CN107095873A - Anti-lung cancer targeted medicament composition with low drug resistance - Google Patents
Anti-lung cancer targeted medicament composition with low drug resistance Download PDFInfo
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- CN107095873A CN107095873A CN201710507221.1A CN201710507221A CN107095873A CN 107095873 A CN107095873 A CN 107095873A CN 201710507221 A CN201710507221 A CN 201710507221A CN 107095873 A CN107095873 A CN 107095873A
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- lung cancer
- mesylate
- buddhist nun
- understand
- drug resistance
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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
- A61K31/395—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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Abstract
The anti-lung cancer targeted medicament composition with low drug resistance is more particularly related to the invention belongs to pharmaceutical technology field, includes the medicine and Bergenin of anti-non-small cell lung cancer, the medicine of its moderate resistance non-small cell lung cancer is primarily referred to as difficult to understand this and replaces Buddhist nun's mesylate.After technical scheme disclosed by the invention, can effectively improve it is difficult to understand this for affinity of Buddhist nun's mesylate to non-small cell lung cancer cell, other normal tissue cells are not influenceed and toxic side effect simultaneously, difficult to understand this shares for Buddhist nun's mesylate and Bergenin to be expected to turn into a kind of efficient target medicine for being directed to non-small cell lung cancer.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to the pharmaceutical technology field of tumour, more particularly relate to
Anti-lung cancer targeted medicament composition with low drug resistance.
Background technology
Lung cancer is that morbidity and mortality growth is most fast, to one of population health and the maximum malignant tumour of life danger.
So far not completely clearly, its clinical manifestation is more complicated the cause of disease of lung cancer, the presence or absence of sings and symptoms, weight and appearance
Sooner or later, depending on tumour happening part, case type, whether there is transfer and whether there is that complication is relevant, while also to consider patient's
The difference of the extent of reaction and tolerance.
The therapeutic modality of lung cancer includes chemotherapy, radiotherapy and surgical intervention.Lung cancer does not often have in early stage
Obvious symptom, show and when being diagnosed when it illness occurs, has been usually that Locally Advanced or late period can not hands
The situation of art excision.In general, patient when being diagnosed to be lung cancer only less than 20% is in can be by surgery excision focus
Early stage, most patient has had already passed by the best opportunity of surgery excision.
Clinically, lung cancer is generally divided into ED-SCLC and non-small cell lung cancer two types, in clinical cases of lung cancer,
Non-small cell lung cancer accounts for 80%, and lung squamous cancer, adenocarcinoma of lung are also included among these.Therefore, it is for the Therapy study of small cell carcinoma of lung
Capture the research emphasis of lung cancer.
In current clinical practice, miss surgical resection focus for those and come so as to effect a radical cure the patient of lung cancer
Say, systemic chemotherapy is the main policies of non-small cell lung cancer multidisciplinary synthesis treatment.At present, conventional chemotherapeutic material
Including cis-platinum plus taxotere, taxol, NVB etc..
These materials are respectively provided with cytotoxicity, and kill tumour cell dependent on cytotoxicity, but its act on it is swollen
During oncocyte, normal tissue cell is inevitably hurt.The targeted drug studied at present is it is possible to prevente effectively from this feelings
Condition, by specific effect in the Cell signal transduction pathway of tumour growth, suppresses propagation, the transfer of tumour cell, so as to reduce pair
The attack of other normal tissue cells, mitigates adverse reaction, can improve the tolerance degree of patient.
Ao Si is for the anti-cancer agent that Buddhist nun's mesylate is Astrazeneca AB's research and development, trade name Tagrisso.Ao Si
For the chemical entitled N- of Buddhist nun's mesylate（2-（N-（2-（Dimethylamino）And）- N- methylaminos）- 4- methoxyl groups -5-
（（4-（1- Methyl-1H-indole -3- bases）Pyrimidine -2-base）Amino）Phenyl）Acrylamide mesylate, its chemical structural formula is：
,
Ao Si is EGFR inhibitor for Buddhist nun's mesylate.The medicine listing that gone through in the U.S. is used for
Treat EGFR mutation or to the patients with advanced NSCLC of other EDFR inhibitor resistances.
