CN106539757A - Application of the ring dinucleotide cGAMP- liposomees in antitumor - Google Patents
Application of the ring dinucleotide cGAMP- liposomees in antitumor Download PDFInfo
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- CN106539757A CN106539757A CN201610155697.9A CN201610155697A CN106539757A CN 106539757 A CN106539757 A CN 106539757A CN 201610155697 A CN201610155697 A CN 201610155697A CN 106539757 A CN106539757 A CN 106539757A
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- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
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Abstract
The invention belongs to applications of the ring dinucleotide cGAMP of pharmaceutical technology field, specially liposome in antitumor.The cGAMP slow releasing pharmaceuticals of liposome can suppress the growth of kinds of tumor cells, can be used to prepare antitumor slow releasing pharmaceutical；, than single cGAMP antitumor good drug efficacy, better than the antitumous effect that cGAMP is used alone, also superior to 5 FU of positive drug, and the acute toxicity of liposome cGAMP slow releasing pharmaceuticals is low for prepared cGAMP liposome slow release antitumor drug.Therefore, the cGAMP of liposome can be used to prepare antitumor slow releasing pharmaceutical.
Description
Technical field
The invention belongs to biomedicine technical field is specifically related to a kind of ring dinucleotide cGAMP- liposomees in antitumor
In and application in antitumor drug is prepared.
Background technology
Tumor is one of major disease of a class serious harm human life and health, shows as cell hyperproliferation and differentiation
It is abnormal.WHO scholarly forecasts, the year two thousand twenty population in the world tumor invasion are up to 2 000 ten thousand people, and death toll is up to 1 200 ten thousand
People, tumor will become the first killer of this century mankind, constitute the threat of most serious to human survival.Pulmonary carcinoma, knot/rectal cancer, stomach
The M ＆ M of cancer, hepatocarcinoma etc. occupies the prostatitis of all kinds of malignant tumor.(2012 issued according to national tumor Register
China's tumour registration annual report》Statistics, annual kainogenesis tumor cases about 3,120,000, average daily 8 550 people, the whole nation per point
Clock has 6 people to be diagnosed as cancer.From the point of view of disease, pulmonary carcinoma, gastric cancer, knot/rectal cancer, hepatocarcinoma and the esophageal carcinoma occupy the whole nation pernicious swollen
First five position of tumor morbidity.With the increase year by year of Cancer Mortality and mortality rate, treating malignant tumor demand is increasing.
Chemotherapy is to treat one of effective ways of tumor.The mechanism of action of classic chemotherapy medicine mainly prevents deoxyribose
The synthesis of nucleic acid (DNA), ribonucleic acid (RNA) or protein, or directly these macromole are had an effect, so as to suppress tumor
The division growth of cell, is allowed to dead.Some medicines can also suppress tumour growth by changing hormone in vivo balance.At present
Antitumor drug has developed to 6 big class：1. antimetabolite；2. alkylating agent；3. cytotoxin class antibiotic；4. plant biological
Alkali and other crude drugs；5. antitumor hormoness；6. platinum class and other antineoplastic agents.With clinical treatment pattern transformation and
The discovery of some new antitumor drug target spots, the research and development of field of antineoplastic medicaments there occurs great variety：With regard to the effect of medicine
For mechanism, the targeted drug exploitation of non-cytotoxicity class has been turned to from traditional nonspecific cytotoxic drug.2012
In the antitumor drug of FDA approvals, small molecule tyrosine kinase inhibitors (TKI) become the most popular class antineoplastic agent of research and development
Thing, especially acts on the TKI (accounting for 3/4) of multiple target spots, by the U.S. FDA of in June, 2013 approval TKI up to 18 kinds.
Additionally, other focus mechanism of action medicines include immunostimulant, angiogenesis inhibitor, cell cycle inhibitor, immunity suppression
Preparation and stimulant, kinases inhibitor etc..
