CN107602716A - Anti-lung cancer sulfated polysaccharides of targeted inhibition angiogenesis and preparation method thereof - Google Patents
Anti-lung cancer sulfated polysaccharides of targeted inhibition angiogenesis and preparation method thereof Download PDFInfo
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- CN107602716A CN107602716A CN201710815875.0A CN201710815875A CN107602716A CN 107602716 A CN107602716 A CN 107602716A CN 201710815875 A CN201710815875 A CN 201710815875A CN 107602716 A CN107602716 A CN 107602716A
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Abstract
The present invention, to PRP structural modifications, obtains currant Phellinus polysaccharide sulfate PRP S16 using improvement chlorosulfonic acid formamide method.Research finds that PRP S16 have significant inhibitory action to mouse transplanting Lewis lung cancer, and its Anticancer Effect and Mechanism is relevant with suppressing Tumor Angiongesis, the tumor vascular generation of expression inhibiting by suppressing VEGF and VEGFR2.
Description
Technical field
The invention belongs to biological technical field, and in particular to the anti-lung cancer sulfated polysaccharides of targeted inhibition angiogenesis and its
Preparation method.
Background technology
Malignancy disease is the common disease and frequently-occurring disease of serious threat human health.Current chemical medicinal treatment and put
Although it is effective to tumour to penetrate therapy etc., toxic side effect is generally larger.Therefore, inquiring into tumorigenic mechanism and research has spy
The new drug of point is still the important topic of antineoplastic research in recent years.
The occurrence and development of tumour generate dependent on new vessels, need new vessels when tumour growth is to certain volume
Nutrition is conveyed for it and is transported metabolic waste, the Folkman of medical college of Harvard University et al. therefore is proposed " oncology hungry to death
Say ", i.e., the nutrition supply for cutting off tumour by a kind of effective angiogenesis inhibitors, which plays, suppresses growth and metastasis of tumours
Effect.At present, using tumor neogenetic blood vessels as target spot, exploitation is efficient, the antineoplastic of low toxicity, high specificity is just turning into domestic and international
The focus of scholar's research.
Currant Phellinus (Phellinus ribis), it is Phellinus medicinal fungi, available for tumour, hepatitis
Etc. the treatment of disease, it is distributed in East Asian countries such as China, South Korea, Japan.Currant Phellinus polysaccharide (abbreviation PRP) is
The novel polysaccharide that we are separated to for the first time from currant Phellinus.Molecular weight 8.59kDa, it is determined that its structure, main chain
It is made up of (see Fig. 1) β-(1 → 6)-glucose and β-(1 → 4)-glucose.
The activity of polysaccharide would generally be strengthened or polysaccharide is produced new activity, therefore mesh by introducing some chemical groups to polysaccharide
In preceding compound of polysaccharide probe process, appropriate focus and emphasis polysaccharide structures being chemically modified as research.At present
The problems such as polysaccharide degraded, substitution value is not high to the method that polysaccharide is chemically modified be present.
The content of the invention
The defects of for prior art, the invention provides the anti-lung cancer sulfated polysaccharides of targeted inhibition angiogenesis and its
Preparation method.
The present invention, to PRP structural modifications, obtains currant Phellinus polysaccharide sulfuric acid using improvement chlorosulfonic acid-formamide method
Ester PRP-S16.Research finds that PRP-S16 has significant inhibitory action to mouse transplanting Lewis lung cancer, its antitumor action machine
System is relevant with suppressing Tumor Angiongesis.
It is an object of the invention to provide a kind of anti-lung cancer sulfated polysaccharides of targeted inhibition angiogenesis, its preparation method takes
Dai Dugao, polysaccharide less degradation, reaction are definite.
Technical scheme is as follows：
The invention provides the preparation method of the anti-lung cancer sulfated polysaccharides of targeted inhibition angiogenesis, comprise the following steps：
Currant Phellinus polysaccharide sample 1g is taken, is dissolved in 5mL formamides, then in ice salt bath, by formyl
Amine:Chlorosulfonic acid（10:3）Mixed liquor 5mL is added dropwise in polysaccharide formamide solution.25 DEG C of stirring reaction 8h, add 4 times of volume second
Alcohol terminating reaction, , Chui Rong funnel filters after settling 10 min, absolute ethyl alcohol washing precipitation.Precipitation 5mL water dissolves, 1%NaOH
PH7.0 is adjusted, 5 times of amount ethanol is added thereto, supernatant is poured out after placement, collects precipitation.Sediment is dissolved with 10mL water again, is added
0.5% NaHSO3,Saturation NaHCO3PH9.5 is adjusted, boils 10min.Cooling, acetic acid adjust pH6.5,0.45 μm of miillpore filter mistake
Filter, 5 times of volume absolute ethyl alcohols are added into filtrate, placed, pour out supernatant, collected precipitation, be redissolved in 5mL water, add 5
Times volume absolute ethyl alcohol, place, pour out supernatant, collect precipitation dehydration, 50~60 DEG C of vacuum drying, it is more to obtain currant Phellinus
Sugar sulfate finished product.
