CN102784164A - Application of polysaccharide sulphate to preparation of tumor treatment neovascularization inhibitors and vascular disrupting agents - Google Patents
Application of polysaccharide sulphate to preparation of tumor treatment neovascularization inhibitors and vascular disrupting agents Download PDFInfo
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- CN102784164A CN102784164A CN2012102618796A CN201210261879A CN102784164A CN 102784164 A CN102784164 A CN 102784164A CN 2012102618796 A CN2012102618796 A CN 2012102618796A CN 201210261879 A CN201210261879 A CN 201210261879A CN 102784164 A CN102784164 A CN 102784164A
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Abstract
The invention provides application of polysaccharide sulphate to preparation of tumor treatment neovascularization inhibitors and vascular disrupting agents. Experiments prove that the neovascularization inhibiting rate, the maturation blood vessel disrupting rate and the concentration of the polysaccharide sulphate are in dosage relying relationship in a certain range, and the maturation blood vessel disrupting rate and the polysaccharide sulphate acting time are in dosage relying relationship. The application provided by the invention has the advantages that the effect of the polysaccharide sulphate in the aspects of tumor neovascularization inhibiting and tumor blood vessel generation disrupting can be proved, and the polysaccharide sulphate can be used for tumor blood vessel generation and other blood vessel generation disease treatment, and can also be used in aspects of tumor chemotherapy and/or auxiliary chemotherapy. Many diseases of people are relevant to the blood vessel generation, and the polysaccharide sulphate as the neovascularization inhibitors and vascular disrupting agents can be widely applied to the treatment of diseases of tumor and the like. The application provided by the invention has the advantages that the application range of the polysaccharide sulphate is widened, and the scientific basis is provided for the purpose development of the polysaccharide sulphate in the anti-tumor aspect and the like.
Description
Technical field
The present invention relates to the new purposes of PSS, relate in particular to PSS in the antiangiogenic agent of preparation treatment tumor and the application in the vascular damaging agents.
Background technology
Tumor is one of the most serious disease of harm humans health; The treatment method for cancer has multiple at present; The anti-angiogenic therapy that develops based on angiogenesis and tumor growth and relations of metastasis is more promising method, has brought new hope also for the treatment of human cancer.Angiogenesis is meant that already present blood vessel is through sprouting or splitted mode produces new blood vessel.Under physiology and the pathological conditions; Take place like the embryo, processes such as female reproduction cycle, inflammatory reaction, wound healing, tumor generation are all being carried out angiogenesis, particularly under the pathological conditions; According to statistics, the approximately rise of 20-40 kind human diseases and angiogenesis or reduce relevant.1971, Folkman set up the theory of getting in touch between angiogenesis and the tumor growth.Propose angiogenesis and not only can keep its vigorous metabolism, created advantageous conditions for tumor cell leaves primary lesion through blood transfer again simultaneously for tumor cell provides abundant nutrition.Therefore, the neovascularity that effectively suppresses tumor inducing generates, and cuts off the nutrition supply and the route of metastasis of tumor cell, can the effectively preventing cancer.Compare with traditional antitumor drug; The antineoplastic new angiogenesis drug is to make the tumor cell proliferation cycle stretch-out through reducing or blocking the supply of tumor tissues peripheral blood; Promote that tumor cell is downright bad and work; Rather than direct kill tumor cell, so no significant side effects, and can overcome the Drug resistance problem in the chemotherapy process.Therefore, seek the new vessels growth inhibitor and become in the world neoplasm growth and the another important directions that shifts treatment in recent years.
Saccharide compound has multiple biological function because of it, receives the extensive concern of Chinese scholars in recent years.So far, found that tens of kinds of saccharide compounds have anti-angiogenesis activity, their wide material sources comprise animal, plant, algae, fungus and semi-synthetic product.Inside and outside pharmacological research to the various saccharides material shows; They have good anti-angiogenesis activity; And have no side effect basically; The particularly good behaviour of PI-88 (Heparan sulfate analog) in clinical trial proved absolutely great potential and important value that the saccharide angiogenesis inhibitor is studied.
PSS (Alginic Sodium Diester) is called for short PSS, is to be basic material with the alginic acid, introduces a kind of sulfated polysaccharide that effective group is synthesized into through chemical method such as hydrolysis, esterification, sulfonation, belongs to acidic polysaccharose class material.PSS has the biological activity of heparinoid appearance, but does not have the toxic and side effects of heparin appearance.Research shows that PSS has the dielectric linear structure of polyanion, can increase the negative electric charge of erythrocyte surface; Repulsive force between wild phase is mutual reaches sticking between erythrocyte and the cell wall so can stop, thereby has the effect of significant blood viscosity lowering between the erythrocyte; Reduce cholesterol, triglyceride, LDL, VLDL in the blood plasma; Simultaneously also have effects such as anticoagulation, blood vessel dilating, blood pressure lowering, blood sugar lowering, safe in clinical practice, side effect is little; And do not see the report that the side effect of blood vessel aspect is arranged, so PSS has application widely clinically.But at present, still there be not the report of PSS as the medicine of treatment tumor.
