seguin N,Sharpe HJ,de Sauvage FJ.Efficacy of Hedgehog pathway inhibitors in Basal cell carcinoma.Molecular Cancer Therapeutics.2015；14:633- 41.], leukaemia [Zeng X, Zhao H, Li Y, et al.Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia.Autophagy.2015；11:355-72.] and non-small cell lung cancer [Leem YE, Ha HL, Bae JH, et al.CDO,an Hh-coreceptor,mediates lung cancer cell proliferation and tumorigenicity through Hedgehog signaling.PloS One.2014；9:E111701.] etc., and can promote Into the growth and invasion of tumour.Research shows that inhibiting Hedgehog access that can significantly inhibit the growth of basal cell cancer cell and lead Cause its apoptosis [Kim EJ, Sahai V, Abel EV, et al.Pilot clinical trial of hedgehog pathway inhibitor GDC-0449(Vismodegib)in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma.Clinical Cancer Research 2014；20:5937-45.].Having listed or be in the Hedgehog signal pathway inhibitor of clinical investigation phase at present is Following three types：(1) SMO inhibitor；Including vismodegib, cyclopamine, saridegib (IPI-926), sonidegib (LDE225),BMS-833923,PF04449913,LEQ506,TAK-441,LY2940680；(2) Hh protein inhibitor；Including Robotnikinin；(3) GLI inhibitor；Including GANT61, GANT58, HIP-1, HIP-2, HIP-3, HIP-4, three oxidations two Arsenic.
Cell autophagy (autophagy) is also known as II type programmed death (type II programmed cell death), It is the significant process of the responsible intracellular matter turnover of evolution conservative in eucaryote body, can decomposes intracellular impaired or extra Organelle and the albumen of aging generate nucleotide, and the small-molecule substances such as amino acid synthesize new protein for cell, and can maintain The stabilization of intracellular microenvironment, research in recent years find its generation and hair with a variety of diseases, especially tumour of cell autophagy It opens up in close relations.The difference of lysosome intracavitary is transported to according to intracellular substrate, mammalian cell autophagy is divided into three kinds Mode：The autophagy that big autophagy (macroautophagy), small autophagy (microautophagy) and molecular chaperones mediate (chaperone-mediated autophagy,CMA).Big autophagy mainly has following characteristics：(1) development process is rapid；(2) The inducibility of autophagy；(3) batch is degraded；(4) non-selectivity swallows；(5) conservative of autophagy；Other two kinds of autophagy and it is big from The main distinction bitten is：Small autophagy is lysosome membrane self-deformation, then wraps up the substrate in phagocyte slurry；And molecule companion The autophagy that companion mediates then can selectively protein degradation.There are research overview big autophagy (hereinafter referred to as autophagy) and tumour Development and treatment relationship the most closely [Sridhar S, Botbol Y, MacianF, et al.Autophagy and disease:always two sides to a problem.J Pathol.2012；226(2):255-73.]；Autophagy is born of the same parents The biological process that slurry macromolecular substances and organelle are largely degraded in duplicature packing bubble, is divided into 4 stages：1. in famine Under the stimulations of certain factors such as hungry, anoxic, interfering effects of drug, the double membrane structure of autophagic vacuole starts to gradually form and be enclosed in be dropped It solves around object, 2. autophagic vacuoles form completely and the substance that will be degraded is completely isolated in cytoplasm, 3. autophagosomes and lyase Body merges to form autophagy lysosome, and 4. autophagy lysosomes are finally dissolved by the hydrolase in lysosome, and catabolite can be thin Recycling intracellular, [Mart í nez-Borra J, L ó pez-Larrea C.Autophagy and self- defense.AdvExp Med Biol.2012；738:169-84.]；