It will be appreciated that the medicine shows stronger drug resistance in some cases, its mechanism is still not clear, and is
Give full play to it is difficult to understand this for selective killing effect of Buddhist nun's mesylate to lung cancer tumor cell, it is just necessary to find new plan
Slightly reverse this drug resistance, improve non-small cell lung cancer cell strain and the susceptibility of Buddhist nun's mesylate is replaced to difficult to understand this, so as to improve
Its application, reaches the purpose of effectively treatment non-small cell lung cancer.
Bergenin is the main active in natural plants purple bergenia herb, is a kind of Dihydroiso-coumarin class compound,
Its structural formula is as follows：
。
Bergenin is typically used for antisussive and expectorant agent, the treatment for chronic bronchitis.With the continuous depth of research
Enter, it has been found that the compound is distributed in various plants.Simultaneously as Bergenin is extracted from different plants
Out, by these originating species, we further develop to the function of Bergenin and probed into.
Also suppress tumor cell proliferation there are some researches show bergenin derivative has in recent years, include Bergenin
Ethanol is extracted for gastric carcinoma cell lines BGC-823, lung carcinoma cell Calus-6 and stomach cancer cell SUN-601 and S-180 tumour
Cell is respectively provided with inhibitory action.Thus these disclosures show that the material has necessarily potential excellent in tumour medicine exploitation
Gesture.
But, not yet having Bergenin and Austria at present, this cooperates with the research precedent used for Buddhist nun's mesylate.
The content of the invention
Buddhist nun's methanesulfonic acid is replaced the invention discloses a kind of anti-lung cancer targeted medicament composition with low drug resistance, including difficult to understand this
Salt and Bergenin.
Further, the mass ratio of Buddhist nun's mesylate and Bergenin is replaced to be 10 we also disclosed difficult to understand this:1~10.
Meanwhile, further, we also disclosed include this anti-lung cancer targeted drug group with low drug resistance
The medicine type of compound, i.e., comprising acceptable auxiliary on anti-lung cancer targeted medicament composition and pharmacy with low drug resistance
Material.
Preferably, our open described anti-lung cancer targeted drug preparations are liposome, the anti-lung cancer with low drug resistance
Mass ratio between targeted medicament composition and phosphatide is 1 ~ 10:100.
Meanwhile, we further disclose the preparation method of anti-lung cancer target liposomes, comprise the following steps, and first will
Anti-lung cancer targeted medicament composition with low drug resistance is dissolved in 20 times（W/v）Ethanol solution in, then shake
Phosphatide is instilled under the conditions of swinging, phosphatide continues to shake 10min after the completion of adding, and removes ethanol solution with Rotary Evaporators afterwards, and
Phosphate buffer is added thereto, and ultrasonically treated rear filtration sterilization is produced.
Concussion condition realizes that the concussion frequency of regulation shaking table, is preferred with 2 times/second as needed generally by shaking table.Phosphorus
The instillation of fat can be according to parcel situation adjustment, and as a rule 1 ~ 2 drop/sec of speed is that we are recommended.After the completion of addition
Concussion can be appropriate raising concussion frequency, for example we generally improved to 4 ~ 5 times/second.Rotary Evaporators can be realized
Close to the low-pressure state of vacuum, so as to farthest protect the activity of Bergenin in liposome.
After technical scheme disclosed by the invention, difficult to understand this can be effectively improved and replace Buddhist nun's mesylate to non-small cell lung cancer
The affinity of cell, while not influenceed on other normal tissue cells and toxic side effect, difficult to understand this replaces Buddhist nun's mesylate and rock white
Dish element, which is shared, to be expected to turn into a kind of efficient target medicine for being directed to non-small cell lung cancer.
Brief description of the drawings
Fig. 1 is Bergenin and Ao Si for the common influence datagram to A549 Apoptosis of Buddhist nun's mesylate；
Fig. 2 is that Bergenin Selective long-range DEPT non-small cell lung cancer cell replaces Buddhist nun's mesylate affinity data figure to difficult to understand this.