In the mammalian cell of infection, microorganism and viral DNA can have by stimulating interferon secretion induction Inner source strengths
The immunne response of power.Endoplasmic reticulum（ER）Receptor protein（STING）It is required factor to the immunne response of cytoplasmic DNA.Nearest
Research shows, is cyclized cGMP-AMP dinucleotide synzyme（cGAS）Under activation condition after with reference to DNA, endogenously it is catalyzed
The synthesis of cGAMP.CGAMP is a kind of cytoplasmic DNA sensor, and it stimulates the sensing of INF- β as second message,second messenger by STING,
The activation of mediation TBK1 and IRF-3, and then start the transcription of INF- β genes.Report recently, cGAS is in DNA conjugation conditions for restructuring
Lower catalytic cyclization cGMP-AMP dinucleotide GAMP.CGAS is also reported with reference to the crystal structure of the complex of 18bp dsDNA
Road, researchs of the cGAMP in terms of antiviral immunity have been found to.CGAMP combines STING, transcription factor IRF3 is activated and is produced
Raw interferon-β.
Liposome sustained release drug delivery developed after tens years, achieved considerable to enter in antitumor field
Step.The membrane material for preparing liposome is mainly phospholipid and cholesterol etc., multiple Liposomal formulation listings existing at present, and in clinic
On achieve and be widely applied.Used as a kind of pharmaceutical carrier, liposome is extending drug half-life, is strengthening drug effect, targeting fixed point
The aspects such as administration have broad application prospects.
The content of the invention
It is an object of the invention to provide applications of the ring dinucleotide cGAMP of liposome in antitumor.
The present invention also aims to propose that the ring dinucleotide cGAMP slow releasing pharmaceuticals of liposome are preparing antitumor
Application in medicine, to prepare the antitumor drug that toxicity is low, effect is good.
Experimentation of the present invention shows that the ring dinucleotide cGAMP of liposome can suppress kinds of tumor cells
Growth, with obvious antitumor action, can be used to prepare antitumor drug.
The invention further relates to utilize the antineoplastic agent prepared by the ring dinucleotide cGAMP of liposome.
Specifically, the tumor is selected from pulmonary carcinoma, gastric cancer, hepatocarcinoma, colorectal carcinoma, melanoma, nephroncus, ovarian cancer, front
Row adenocarcinoma, bladder cancer, breast carcinoma, the esophageal carcinoma, colorectal cancer, nasopharyngeal carcinoma, the cerebral tumor, cervical cancer, leukemia, osteocarcinoma, lymphatic cancer, pancreas
Cancer etc..
Liposome of the present invention includes but is not limited to phospholipid etc..
Ring dinucleotide cGAMP of the present invention, is such as not added with explanation, refers to 2 ' 3 '-cGAMP or Cyclic [G
(2’,5’)pA(3’,5’)p]。
What the present invention was obtained has the beneficial effect that：
The ring dinucleotide cGAMP slow release antitumor drug of the liposome used by the present invention can extend cGAMP metabolism week
Phase, strengthen antineoplaston effect, better than positive drug 5-FU, and better than exclusive use cGAMP antineoplaston effects.
Specific embodiment
Present disclosure is illustrated below by embodiment.In the present invention, embodiments discussed below be in order to
The present invention is preferably illustrated, is not for limiting the scope of the present invention.
Embodiment 1：The preparation of the cGAMP slow release antitumor drug of liposome
cGAMP （Cyclisation-GMP-AMP）Under by activation condition of the literature method after with reference to DNA, by cyclisation bis- cores of cGMP-AMP
Thuja acid synzyme（cGAS）Catalyze and synthesize.Purity is more than 98%.（Li P.W, et al., Immunity, 2013,39
(6), 1019-1031.）Liposome prepares and wraps up cGAMP according to disclosed literature method, is prepared into liposome
CGAMP medicines, liposome preparation is broadly divided into following steps:Phospholipid etc. is dissolved in into organic solvent, lipid soln is formed, is removed
Organic solvent, forms lipid membrane, is then dispersed in thin film sonicated into homogeneous liposome in cGAMP aqueous solutions.
（Chen X., et al.,Int J Nanomedicine,2012,7:1139-1148; Waldrep J.C.,et al.,
Int J Pharm, 1998, 160(2):239-249）
Embodiment 2：The antitumor action of cGAMP slow releasing pharmaceuticals of detection liposome is carried out using lotus knurl mouse model i.e. to dynamic
The inhibitory action of thing subcutaneous transplantation tumor growth.