Studies have shown that autophagy can change cell to external environment and various stimulations generate stress reaction.Cell is being grown Under the conditions of the autophagy of reduced levels can occur, also referred to as basic autophagy, however, once by extraneous stimulation, such as starvation, anoxic, High temperature, high-cell density or growth factor are deprived, and the level of cell autophagy will raise rapidly, are such as lacked in nutriment In the case where, non-viable non-apoptotic cell device generates amino acid etc. and synthesizes new protein for cell in cell autophagy energy decomposer, remains thin Survival [1. Piacentini M, D'Eletto M, Falasca L, et al.Transglutaminase the 2at the of born of the same parents crossroads between cell death and survival.AdvEnzymolRelat Areas Mol Biol.2011；78:197-246；②Cook KL,Shajahan AN,Clarke R.Autophagy and endocrine resistance in breast cancer.Expert Rev Anticancer Ther.2011；11(8):1283-94.；③ Wirawan E,VandenBerghe T,Lippens S,et al.Autophagy:for better or for worse.Cell Res.2012；22(1):43-61.]；However, one kind as apoptosis, cell autophagy can lead to Crossing number of ways either directly or indirectly leads to cell death, and this killing may be by inducing cell apoptosis, necrosis, aging etc. Mechanism occurs, it is also possible to make cell that autophagy death [Denton D, Nicolson S, Kumar S.Cell directly occur death by autophagy:facts and apparent artefacts.Cell Death Differ.2012；19(1): 87-95.]。
Since there are potential drug resistances for Hedgehog signal pathway inhibitor treatment tumour, this is limited to a certain extent Its application；Existing kinds of tumors, which is reported, has tolerance for the treatment of Hedgehog signal pathway inhibitor, wherein wrapping Include basal-cell carcinoma and lung cancer.
Status based on the prior art, present inventor is quasi- to provide a kind of compound medicine or pharmaceutical composition to overcome Inhibition problem existing for such drug；Especially provide made of Hedgehog signal pathway inhibitor and cell autophagy inhibitor Pharmaceutical composition or compound medicine.
Summary of the invention
The object of the present invention is to provide a kind of new antitumor synergism medicine composition and preparation method thereof, especially one Kind is with pharmaceutical composition or compound medicine made of Hedgehog signal pathway inhibitor and cell autophagy inhibitor.
In the present invention, by a kind of Hedgehog signal pathway inhibitor and one or more cell autophagy inhibitor group patent medicine Compositions or compound medicine；Its solve key technical problem be by one or more methods promoted tumour cell for The sensibility of Hedgehog signal pathway inhibitor, to generate stronger antitumor curative effect.
Administering drug combinations can be used in pharmaceutical composition of the invention or the sequential mode used uses, for treating lung cancer, liver Cancer, the treatment of gastric cancer, the carcinoma of the rectum, melanoma, leukaemia and lymthoma.
More specifically, one kind of the invention is with medicine made of Hedgehog signal pathway inhibitor and cell autophagy inhibitor Compositions or compound medicine are made of the inhibitor and cell autophagy inhibitor of one or more Hedgehog signal paths； The pharmaceutical composition or compound medicine, which uses sequential use or mode is used in combination, can enhance the suppression of Hedgehog signal path The curative effect of preparation.
In the present invention, Hedgehog signal pathway inhibitor includes but is not limited to：Vismodegib, Cyclopamine (cyclopamine)、sonidegib(LDE225)、BMS-833923、PF04449913、LEQ506、TAK-441、 LY2940680, Robotnikinin, GANT61, GANT58, HIP-1, HIP-2, HIP-3 and HIP-4, the embodiment of the present invention In preferred Hedgehog signal pathway inhibitor be vismodeigb.
In the present invention, cell autophagy inhibitor includes but is not limited to：Chloroquine (Chloroquine) and hydroxychloroquine (hydroxychloroquine), 3-MA (3-Methyladenine), wortmannin (wortmannin), LY294002, put Line bacterium ketone, Bava Lip river mycin A1 (Bafilomycin A1), ammonium chloride (NH4) or combinations thereof Cl object, in the embodiment of the present invention Preferred cell autophagy inhibitor is chloroquine.