Embodiment
Bergenin extracts separation by this laboratory and obtained, extraction separation method cf. publication.（For example：Wang Junping,
Assay [J] Chinese patent drugs of Bergenin, 1991,13 in the China of Lee hundred, Rodgersia podophylla A. Grays（2））.
Not specified material is commercially available prod in the present invention.
Embodiment 1
Lung cell A549 is cultivated in DMEM and 10% hyclone nutrient solution, condition of culture is 37 DEG C, 5%
CO2 moistening gnotobasis.When cell length to 80%-90% is merged, washed with PBS 2 times, the digestion of 0.25% pancreatin.By thin
Born of the same parents measure 6 × 104/ holes and are inoculated in 24 porocyte culture plates.
It is respectively that difficult to understand this replaces Buddhist nun mesylate 50ng/ml after after cell attachment growth completely, adding medicine, difficult to understand this replaces Ni Jia
Sulfonate 100ng/ml；Bergenin 10nM, difficult to understand this replaces Buddhist nun mesylate 50ng/ml+ Bergenin 10nM, and difficult to understand this replaces Buddhist nun's first sulphur
Hydrochlorate 100ng/ml+ Bergenins 10nM；Bergenin 100nM, difficult to understand this replaces Buddhist nun's mesylate 50ng/ml+ Bergenins
100nM, difficult to understand this replaces Buddhist nun's mesylate 100ng/ml+ Bergenins 100nM；Bergenin 1000nM, difficult to understand this replaces Buddhist nun's mesylate
50ng/ml+ Bergenin 1000nM, difficult to understand this replaces Buddhist nun's mesylate 100ng/ml+ Bergenins 1000nM；Bergenin
10000nM, difficult to understand this replaces Buddhist nun mesylate 50ng/ml+ Bergenin 10000nM, and difficult to understand this replaces Buddhist nun's mesylate 100ng/ml+ rocks white
Dish element 10000nM；Every group of 3 holes, cell is collected after drug-treated 12h, is washed with precooling PBS 2 times, adds EGFP marks
AnnexinV (2 μ L), is incubated 20min on ice, is rapidly added PI (1 μ g/mL), in detection Apoptosis feelings on flow cytometer
Condition, AnnexinV (+)/PI (-) is viable apoptotic cell.
As a result：A549 cells are investigated using the double dye methods of AnnexinV/PI the sensitiveness of Buddhist nun's mesylate is replaced to difficult to understand this, find
In the presence of without Bergenin, difficult to understand this can cause fraction A549 thin for Buddhist nun's mesylate 50ng/ml or 100ng/ml
Born of the same parents' apoptosis (Fig. 1), when adding Bergenin concentration≤100nM, the A549 Apoptosis that Buddhist nun's mesylate is induced is replaced to difficult to understand this
Synergistic effect is not strong, but when adding rotenone concentration ＞ 100nM, it can be clearly seen that Bergenin significantly increases difficult to understand this and replaced
The A549 Apoptosis of Buddhist nun's mesylate induction, such as in Bergenin 1000nM, can replace Buddhist nun's mesylate 100ng/ by difficult to understand this
The Apoptosis of ml inductions brings up to 26.8% by 15.3%, similarly, in 10 μM of Bergenin, difficult to understand this can be replaced into Buddhist nun's first sulphur
The Apoptosis of hydrochlorate induction brings up to 72.5% by 25.3%, thus, and (100nM-10 μM) of Bergenin can conspicuousness enhancing
Ao Si is for compatibility of Buddhist nun's mesylate to A549 cells.
Embodiment 2
By HEK293 cells and A549 cells respectively at being cultivated in the nutrient solution that DMEM and 10% hyclone are mixed, cultivate
Condition is 37 DEG C, 5%CO2 moistening gnotobasis.Cell length to 80%-90% merge when, washed with PBS 2 times, 0.25% pancreas
Enzymic digestion.It is inoculated in by the hole of cell concentration 5 × 103/ in 96 porocyte culture plates.Add difficult to understand this and replace Buddhist nun's mesylate 100ng/ml+
After 1 μM of processing 12h of Bergenin, 3 holes of every group of repetition, processing 12h, cell is collected, is examined in the way of disclosed in embodiment one
Survey A549 and HEK293 Apoptosis.