Molecular weight determination, elementary analysis, angle-of-rotation measuring, infrared spectrum are carried out to currant Phellinus polysaccharide sulfate
Analysis.
Anti-lung cancer sulfated polysaccharides provided by the invention is currant Phellinus polysaccharide sulfate.
Preferably, currant Phellinus polysaccharide sulfate molecular weight is 18.3 kDa；
C% is 17.79%, H% 2.98%, S% 12.81%；
Specific rotatory power is+2.38° (c 0.1, H2O)；
For currant Phellinus polysaccharide sulfate infrared spectrum compared with currant Phellinus polysaccharide, currant Phellinus are more
Sugar sulfate is in 1258 cm-1With 810 cm-1Neighbouring more two peaks, respectively S=O stretching vibration peak and the flexible of C-O-S shake
Dynamic peak.
4. anti-lung cancer sulfated polysaccharides according to claim 3, it is characterised in that：Described currant timber layer hole
Granulose sulfuric ester suppresses Tumor Angiongesis.
Preferably, currant Phellinus polysaccharide sulfate suppresses VEGF and VEGFR2 expression.
Currant Phellinus polysaccharide sulfate provided by the invention is used for the medicine for preparing treatment lung cancer.
Preferably, currant Phellinus polysaccharide sulfate is used for the medicine for preparing treatment Lewis lung cancer.
Usefulness of the present invention is：
First, in sulphation process, polysaccharide is not degraded substantially.PRP molecular weight 8.59kDa, are obtained after sulphation after testing
PRP-S16 molecular weight is 18.3 kDa, is illustrated in sulphation process, polysaccharide is not degraded substantially.
Second, S substitution value is high.Determined through Perkin-Elmer2400, C% 17.79%, H% 2.98%, S% are
12.81%, S substitution value DS are 1.62.
Third, substitution reaction definitely occurs.PRP-S16 IR collection of illustrative plates is compared with PRP, and PRP-S16 is in 1258 cm-1With 810
cm-1Two peaks, respectively S=O stretching vibration peak and C-O-S stretching vibration peak have significantly nearby been had more, have been illustrated through over cure
Acidification reaction, oneself is combined on sugar chain for sulfate radical.
Fourth, PRP-S16 provided by the invention has the effect of definite treatment lung cancer, can be used for preparing anti-lung cancer
Medicine.
Brief description of the drawings
Fig. 1 is the structure chart of currant Phellinus polysaccharide PRP repeat units.
Fig. 2 is PRP and PRP-S16 infrared spectrogram.
Fig. 3 is tumors in vivo volume growth curve.
Fig. 4 is the influence that PRP-S16 is expressed CD31, VEGF and VEGFR-2 in tumor tissues.
Fig. 5 is that PRP-S16 influences score value to VEGF in tumor tissues and VEGFR-2 expression.
Embodiment
The above of the present invention is described in further detail below by specific embodiment.But this should not be managed
The scope solved as the above-mentioned theme of the present invention is only limitted to following instance.All technologies realized based on the above of the present invention are belonged to
The technical scope of the present invention.
The currant Phellinus polysaccharide sulfate PRP-S16 of embodiment 1 preparation
Currant Phellinus polysaccharide sample 1g is taken, is dissolved in 5mL formamides, then in ice salt bath, by formyl
Amine:Chlorosulfonic acid（10:3）Mixed liquor 5mL is added dropwise in polysaccharide formamide solution.25 DEG C of stirring reaction 8h, add 4 times of volume second
Alcohol terminating reaction, , Chui Rong funnel filters after settling 10 min, absolute ethyl alcohol washing precipitation.Precipitation 5mL water dissolves, 1%NaOH
PH7.0 is adjusted, 5 times of amount ethanol is added thereto, supernatant is poured out after placement, collects precipitation.Sediment is dissolved with 10mL water again, is added
0.5% NaHSO3,Saturation NaHCO3PH9.5 is adjusted, boils 10min.Cooling, acetic acid adjust pH6.5,0.45 mm miillpore filter mistakes
Filter, 5 times of volume absolute ethyl alcohols are added into filtrate, placed, pour out supernatant, collected precipitation, be redissolved in 5mL water, add 5
Times volume absolute ethyl alcohol, place, pour out supernatant, collect precipitation dehydration, 50~60 DEG C of vacuum drying, obtain finished product.