Summary of the invention
The invention provides PSS in the antiangiogenic agent of preparation treatment tumor and the application in the vascular damaging agents; The present invention utilizes the construction features and the multiple physiologically active of PSS; Through experiment proved PSS suppress that the tumor neovascularity generates and the mature blood tube damage aspect in effect; Further shown it in antitumor drug prevent and treat function, for the novel clinical use of exploitation PSS provides theoretical foundation.
For realizing the foregoing invention purpose, the present invention adopts following technical proposals to be achieved:
The invention provides PSS in the antiangiogenic agent of preparation treatment tumor and the application in the vascular damaging agents.
Wherein, when the concentration of PSS was 12.5-100 μ g/mL, neovascularity generates suppression ratio and the alginate diester na concn is the dose dependent relation.
When the concentration of PSS was 12.5-100 μ g/mL, the destructive rate of ripe blood vessel and alginate diester na concn were the dose dependent relation.
The action time of PSS is when being 0.5-7h, the destructive rate of ripe blood vessel and be the time-dependent sexual relationship action time of PSS.
Further, said antiangiogenic agent and vascular damaging agents are liquid preparation or solid preparation.
Said solid preparation is granule, tablet, capsule or drop pill.
Said liquid preparation is the injecting fluid preparation.
In PSS and paclitaxel, amycin, cisplatin, fluorouracil, cyclophosphamide, vinorelbine or the oxaliplatin one or more are united use.
Compared with prior art, advantage of the present invention and good effect are:
PSS is anticoagulant, a fat-reducing medicament commonly used clinically in the prior art, is used to treat diseases such as hyperlipemia, cerebral embolism, coronary heart disease all the time, and the present invention is the (patent No.: 93111311.3) on the early stage basis of studying to the PSS function; Anti-tumor activity to PSS is studied; Prove PSS in the effect aspect neovascularity generation of inhibition tumor and the destruction tumor-blood-vessel growth through experiment, and it is used for tumor-blood-vessel growth and other angiogenesis treatment of diseases, except that tumor; Also has diabetic renal papillary necrosis with the excessive diseases associated of angiogenesis; Rheumatic arthritis, psoriasis, hemangioma; Atherosclerosiss etc. can also be used for the treatment of chemotherapy of tumors and/or NACT aspect.Human numerous disease all with associated angiogenesis, PSS will be used widely in treatment of diseases such as tumor as antiangiogenic agent and vascular damaging agents.
The present invention has carried out secondary development for the pharmacological action of PSS, has expanded the range of application of PSS, for PSS provides scientific basis in aspect purposes exploitations such as antitumor.
After the advantages specific embodiment of the present invention, other characteristics of the present invention and advantage will become clearer.
Description of drawings
Fig. 1 generates inhibiting Electronic Speculum figure for the PSS of variable concentrations to the vascular endothelial cell neovascularity.
Fig. 2 is the PSS of variable concentrations and the graph of a relation that the vascular endothelial cell neovascularity generates suppression ratio.
Fig. 3 is the Electronic Speculum figure of the PSS of variable concentrations to the effect of vascular endothelial cell angiolysis.
Fig. 4 is the PSS of different effects time and the graph of a relation of vascular endothelial cell angiolysis rate.
Fig. 5 is the PSS of variable concentrations and the graph of a relation of vascular endothelial cell angiolysis rate.
The specific embodiment
Below in conjunction with the accompanying drawing and the specific embodiment technical scheme of the present invention is done further detailed explanation.
Embodiment 1: the inhibitory action that PSS generates the Human umbilical vein endothelial cells neovascularity
Experimental technique: at 37 ℃, 5% CO
2In the incubator Human umbilical vein endothelial cells (HUVECs) cultivation is being contained 10%FBS, in the F-12 culture medium of 100IU/mL penicillin.200 μ L rifle heads and 96 orifice plates in-20 ℃ of pre-coolings.Get Matrigel (matrigel) 55 μ L/ holes with the rifle head of pre-cooling and join in 96 orifice plates of pre-cooling, then 96 orifice plates are put into 37 ℃ of incubator 30min Matrigel is solidified.The Human umbilical vein endothelial cells suspension (9 * 10 that comprises variable concentrations PSS (12.5,25,37.5,50,100 μ g/mL)
4Cells/mL) be inoculated in the Matrigel hole of having solidified, make drug effect 7h after, choose the unified visual field and take pictures (Olympus, Japan, * 100) in microscopically, the experiment triplicate.An observed loop configuration is a tube chamber under field of microscope; Tube chamber forms suppression ratio and counts control wells * 100% by calculating suppression ratio (%)=(tube chamber is counted control wells-tube chamber and counted dosing holes)/tube chamber with formula, and this tube chamber is counted the blank group tube chamber number that control wells is corresponding time point.