In the present invention, the compound medicine can also be prepared by mixing into nano compound drug with nano-carrier, further Enhance its curative effect, wherein using liposome, soft phosphatide, PAMAM, mesoporous silicon as nano-carrier, preferably nano-carrier is lipid Body.
Pharmaceutical composition or compound medicine of the invention is for treating tumour；The tumour include but is not limited to lung cancer, Liver cancer, gastric cancer, the carcinoma of the rectum, melanoma, leukaemia and lymthoma；Preferably lung cancer, including Small Cell Lung Cancer and non-small cell Lung cancer.
The present invention provides a kind of Hedgehog signal pathway inhibitors and one or more cell autophagy inhibitor to form Pharmaceutical composition or compound medicine can promote tumour cell for the sensibility of Hedgehog signal pathway inhibitor, to produce Raw stronger antitumor curative effect, especially be administered in combination or the sequential mode used for treat lung cancer, liver cancer, it is gastric cancer, straight Intestinal cancer, melanoma, leukaemia and lymthoma.Pharmaceutical composition preparation process of the invention is simple, be suitble to large-scale production and Preparation.
Detailed description of the invention
Fig. 1, pharmaceutical composition are thinner to A549 (A) and NCI-H1975 (B) non-small cell lung cancer than simple Vismodegib Born of the same parents have stronger lethal effect.
The transplantable tumor internal anatomy of Fig. 2, A549 (A) and NCI-H1975 (B).
The tumor growth curve of Fig. 3, A549 (A) and NCI-H1975 (B).
Fig. 4, cell autophagy inhibitor chloroquine and Vismodegib more simple Vismodegib are in treatment non-small cell lung There is better curative effect in cancer A549 (A) and NCI-H1975 (B) transplantable tumor.
Specific embodiment
Embodiment 1. prepares pharmaceutical composition
Prepare cell autophagy inhibitor solution：Appropriate chloroquine is taken to be dissolved in the storing liquid that PBS is made into 10mg/mL, with 0.1 μm After filter filtration sterilization, and be packed as 100 μ L/ branch, one every time when use, subcutaneous or intraperitoneal injection for inhibit in vivo from It bites；It takes appropriate hydroxychloroquine to be dissolved in the storing liquid that PBS is made into 10mg/mL, after 0.1 μm of filter filtration sterilization, and is packed as 100 μ L/ branch, one every time when use, subcutaneous or intraperitoneal injection for inhibiting autophagy in vivo；It takes appropriate 3-MA to be dissolved in PBS and is made into 4mg/ The storing liquid of mL after 0.1 μm of filter filtration sterilization, and is packed as 100 μ L/ branch, used for intravenous injection one every time when use In inhibition autophagy in vivo；
Prepare Hedgehog signal pathway inhibitor：It takes appropriate Vismodegib to be dissolved in 25% HP- β-CD solution to make At the solution of 10mg/mL, and 100 μ L/ branch are packed as, one every time when use, is administered orally for inhibiting Hedgehog signal Access；It takes appropriate Cyclopamine to be dissolved in 25% HP- β-CD solution and the solution of 10mg/mL is made, and be packed as 100 μ L/ branch, make It used time one every time, is administered orally for inhibiting Hedgehog signal path；Appropriate Sonidegib is taken to be dissolved in 25% HP- β- The solution of 10mg/mL is made in CD solution, and is packed as 100 μ L/ branch, one every time when use, is administered orally for inhibiting Hedgehog signal path；
Prepare Hedgehog signal pathway inhibitor and cell autophagy inhibitor compound：
Prepare Vismodegib and chloroquine preparation compound：Vismodegib is dissolved in the aqueous solution of 25%HP- β-CD extremely Chloroquine powder is dissolved in wherein later and chloroquine final concentration is made to reach 10mg/mL by 10mg/mL, is freeze-dried after all dissolutions, Powder is collected completely and capsule is made；It is used for oral or stomach-filling；
Prepare Vismodegib and hydroxychloroquine preparation compound：Vismodegib is dissolved in the aqueous solution of 25%HP- β-CD extremely Hydroxychloroquine powder is dissolved in wherein later and hydroxychloroquine final concentration is made to reach 10mg/mL by 10mg/mL, freezes after all dissolutions It is dry, powder is collected completely and capsule is made；It is used for oral or stomach-filling；