Animal
Kind, strain, sex, body weight, source, the quality certification
The common mice of BALB/c nude mices, BALB/c, the common mices of C57/BL6, male, body weight 16-18g, 6-8 week old, SPF
Level, is purchased from Shanghai Slac Experimental Animal Co., Ltd.'s [Quality of Experimental Animals quality certification number：SCXK （Shanghai）2007-0005
]。
Rearing conditions
All mices are freely looked for food and drink water, in room temperature（23±2）Raise at DEG C in army medical university of the Chinese People's Liberation Army
Experimental Animal Center.Feedstuff and the equal Jing autoclavings of water are processed, and all experimentss feeding process is SPF levels.
Dosage is arranged
Intravenous injection into mice, arranges 1 dosage group：10 mg/kg
Experimental control
Negative control：Normal saline solution
Positive control 1：5-fluorouracil（5-FU）, 10 mg/kg of dosage
Positive control 2：CGAMP, 10 mg/kg of dosage
Medication
Route of administration：Tail vein injection is administered
Administered volume：100 microlitres/only
Administration number of times：Once a day, continuous 21 days
Every group of number of animals：10
Tumor cell line
Human stomach cancer cell line MNK-45, human A459 lung cancer cell line, human colon cancer cell strain Lovo, human hepatoma cell strain
SMMC-7721, human prostate cancer cell line PC-3, human pancreatic cancer cell SW1990, mice colorectal cancer cell lines CT26, mice
Lung cancer Lewis tumor strain LL/2, is purchased from Chinese Academy of Sciences's cell bank.
Test key step
1. the foundation of tumor model Mus and intervention
Cell culture, passes on, and collects cell in the cell log phase, makes concentration for (1.0 × 107) per milliliter of cell suspension,
0.2 ml cell suspension is injected in mice right fore oxter, and (cell number is 2.0 × 106Individual/only), 10 d or so tumors length is to straight
About 5 mm of footpath, tumorigenesis success are divided into 4 groups at random.Four groups are respectively A：Negative control group（Intravenous injection physiological saline group）、B：
5-FU groups (intravenous injection 5-FU 10mg/kg groups), C：CGAMP groups (intravenous injection cGAMP) 10mg/kg, D：CGAMP- liposomees
Group (intravenous injection cGAMP groups) 10 mg/kg.It is administered once daily, successive administration 21 days.After 21 days, put to death mice and claim tumor body
Weight, tumour inhibiting rate=[the average knurl weight of 1- experimental grouies (B, C, D group is the experimental group)/average knurl weight of A groups)] × 100%.
8 kinds of subcutaneous transplantation tumor models are prepared respectively：Human stomach cancer cell line MNK-45, human A459 lung cancer cell line, people's knot
Colon-cancer cell strain Lovo, human hepatoma cell strain SMMC-7721, human prostate cancer cell line PC-3, human pancreatic cancer cell SW1990,
Nude mice is transplanted to, mice colorectal cancer cell lines CT26 is transplanted to the common mices of BalB/C, mice lung cancer Lewis tumor strain LL/
2, C57/BL6 mices are transplanted to, cGAMP- liposome medicament antitumous effects are observed.
2. statistical analysiss
Data are represented with x ± s, are processed using SPSS10.0 softwares, using one factor analysis of variance（one-way ANOVA）
The significance of each group knurl weight difference, significance level a=0.05 are compared in inspection.
As a result
Subcutaneous transplantation tumor model, cGAMP- liposomees, 5-FU and cGAMP are successfully prepared after mouse hypodermic inoculation tumor cell
Tumour growth, the knurl weight after being administered 21 days is substantially suppressed to be substantially less than negative control group（P<0.05, P<0.01）, cGAMP-
Liposome is better than 5-FU and cGAMP independent medications, shows that cGAMP- liposomees have more excellent antitumor action.Concrete outcome is shown in
Table 1- tables 8.
Effect of the 1 cGAMP- liposomees of table to nude mice human stomach cancer cell line MNK-45 subcutaneous transplantation tumors
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.528 ± 0.247（g） -
5-FU groups 0.746 ± 0.299（g）** 70.5
CGAMP groups 0.743 ± 0.121（g）** 70.6
CGAMP- liposomees group 0.417 ± 0.101（g）** 83.5
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups.