Experimental result is as illustrated in fig. 1 and 2; PSS suppresses the Human umbilical vein endothelial cells neovascularity with dosage dependence mode and generates; Behind the dosing effect 7h; When the concentration of PSS is 12.5,25,37.5,50,100 μ g/mL, the Human umbilical vein endothelial cells neovascularity is generated suppression ratio be respectively 29.4%, 57.8%, 74.5%, 88.2% and 100%.Said dosage property dependence is that neovascularity generates suppression ratio and raises gradually thereupon along with the alginate diester na concn raises.
Embodiment 2: PSS is to the destruction of the ripe blood vessel of Human umbilical vein endothelial cells
Experimental technique: get Matrigel and place on ice, make it to melt, rifle head and 96 orifice plates are in-20 ℃ of pre-coolings simultaneously.Get Matrigel 55 μ L/ holes with the rifle head of pre-cooling and join in 96 orifice plates of pre-cooling, then 96 orifice plates are put into 37 ℃ of incubator 30min Matrigel is solidified.With Human umbilical vein endothelial cells (9 * 10
4Cells/mL) be inoculated in the Matrigel hole of solidifying; Cultivate the tube chamber that 6h forms maturity state in 37 ℃; Add variable concentrations PSS 12.5,25,37.5,50,100 μ g/mL then and act on 0.5h, 1h, 3h, 5h, 7h respectively, choose the same visual field take pictures (Olympus, Japan at each time point; * 40), the experiment repetition is 3 times.An observed loop configuration is a tube chamber under field of microscope; Tube chamber forms destructive rate by calculating with formula: destructive rate (%)=(tube chamber is counted control wells-tube chamber and counted dosing holes)/tube chamber is counted control wells * 100%, and this tube chamber is counted the blank group tube chamber number that control wells is corresponding time point.
Experimental result is shown in Fig. 3-5, and Fig. 3 and 4 shows that PSS can destroy the tube chamber that has formed with the time-dependent mode, after the administration in the 1h; PSS has only shown slight tube chamber destruction under each concentration, but along with prolong action time, its tube chamber destroys activity to be strengthened gradually; And behind 3h after the administration, PSS promptly shows the broken ring effect of significant tube chamber under high concentration, behind the administration 7h; PSS has all shown the broken ring effect of significant tube chamber under each administration concentration; For example, when the alginate diester na concn is 100 μ g/mL, its destructive rate to tube chamber can reach 97.1%.Said time-dependent sexual relationship is along with the PSS prolongation of action time, and mature blood tube damage rate raises thereupon gradually.
Simultaneously, PSS can also destroy the tube chamber that has formed with dosage dependence mode, shown in Fig. 3 and 5; When the alginate diester na concn is 12.5 μ g/mL; Can show certain tube chamber destruction, along with the alginate diester na concn increases, its tube chamber destruction strengthens gradually.For example, during dosing effect 7h, when the concentration of PSS was 25 μ g/mL, its tube chamber destructive rate was 46.1%, and concentration is when being 100 μ g/mL, and its tube chamber destructive rate can reach 97.1%.Said dosage property dependence is that mature blood tube damage rate raises thereupon gradually along with the alginate diester na concn raises.
Angiogenesis receives the adjusting of somatomedin such as bFGF and VEGF usually, and these somatomedin can interact with the ammonia polyose of candy (GLG) that exists in cellular matrix, basement membrane and the cell surface receptor and heparin sulfate glycoprotein (HSPG) and then regulate cell growth, propagation, migration and differentiation etc.For example; HSPG can form the HSPG-bFGF-FGFR complex with bFGF and produce the effect that promotes angiogenesis; And the polysaccharide of the different polysaccharide similar in some and animal body basement membrane extracellular matrix (ECM) source has a large amount of negative charges and has the heparin binding characteristic; The affinity of they and the short factor, receptor more is prone to form complex by force, combines angiogenesis to promote the receptor of the factor to play the effect that suppresses angiogenesis through competition.PSS among the present invention has a large amount of negative charges; Negative charge is mainly produced by sulfate radical; PSS promptly combines angiogenesis to promote the receptor of the factor to play the effect that suppresses angiogenesis through competition, and it is one type has blood vessel and suppress active polysaccharide.