The currant Phellinus polysaccharide sulfate PRP-S16 of embodiment 2 sign measurement analysis
The PRP-S16 molecular weight of embodiment 2.1
Determined by HPSEC-MALLS, use Astra DAS (version 5.3.4.13）Data are acquired
And analysis, it is 18.3 kDa to obtain PRP-S16 molecular weight, is illustrated in sulphation process, polysaccharide is not degraded substantially.
The PRP-S16 of embodiment 2.2 elementary analysis
Determined through Perkin-Elmer2400, C% 17.79%, H% 2.98%, S% 12.81%, S substitution value DS are
1.62。
The PRP-S16 of embodiment 2.3 optical activity
PRP-S16 replication 3 times on automatic polarimeter, the specific rotatory power for being computed PRP-S16 are+2.38° (c
0.1, H2O)。
The PRP-S16 infrared spectrums of embodiment 2.4（IR）
PRP-S16 IR collection of illustrative plates is shown in Fig. 2, and compared with PRP, PRP-S16 is in 1258 cm-1With 810 cm-1Nearby significantly have more
Two peaks, respectively S=O stretching vibration peak and C-O-S stretching vibration peak, illustrate to pass through sulfating reaction, the own warp of sulfate radical
It is incorporated on sugar chain.
Effect of anti-lung cancer is studied inside the currant Phellinus polysaccharide sulfate PRP-S16 of embodiment 3
The foundation and packet of the Lewis mice model of lung cancer of embodiment 3.1
The C57BL/6J mouse 5 for taking adaptability to grow 1 week, Lewis lung carcinoma cells are collected, adjust cell number 1 × 107Individual/mL
1 is pressed with Matrigel:1 ratio mixes, and it is subcutaneous to be inoculated in the right armpit of mouse rapidly, every 0.2 mL.Prepare tumor-bearing mice.
The above-mentioned d of growth 10 tumor-bearing mice is taken, cervical vertebra is taken off and puts to death, take tumor tissue, it is 1 mm that tumor tissue is cut into length and width
The tumour fritter of size is some standby.C57BL/6J mouse 50 are taken, right preceding oxter is connect ready tumor mass with trochar
Kind is subcutaneous in right armpit.Above-mentioned mouse is randomly divided into 5 groups：Model group, positive group（RhEndostatin group）, PRP-S16 low dose groups, PRP-
S16 middle dose groups, PRP-S16 high dose groups.Separately 10 C57BL/6J normal mouses are taken as normal group.Basic, normal, high dosage
Start within the 2nd day respectively by 10,20,40 mgkg after the inoculation of PRP-S16 groups-1Dosage intraperitoneal injection, one time a day.Sun
Property control group presses 5 mgkg-1RhEndostatin is injected intraperitoneally in dosage, once every other day, model group and normal group intraperitoneal injection of saline,
One time a day, continuous 14 d.
The mouse tumor volume of embodiment 3.2
Start within the 8th day after inoculation to calculate gross tumor volume with vernier caliper measurement mouse tumor most major diameter and most minor axis daily, draw
Tumor growth curve.From the figure 3, it may be seen that with the growth of time, the volume of each group mouse transplanting tumor is increasing, and PRP-S16 is high
Dosage group and rhEndostatin suppress more apparent to gross tumor volume, compared with model group, significant difference（P<0.01）, see Fig. 3.
The mouse tumor inhibiting rate of embodiment 3.3
After the h of last dose 24, cervical vertebra processing mouse, the complete solid tumor mass for taking out mouse are taken off after taking blood.Weighed quality, root
Tumor control rate is calculated according to below equation：Inhibition rate of tumor growth（%）=（The average knurl matter of the average knurl quality-treatment group of model group
Amount）Average knurl quality × 100% of/model group.