Effect of the 2 cGAMP- liposomees of table to nude mice human A459 lung cancer cell line subcutaneous transplantation tumor
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.439 ± 0.372（g） -
5-FU groups 0.843 ± 0.217（g）** 65.4
CGAMP groups 0.729 ± 0.132（g）** 70.1
CGAMP- liposomees group 0.514 ± 0.165（g）** 78.9
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups.
Effect of the 3 cGAMP- liposomees of table to xenografts in nude mice colon cancer cell line Lovo subcutaneous transplantation tumors
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.124 ± 0.243（g） -
5-FU groups 0.781 ± 0.243（g）** 63.2
CGAMP groups 0.714 ± 0.159（g）** 66.4
CGAMP- liposomees group 0.437 ± 0.167（g）** 79.4
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups.
Effect of the 4 cGAMP- liposomees of table to hepatocellular carcinoma xenografts in nude mice cell strain SMMC-7721 subcutaneous transplantation tumors
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.765 ± 0.234（g） -
5-FU groups 0.879 ± 0.236（g）** 68.2
CGAMP groups 0.788 ± 0.285（g）** 71.5
CGAMP- liposomees group 0.511 ± 0.112（g）** 81.5
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups.
Effect of the 5 cGAMP- liposomees of table to xenografts in nude mice ptostate cancer PC 3 cell line subcutaneous transplantation tumor
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.578 ± 0.267（g） -
5-FU groups 0.823 ± 0.212（g）** 68.1
CGAMP groups 0.855 ± 0.146（g）** 66.8
CGAMP- liposomees group 0.512 ± 0.111（g）** 80.1
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups.
Effect of the 6 cGAMP- liposomees of table to nude mice human pancreatic cancer cell SW1990 subcutaneous transplantation tumors
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.467 ± 0.243（g） -
5-FU groups 0.724 ± 0.232（g）** 70.7
CGAMP groups 0.741 ± 0.147（g）** 70.0
CGAMP- liposomees group 0.517 ± 0.121（g）** 79.0
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups.
Effect of the 7 cGAMP- liposomees of table to BalB/C Mus colorectal cancer cell CT26 subcutaneous transplantation tumors
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.244 ± 0.266（g） -
5-FU groups 0.765 ± 0.246（g）** 65.9
CGAMP groups 0.784 ± 0.185（g）** 65.0
CGAMP- liposomees group 0.439 ± 0.146（g）** 80.4
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups.
Effect of the 8 cGAMP- liposomees of table to C57 Mus lung cancer Lewis tumor strain LL-2 subcutaneous transplantation tumors
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.940 ± 0.337（g） -
5-FU groups 0.846 ± 0.298（g）** 71.2
CGAMP groups 0.828 ± 0.237（g）** 71.8
CGAMP- liposomees group 0.511 ± 0.132（g）** 82.6
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups.
The studies on acute toxicity of 3 cGAMP- liposomees of embodiment
Experiment material
ICR mices 20（It is purchased from Shanghai Slac Experimental Animal Co., Ltd.'s [Quality of Experimental Animals quality certification number：
SCXK （Shanghai）2007-0005 ] ）, male and female half and half, 18～22g of body weight, animal are fed with pellet, freely ingest and drink
Water.
CGAMP- liposomees are prepared by embodiment 1, with normal saline into the solution that concentration is 200 mg/mL.
Experimental technique
CGAMP- liposome slow releasing pharmaceutical of the ICR mices by body weight single tail vein injection 2g/kg, mice 14 after observation administration
Toxic reaction and death condition in it.As a result find, after the administration of mice single tail vein injection, mice activity is normal.Administration
Afterwards in 14 days, there is not death in mice, and the 15th day, whole sacrifices were dissected, and each internal organs of macroscopy are showed no obvious disease
Become.
Experimental result
Above-mentioned acute toxicity testing result shows that intravenous injection administration maximum tolerated dose MTD is not less than 2 g/Kg, explanation
The acute toxicity of cGAMP- liposome medicaments is low.
Claims (5)
- Application of the 1.cGAMP- liposomees in antitumor.
- Application of the 2.cGAMP- liposomees in antitumor drug is prepared.