Prepare Vismodegib and 3-MA preparation compound：Vismodegib is dissolved in the aqueous solution of 25%HP- β-CD extremely 3-MA powder is dissolved in wherein later and 3-MA final concentration is made to reach 4mg/mL by 10mg/mL, is freeze-dried after all dissolutions, Powder is collected completely and capsule is made；It is used for oral or stomach-filling；
Tumor killing effect experiment：The pharmaceutical composition being made of Hedgehog signal pathway inhibitor and cell autophagy inhibitor It can more effective killing tumor cell：
After inhibiting autophagy by three kinds of different cell autophagy inhibitor, either A549 (as shown in Figure 1A) as the result is shown Or NCI-H1975 cell (as shown in Figure 1B) starts the processing of Vismodegib to become sensitive；With 30 μM After Vismodegib handles 72h, 40% is fallen below hereinafter, and individually using added with the cell viability of the group of autophagy inhibitor Vismodegib processing cell is only capable of that cell viability is made to drop to 81.4% (NCI-H1975) and 76.3% (A549), and the two is deposited In significant difference.
The pharmaceutical composition that embodiment 2 is made of Hedgehog signal pathway inhibitor and cell autophagy inhibitor is in nude mice Inhibit the zoopery of the growth of non-small cell lung cancer in vivo
BALB/c nude mice (male, 6 weeks) raising is weighed in after a week reaches 20g ± 2g for transplantable tumor modeling.A549 Cell presses 5 × 106cells/mouse；NCI-H1975 presses 1 × 107Cells/mouse inoculation nude mice by subcutaneous is simultaneously divided by N=7 at random It is 5 groups, specially Vehicle (negative control group), CQ (CQ is injected intraperitoneally merely), Vismodegib (simple oral stomach-filling Vismodegib), Vismodegib (Vismodegib and CQ combination group) and cyclophosphamide (oral cyclophosphamide), wherein comforting The cyclodextrin (Vismodegib solvent) and/or intraperitoneal injection PBS that agent is oral 25%, tumour is long to 75mm after a week3± 15mm3Start to be administered；
When control group tumour is long to 800~1200mm3When (28 days), put to death mouse and simultaneously take subcutaneous tumor, experiment carries out It is the CQ and control group of middle A549 transplantable tumor each dead two, the CQ and control group of NCI-H1975 each dead one, last resulting Tumour internal anatomy is as shown in Fig. 2, the growth curve of each group tumour is as shown in Figure 3 simultaneously；The experimental results showed that with cell experiment As a result similar, A549 and NCI-H1975 transplantable tumor treats tolerance to simple Vismodegib, and Vismodegib and CQ is combined But the growth of internal transplantable tumor can effectively be inhibited, curative effect is better than cyclophosphamide (CTX), while the individually mouse of intraperitoneal injection CQ Intracorporal tumour compares for control group, and there is no apparent differences, it was demonstrated that inhibits cell autophagy that can enhance in vivo Fragmentation effect of the Vismodegib to non-small cell lung cancer；
Meanwhile weighing to transplantable tumor, as a result as shown in figure 4, when experiment was carried out to 28 days：
The control group exemplary embodiment lock of A549 transplantable tumor is 1153mg, and the control group tumour of NCI-H1975 transplantable tumor is flat Equal weight is 803mg；
The CQ group exemplary embodiment lock of A549 transplantable tumor is 1039mg, and the CQ group tumour of NCI-H1975 transplantable tumor is averagely heavy Amount is 797mg；
The exemplary embodiment lock of the Vismodegib group of A549 transplantable tumor is 806mg, NCI-H1975 transplantable tumor The exemplary embodiment lock of Vismodegib group is 574mg；
Vismodegib the and CQ combination group exemplary embodiment lock of A549 transplantable tumor is 397mg, NCI-H1975 transplantable tumor Vismodegib and CQ combination group exemplary embodiment lock is 158mg；
The CTX group exemplary embodiment lock of A549 transplantable tumor is 614mg, and the CTX group tumour of NCI-H1975 transplantable tumor is averagely heavy Amount is 232mg；
Experiment, which confirms, inhibits cell autophagy that can greatly improve Vismodegib to the curative effect of non-small cell lung cancer, and thin Inhibitory rate associated with born of the same parents' autophagy inhibitor and Vismodegib is to 65.6% (A549 transplantable tumor) and 80.3% (NCI- H1975 cell), there is significant tumor killing effect.