It the results are shown in Table 1.Compared with model group, rhEndostatin group, low dose group, middle dose group and high dose group mouse tumor
Growth in various degree be suppressed, knurl weight average value is obviously reduced compared with model group, tumour inhibiting rate with the increase of PRP-S16 dosage and
Increase, in obvious dose-effect relationship.Wherein, the knurl weight of high dose group and rhEndostatin group compared with model group with significant differences
（P﹤ 0.01）, middle dose group knurl weight is also significantly lower than model group（P﹤ 0.05）, and low dose group nothing compared with the knurl weight of model group
Statistical significance（P﹥ 0.05）.Low dose group knurl weight is compared with rhEndostatin group with significant difference（P﹤ 0.05）, high dose group and
The knurl weight of middle dose group and rhEndostatin group are more not statistically significant（P﹥ 0.05）.These results illustrate that PRP-S16 is to Lewis lungs
The growth of cancer has obvious inhibiting effect, and wherein high dose group acts on most obvious.
Inhibitory action of the PRP-S of table 1 to Mice Bearing Lewis Lung Cancer growth of transplanted human
| Group | Number of cases（Only） | Knurl weight (g) | Tumour inhibiting rate（%） |
| Model group | 10 | 3.66±0.32 | - |
| RhEndostatin group | 10 | 1.99±0.13** | 45.7 |
| Low dose group | 10 | 3.39±0.35# | 7.38 |
| Middle dose group | 10 | 2.60±0.13* | 28.9 |
| High dose group | 10 | 1.73±0.21** | 52.6 |
Note：Compared with model group：*P<0.05,**P<0.01；Compared with rhEndostatin group：# P<0.05。
Microvessel density in the tumor tissues of embodiment 3.4（MVD）And Angiogenesis Stimulators in Human expression
The mouse tumor tissue being fixed in 10% formalin is taken, FFPE is simultaneously cut into slices.CD31, VEGF and VEGFR2 are one
Anti-, negative control replaces primary antibody with phosphate buffer PBS, and SABC method immunohistochemical stainings are carried out according to kit specification.
CD31 positive Endothelial Cells are dyed to brown color, are defined by blood vessel compact district during counting, avoid hardening zone and necrosis
Area.In section any brown transfected endothelial cell and cell mass clearly distinguished with surrounding tissue by independent capilary respectively based on
Number.5 high power field of view are chosen, calculate average value, the MVD count values using average value as tumor tissues.VEGF and VEGFR2
Expression of results determined according to the dyeing depth, and dyeing scoring is carried out to the coloration result of each group selection area：0 is negative knot
Fruit；1 is that 0-25% is dyed；2 be that 25%-50% is dyed；3 be that 50%-75% is dyed, and 4 be that 75%-100% is dyed.
PRP-S16 is shown in Table 1 to influence such as Fig. 4 of MVD in Lewis lung cancer in mice tumor tissues, quantitative analysis results, model
The microvessel density of group SABC detection divides for the microvessel density of the basic, normal, high dosage groups of 105.37 ± 12.85, PRP-S16
Wei 97.61 ± 16.38,74.79 ± 18.93,51.72 ± 15.49.Compared with model group, micro- blood of PRP-S16 high dose groups
Pipe density significantly reduces, and has statistical significant difference（P<0.01）.PRP-S16 middle dose groups compared with model group,
Microvessel density reduces, and difference has statistical significance therebetween（P<0.05）.PRP-S16 low dose groups and model group phase
Than, microvessel density slight decrease, no difference of science of statistics therebetween.Illustrate that PRP-S16 can suppress Tumor Angiongesis.
Influence such as Fig. 4, PRP-S16 each dosage of the PRP-S16 to VEGF and VEGFR2 in Lewis lung cancer in mice tumor tissues
Group significantly reduces VEGF and VEGFR2 expression, dyes and weakens compared with model group.As shown in Figure 5, compared with model group,
The middle and high dosage groups of PRP-S16 have the inhibitory action of highly significant to VEGF and VEGFR2（P<0.05）；Low dose group VEGF and
VEGFR2 expression slightly reduces, but no difference of science of statistics（P>0.05）.Illustrate PRP-S16 may by suppress VEGF and
VEGFR2 expression inhibiting Tumor Angiongesis.
MVD count value in each group Lewis lung cancer in mice tumor tissues of table 2
| Group | Number of cases（Only） | MVD |
| Model group | 10 | 105.37±12.85 |
| RhEndostatin group | 10 | 52.35±11.87** |
| Low dose group | 10 | 97.61±16.38 |
| Middle dose group | 10 | 74.79±18.93* |
| High dose group | 10 | 51.72±15.49** |
Note：Compared with model group, *P<0.05, * *P<0.01。
The above-mentioned embodiment to the present invention is described, but not limiting the scope of the invention, institute
Category art personnel should be understood that on the basis of technical scheme those skilled in the art need not pay wound
The various modifications or deformation that the property made work can be made are still within protection scope of the present invention.