Said antiangiogenic agent and vascular damaging agents are liquid preparation or solid preparation.Said solid preparation is granule, tablet, capsule or drop pill, and said liquid preparation is the injecting fluid preparation.In PSS and paclitaxel, amycin, cisplatin, fluorouracil, cyclophosphamide, vinorelbine or the oxaliplatin one or more are united use.
Above embodiment is only in order to explaining technical scheme of the present invention, but not limits it; Although the present invention has been carried out detailed explanation with reference to previous embodiment, for the person of ordinary skill of the art, still can make amendment to the technical scheme that previous embodiment is put down in writing, perhaps part technical characterictic wherein is equal to replacement; And these modifications or replacement do not make the essence of relevant art scheme break away from the spirit and the scope of the present invention's technical scheme required for protection.
Claims (8)
1. PSS is in the antiangiogenic agent of preparation treatment tumor and the application in the vascular damaging agents.
2. PSS according to claim 1 is in the antiangiogenic agent of preparation treatment tumor and the application in the vascular damaging agents; When the concentration that it is characterized in that PSS was 12.5-100 μ g/mL, neovascularity generates suppression ratio and the alginate diester na concn is the dose dependent relation.
3. PSS according to claim 1 is in the antiangiogenic agent of preparation treatment tumor and the application in the vascular damaging agents; When the concentration that it is characterized in that PSS was 12.5-100 μ g/mL, the destructive rate of ripe blood vessel and alginate diester na concn were the dose dependent relation.
4. treat the antiangiogenic agent of tumor and the application in the vascular damaging agents according to claim 1 or 3 described PSSs in preparation; The action time that it is characterized in that PSS is when being 0.5-7h, the destructive rate of ripe blood vessel and be the time-dependent sexual relationship action time of PSS.
5. PSS according to claim 1 is characterized in that in the antiangiogenic agent of preparation treatment tumor and the application in the vascular damaging agents said antiangiogenic agent and vascular damaging agents are liquid preparation or solid preparation.
6. PSS according to claim 5 is characterized in that in the antiangiogenic agent of preparation treatment tumor and the application in the vascular damaging agents said solid preparation is granule, tablet, capsule or drop pill.
7. PSS according to claim 5 is characterized in that in the antiangiogenic agent of preparation treatment tumor and the application in the vascular damaging agents said liquid preparation is the injecting fluid preparation.
8. PSS according to claim 1 is in the antiangiogenic agent of preparation treatment tumor and the application in the vascular damaging agents, it is characterized in that in PSS and paclitaxel, amycin, cisplatin, fluorouracil, cyclophosphamide or the oxaliplatin one or more unite use.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142639A (en) * | 2013-03-21 | 2013-06-12 | 青岛正大海尔制药有限公司 | Application of polysaccharide sulfate in medicament for treating breast cancer |
| CN110559311A (en) * | 2018-08-27 | 2019-12-13 | 青岛海洋生物医药研究院股份有限公司 | Application of polysaccharide sulfate in preparation of medicine for preventing or treating tumor metastasis |
Citations (3)
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| CN1089619A (en) * | 1993-01-06 | 1994-07-20 | 山东烟台西苑制药厂 | A kind of production method of propylene glycol alginate sodium sulfate |
| US20030232198A1 (en) * | 2002-02-21 | 2003-12-18 | Encelle, Inc. | Immobilized bioactive hydrogel matrices as surface coatings |
| CN100540568C (en) * | 2007-04-20 | 2009-09-16 | 中国科学院海洋研究所 | A kind of method of extracting algal polysaccharide sulfate |
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Patent Citations (3)
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| CN1089619A (en) * | 1993-01-06 | 1994-07-20 | 山东烟台西苑制药厂 | A kind of production method of propylene glycol alginate sodium sulfate |
| US20030232198A1 (en) * | 2002-02-21 | 2003-12-18 | Encelle, Inc. | Immobilized bioactive hydrogel matrices as surface coatings |
| CN100540568C (en) * | 2007-04-20 | 2009-09-16 | 中国科学院海洋研究所 | A kind of method of extracting algal polysaccharide sulfate |
Non-Patent Citations (1)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142639A (en) * | 2013-03-21 | 2013-06-12 | 青岛正大海尔制药有限公司 | Application of polysaccharide sulfate in medicament for treating breast cancer |
| CN110559311A (en) * | 2018-08-27 | 2019-12-13 | 青岛海洋生物医药研究院股份有限公司 | Application of polysaccharide sulfate in preparation of medicine for preventing or treating tumor metastasis |
| CN110559311B (en) * | 2018-08-27 | 2020-09-04 | 青岛海洋生物医药研究院股份有限公司 | Application of polysaccharide sulfate in preparation of medicine for preventing or treating tumor metastasis |
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Application publication date: 20121121 |