- 3. application of the cGAMP- liposomees according to claim 2 in antitumor drug is prepared, it is characterised in that described Tumor includes but is not limited to gastric cancer, pulmonary carcinoma, colon cancer, hepatocarcinoma, carcinoma of prostate or cancer of pancreas etc..
- 4. using ring dinucleotide-liposome preparation slow release antitumor drug such as cGAMP.
- 5. liposome ring dinucleotide is used, slow releasing pharmaceutical is prepared, strengthens the disease-resistant drug effect of ring dinucleotide.
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| CN201610155697.9A CN106539757A (en) | 2016-03-20 | 2016-03-20 | Application of the ring dinucleotide cGAMP- liposomees in antitumor |
| PCT/CN2017/076383 WO2017162055A1 (en) | 2016-03-20 | 2017-03-12 | Application of cyclic dinucleotide cgamp-liposome for resisting tumours |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112957475A (en) * | 2021-02-04 | 2021-06-15 | 李文峰 | Composition for preventing and/or treating tumors and application thereof |
| CN114903856A (en) * | 2022-05-06 | 2022-08-16 | 四川大学华西医院 | 2 ', 3' -cGAMP-loaded liposome nano preparation and preparation method and application thereof |
| CN115252554A (en) * | 2021-05-01 | 2022-11-01 | 杭州星鳌生物科技有限公司 | Preparation and composition of novel 4 (3H) -quinazolinone analogue/cyclic dinucleotide cGAMP (cyclic-gated AMP) co-carried liposome and application of liposome in antitumor drugs |
| WO2022228469A1 (en) * | 2021-04-28 | 2022-11-03 | 苏州大学 | Polymersome nano-sting agonist, preparation method therefor, and application thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG10201912074PA (en) | 2016-03-18 | 2020-02-27 | Immune Sensor Llc | Cyclic di-nucleotide compounds and methods of use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014179760A1 (en) * | 2013-05-03 | 2014-11-06 | The Regents Of The University Of California | Cyclic di-nucleotide induction of type i interferon |
| CN104540945A (en) * | 2012-04-30 | 2015-04-22 | 格伦·N·巴伯 | Modulating immune responses |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| MX361680B (en) * | 2012-12-13 | 2018-12-13 | Aduro Biotech Inc | Compositions comprising cyclic purine dinucleotides having defined stereochemistries and methods for their preparation and use. |
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2016
- 2016-03-20 CN CN201610155697.9A patent/CN106539757A/en active Pending
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- 2017-03-12 WO PCT/CN2017/076383 patent/WO2017162055A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104540945A (en) * | 2012-04-30 | 2015-04-22 | 格伦·N·巴伯 | Modulating immune responses |
| WO2014179760A1 (en) * | 2013-05-03 | 2014-11-06 | The Regents Of The University Of California | Cyclic di-nucleotide induction of type i interferon |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112957475A (en) * | 2021-02-04 | 2021-06-15 | 李文峰 | Composition for preventing and/or treating tumors and application thereof |
| WO2022228469A1 (en) * | 2021-04-28 | 2022-11-03 | 苏州大学 | Polymersome nano-sting agonist, preparation method therefor, and application thereof |
| CN115252554A (en) * | 2021-05-01 | 2022-11-01 | 杭州星鳌生物科技有限公司 | Preparation and composition of novel 4 (3H) -quinazolinone analogue/cyclic dinucleotide cGAMP (cyclic-gated AMP) co-carried liposome and application of liposome in antitumor drugs |
| WO2022233255A1 (en) * | 2021-05-01 | 2022-11-10 | 杭州星鳌生物科技有限公司 | Preparation and composition of novel 4(3h)-quinazolinone analogue/cyclic dinucleotide cgamp co-loaded liposome and application thereof in antitumor drugs |
| CN115252554B (en) * | 2021-05-01 | 2023-08-25 | 杭州星鳌生物科技有限公司 | Preparation, composition and application of novel 4 (3H) -quinazolinone analogue/cyclic dinucleotide cGAMP co-carrier liposome in antitumor drugs |
| CN114903856A (en) * | 2022-05-06 | 2022-08-16 | 四川大学华西医院 | 2 ', 3' -cGAMP-loaded liposome nano preparation and preparation method and application thereof |
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Application publication date: 20170329 |