Claims (10)

1. a kind of antitumor synergism medicine composition, it is characterised in that：Described pharmaceutical composition (1) is by one or more The inhibitor and cell autophagy inhibitor of Hedgehog signal path form；(2) it is logical to enhance Hedgehog signal for sequential use The curative effect of road inhibitor.
2. antitumor synergism medicine composition according to claim 1, it is characterised in that：The Hedgehog signal is logical Road inhibitor is selected from：Vismodegib, Cyclopamine (cyclopamine), sonidegib (LDE225), BMS-833923, PF04449913、LEQ506、TAK-441、LY2940680、Robotnikinin、GANT61、GANT58、HIP-1、HIP-2、 HIP-3 or HIP-4.
3. antitumor synergism medicine composition according to claim 1, it is characterised in that：The cell autophagy inhibitor It is selected from：It is chloroquine (Chloroquine) and hydroxychloroquine (hydroxychloroquine), 3-MA (3-Methyladenine), wet Graceful penicillin (wortmannin), LY294002, cycloheximide, Bava Lip river mycin A1 (Bafilomycin A1), ammonium chloride (NH4) or combinations thereof Cl object.
4. antitumor synergism medicine composition as described in claim 2, it is characterised in that：The Hedgehog signal is logical Road inhibitor is vismodeigb.
5. antitumor synergism medicine composition according to claim 3, it is characterised in that：The cell autophagy inhibitor It is chloroquine.
6. antitumor synergism medicine composition according to claim 1, it is characterised in that：The pharmaceutical composition is made The curative effect that can promote Hedgehog signal path is used in combination in compound medicine.
7. antitumor synergism medicine composition according to claim 6, it is characterised in that：The compound medicine and nanometer Carrier is prepared by mixing into nano compound drug.
8. antitumor synergism medicine composition according to claim 7, it is characterised in that：In the nano compound drug Nano-carrier be selected from：Liposome, soft phosphatide, PAMAM or mesoporous silicon.
9. antitumor synergism medicine composition according to claim 8, it is characterised in that：The nano-carrier is lipid Body.
10. antitumor synergism medicine composition according to claim 1, it is characterised in that：The tumour is lung cancer, liver Cancer, gastric cancer, the carcinoma of the rectum, melanoma, leukaemia or lymthoma.
CN201710330477.XA 2017-05-11 2017-05-11 A kind of antitumor synergism medicine composition and its preparation method and application Pending CN108853507A (en)

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CN105163720A (en) * 2013-02-01 2015-12-16 佐尼奥尼制药股份有限公司 Remote loading of sparingly water-soluble drugs into liposomes
CN104324035A (en) * 2013-07-23 2015-02-04 复旦大学 Composition of autophagy inhibitor and lapatinib, and application thereof
CN106999419A (en) * 2014-08-04 2017-08-01 佐尼奥尼制药股份有限公司 Remote loading sparingly water-soluble medicine is to lipid film bubble
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Publication number Priority date Publication date Assignee Title
CN111821458A (en) * 2019-04-18 2020-10-27 复旦大学 Pharmaceutical composition for treating non-small cell lung cancer

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