Claims (7)
1. the preparation method of the anti-lung cancer sulfated polysaccharides of targeted inhibition angiogenesis, comprises the following steps：
Currant Phellinus polysaccharide sample 1g is taken, is dissolved in 5mL formamides, then in ice salt bath, by formyl
Amine:Chlorosulfonic acid（10:3）Mixed liquor 5mL is added dropwise in polysaccharide formamide solution；
25 DEG C of stirring reaction 8h, 4 times of volume ethanol terminating reactions are added, , Chui Rong funnel filters after settling 10 min, absolute ethyl alcohol
Washing precipitation；
Precipitation 5mL water dissolves, and 1%NaOH adjusts pH7.0, adds 5 times of amount ethanol thereto, supernatant is poured out after placement, it is heavy to collect
Form sediment；
Sediment is dissolved with 10mL water again, adds 0.5% NaHSO3,Saturation NaHCO3PH9.5 is adjusted, boils 10min；
Cooling, acetic acid adjust pH6.5,0.45 μm of filtering with microporous membrane, 5 times of volume absolute ethyl alcohols are added into filtrate, places, pour out
Supernatant, precipitation is collected, is redissolved in 5mL water, add 5 times of volume absolute ethyl alcohols, placed, pour out supernatant, it is de- to collect precipitation
Water, 50~60 DEG C of vacuum drying, obtains currant Phellinus polysaccharide sulfate finished product；
Molecular weight determination, elementary analysis, angle-of-rotation measuring, infrared spectrum point are carried out to currant Phellinus polysaccharide sulfate
Analysis.
2. the preparation method of the anti-lung cancer sulfated polysaccharides of targeted inhibition angiogenesis according to claim 1 is prepared anti-
Lung cancer sulfated polysaccharides, it is characterised in that：The anti-lung cancer sulfated polysaccharides is currant Phellinus polysaccharide sulfate.
3. anti-lung cancer sulfated polysaccharides according to claim 2, it is characterised in that：Currant Phellinus polysaccharide sulfate
Molecular weight is 18.3 kDa；
C% is 17.79%, H% 2.98%, S% 12.81%；
Specific rotatory power is+2.38° (c 0.1, H2O)；
For currant Phellinus polysaccharide sulfate infrared spectrum compared with currant Phellinus polysaccharide, currant Phellinus are more
Sugar sulfate is in 1258 cm-1With 810 cm-1Neighbouring more two peaks, respectively S=O stretching vibration peak and the flexible of C-O-S shake
Dynamic peak.
4. anti-lung cancer sulfated polysaccharides according to claim 3, it is characterised in that：Described currant Phellinus polysaccharide
Sulfuric ester suppresses Tumor Angiongesis.
5. anti-lung cancer sulfated polysaccharides according to claim 4, it is characterised in that：Described currant Phellinus polysaccharide
Sulfuric ester suppresses VEGF and VEGFR2 expression.
6. the anti-lung cancer sulfated polysaccharides according to claim 3-5, it is characterised in that：Described currant Phellinus are more
Sugar sulfate is used for the medicine for preparing treatment lung cancer.
7. the anti-lung cancer sulfated polysaccharides according to claim 3-5, it is characterised in that：Described currant Phellinus are more
Sugar sulfate is used for the medicine for preparing treatment Lewis lung cancer.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101077891A (en) * | 2007-06-26 | 2007-11-28 | 山东大学 | Sepia polysaccharide sulfated derivative and preparing method thereof |
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2017
- 2017-09-12 CN CN201710815875.0A patent/CN107602716A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101077891A (en) * | 2007-06-26 | 2007-11-28 | 山东大学 | Sepia polysaccharide sulfated derivative and preparing method thereof |
Non-Patent Citations (4)
| Title |
|---|
| YUHONG LIU ET AL.: "Preparation, antiangiogenic and antitumoral activities of the chemically sulfated glucan from Phellinus ribis", 《CARBOHYDRATE POLYMERS》 * |
| YUHONG LIU ET AL.: "Sulfation of a polysaccharide obtained from Phellinus ribis and potential biological activities of the sulfated derivatives", 《CARBOHYDRATE POLYMERS》 * |
| 刘玉红: "茶藨子木层孔菌多糖及其硫酸化衍生物的制备、结构分析与生物活性研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
| 张诗军 等: "《肿瘤中医生物养生治疗学》", 31 July 2013, 广州：广东科技出版社 * |
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