As a result：With reference to Fig. 2, in the case of substantially induction A549 Apoptosis, difficult to understand this replaces Buddhist nun's mesylate and purple bergenia herb
The mixture of element, without obvious toxicity, illustrates that difficult to understand this has for Buddhist nun's mesylate with Bergenin to tumour to normal cell HEK293
There is obvious selectivity, be the therapeutic scheme with DEVELOPMENT PROSPECT.
Embodiment 3
The preparation method of anti-lung cancer target liposomes, comprises the following steps, and replaces Buddhist nun's mesylate and 5g rocks white difficult to understand these of 10g first
Dish element is dissolved in 300ml ethanol solution, and phosphatide is then instilled under the concussion frequency of time/second of earthquake condition 2, and phosphatide is added
After the completion of continue to shake 10min, concussion frequency is 4 ~ 5 times/second, afterwards with Rotary Evaporators removal ethanol solution, and thereto
Phosphate buffer is added, ultrasonically treated rear filtration sterilization is produced.
The experiment of envelop rate and stability is carried out to liposome, as a result shows that Ao Si in liposome replaces the bag of Buddhist nun's mesylate
Envelope rate is 98%, and the envelop rate of Bergenin is 96%, illustrates that liposome encapsulation is good.Meanwhile, liposome places 6 at room temperature
Nodeless mesh is redissolved with water to separate out and without coherent condition, show that stability is good after individual month.
Claims (5)
1. the anti-lung cancer targeted medicament composition with low drug resistance, it is characterised in that：Buddhist nun's mesylate and rock are replaced including difficult to understand this
Chinese cabbage element.
2. the anti-lung cancer targeted medicament composition according to claim 1 with low drug resistance, it is characterised in that：Ao Si is replaced
The mass ratio of Buddhist nun's mesylate and Bergenin is 10:1~10.
3. a kind of anti-lung cancer targeted drug preparation, it is characterised in that：Including there is low drug resistance described in claim 1 or 2
Anti-lung cancer targeted medicament composition and pharmacy on acceptable auxiliary material.
4. anti-lung cancer targeted drug preparation according to claim 3, it is characterised in that：Described anti-lung cancer targeted drug system
Agent is liposome, and the mass ratio between anti-lung cancer targeted medicament composition and phosphatide with low drug resistance is 1 ~ 10:100.
5. the preparation method of anti-lung cancer target liposomes, it is characterised in that：Comprise the following steps, first by anti-lung cancer targeting lipids
Body is dissolved in 20 times of ethanol solution, and phosphatide is then instilled under the conditions of earthquake, and phosphatide continues to shake after the completion of adding
10min, removes ethanol solution with Rotary Evaporators afterwards, and adds phosphate buffer thereto, and ultrasonically treated rear cross filters out
Bacterium produces.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710507221.1A CN107095873A (en) | 2017-06-28 | 2017-06-28 | Anti-lung cancer targeted medicament composition with low drug resistance |
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| Application Number | Priority Date | Filing Date | Title |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103181897A (en) * | 2011-12-30 | 2013-07-03 | 沈阳药科大学 | Gefitinib liposome preparation and preparation method thereof |
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN106632373A (en) * | 2016-09-30 | 2017-05-10 | 陕西科技大学 | A D crystal form solid substance of bergenin, a preparing method thereof and uses of the substance |
-
2017
- 2017-06-28 CN CN201710507221.1A patent/CN107095873A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
| CN103181897A (en) * | 2011-12-30 | 2013-07-03 | 沈阳药科大学 | Gefitinib liposome preparation and preparation method thereof |
| CN106632373A (en) * | 2016-09-30 | 2017-05-10 | 陕西科技大学 | A D crystal form solid substance of bergenin, a preparing method thereof and uses of the substance |
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Application publication date: 20170829 |