CN105315349B - A kind of the polypeptide NR16 and its transformation peptide of anti-angiogenesis - Google Patents
A kind of the polypeptide NR16 and its transformation peptide of anti-angiogenesis Download PDFInfo
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Abstract
The invention belongs to biopharmaceutical technologies, and in particular to a kind of polypeptide NR16 and its transformation peptide [D Ala with blood vessel formation against function1]AR17.NR16 contains 16 amino acid, molecular weight 1683.0, and amino acid sequence is：NLLMAASAAATWLPPR；Peptide [D Ala are transformed in NR161] AR17, including 17 amino acid, molecular weight 1754.1, specific amino acid sequence are：D‑ANLLMAASAAATWLPPR.There is certain similar degree with polypeptide A S16 structures in the present invention, equally show preferable tumor killing effect, can polypeptide A S16 be even preferably substituted as the supplement of polypeptide A S16, while also be that the development of the following new oncology pharmacy, exploitation provide new reference and possible.
Description
Technical field
The invention belongs to biopharmaceutical technologies, and in particular to a kind of polypeptide NR16 with blood vessel formation against function and
Peptide [D-Ala is transformed in it1]AR17。
Background technology
Angiogenesis is the natural process that new blood vessel is formed on the basis of original vascular endothelial cell.Studies have shown that real
The growth of body tumor is generated dependent on new vessels, and angiogenesis plays very important work during growth and metastasis of tumours
With, oxygen and nutriment necessary to can not only be provided for growth and metastasis of tumours, but also can be with excretion metabolism product.It is anti-swollen
Tumor angiogenesis therapy has lot of advantages：1. having high efficiency, destroying a small amount of blood vessel can make by a large amount of of growth
Ischemic necrosis occurs for tumour cell；2. vascular cell without or few mutation, be not likely to produce drug resistance, can long-term administration；3. extensively
Tumor suppression spectrum, the vascular endothelial cell of different tumours often expresses identical specific proteins molecule, for this protein molecular
A kind of therapy may be suitable for kinds of tumors；4. drug target cell easy to reach, vascular endothelial cell are directly exposed to blood
In liquid, drug can directly play a role.
Endothelial receptor tyrosine kinases VEGF-R2 and Tie-2 and its ligand vascular endothelial growth factor（VEGF）With
Angiogenin Ang1 and Ang2, play an important role in angiogenesis.By closing vegf receptor approach or closing
Tie-2 receptor pathways can inhibit Tumor Angiongesis and tumour growth, and inhibit vegf receptor pathway cannot be by
Tie-2 pathways are compensated, and vice versa, and two approach are relatively independent, and no less important；Inhibit simultaneously by VEGFR-2
There are stronger maintenance normal blood vessels and tumor-associated vessels with the Tie-2 independent inhibition wherein access of signal path ratio mediated
Ability that is complete and stablizing.
AS16 is as one kind by VEGFR2 receptor antagonists ATWLPPR（V1 peptides）With Tie2 receptor antagonists NLLMAAS（V2
Peptide）Pass through flexible linker（A—A）The polypeptide of connection has obtained more fully disclosing in existing patent（CN101830971,
A kind of novel antiangiogenic polypeptide）.But as a kind of polypeptide drug, since its molecular weight is smaller, in organism
It is inside easy to be degraded by enzymes, half-life short, thus therapeutic effect is easy to be a greater impact, while it is for inhibiting tumor neogenetic blood
There is also the spaces further promoted for the function and effect that pipe generates.
Invention content
Present invention is primarily intended on the basis of existing AS16 polypeptides, by studying it transformation, obtain a kind of new
Polypeptide NR16 and its transformation peptide [D-Ala1] AR17, new polypeptide structure compared to original AS16 polypeptides, equally show compared with
Antineoplastic angiogenesis acts on well, and new possibility is provided for the application of anti-tumor agents.
Technical scheme of the present invention is described in detail as follows below.
A kind of anti-angiogenesis polypeptide NR16 and its transformation peptide, the polypeptide NR16 contain 16 amino acid, and molecular weight is
1683.0, as shown in sequence table SEQ ID NO.1, specific amino acid sequence is sequence：
Asn-Leu-Leu-Met-Ala-Ala-Ser-Ala-Ala-Ala-Thr-Trp-Leu-Pro-Pro-Arg, i.e.,
NLLMAASAAATWLPPR；
Compared to original polypeptide A S16, its main distinction is the connection of ATWLPPR peptide fragments and NLLMAAS peptide fragments in structure
Sequence has occurred reverse；
The AS16 is published in existing patent（Application number：2010101722261, publication number：
CN101830971A, a kind of novel antiangiogenic polypeptide become V3 peptides in that patent）Polypeptide sequence.
Peptide is transformed in the NR16, is named as [D-Ala1] AR17, including 17 amino acid, molecular weight 1754.1, sequence
It arranges shown in institute SEQ ID NO.2, specific amino acid sequence is：
D-Ala-Asn-Leu-Leu-Met-Ala-Ala-Ser-Ala-Ala-Ala -Thr-Trp-Leu-Pro-Pro-
Arg, i.e.,
D-ANLLMAASAAATWLPPR；
The NR16 transformation peptides [D-Ala1] AR17, it is realized by increasing a D-Ala in NR16 peptide N-terminals；
Described D-Ala, D-A represent in the polypeptide sequence first amino acid alanine as D-form.
The anti-angiogenesis polypeptide NR16 and its preparation method that peptide is transformed, are all made of Fomc solid phase polypeptide synthesis systems
Standby to form, process is：
First amino is connected to by the amino acid of Fmoc radical protections on insoluble solid phase carrier Wang resins first,
Then the protecting group of amino is taken off, first amino acid is connected on solid phase carrier；
Secondly amino is activated by the carboxyl of second amino acid of Fmoc radical protections with condensing agent, the amino after activation
With the amino for first amino acid for being connected on solid phase carrier dehydration condensation occurs for acid again, forms peptide bond；
It repeats above-mentioned peptide bond and forms reaction, peptide chain is made to be grown from C-terminal to N-terminal, until reach required peptide chain length,
The polypeptide for finally cutting synthesis precipitates and is washed by ether, obtains thick peptide；
It can be prepared by the polypeptide sample of higher degree after purification through HPLC.
Specifically include following steps：
（1）Swellable resins are swollen Wang resins in Peptide synthesizer；
（2）The addition of first amino acid, calculating weigh arginine, while being proportionally added into HOBT (1- hydroxy benzenes the third three
Azoles）、DIC（N, N- diisopropyl diimine）, react, seal up first liquid end socket after reaction, wash；
（3）The addition of second amino acid, that is, proline, synthesis is carried out from the C-terminal of peptide chain to N-terminal direction, to step
（2）In after an amino acid adding resin be deprotected, washing, then indenes examine, be proportionally added into second amino proline,
HOBT, DIC react, washing；
（4）The addition of subsequent amino-acid, the method for addition with above-mentioned second amino acid adding procedure, until adding institute
There is amino acid；
Preparing NR16 transformation peptides [D-Ala1] AR17 when, it should be noted that in addition to the last one amino acid is changed to D
Type alanine, other amino acid are L-type amino acid；
（5）The cutting of polypeptide, to step（4）In equipped with resin Peptide synthesizer in suitable deprotection liquid is added, wash
It washs；Then the cutting reagent configured is poured into draught cupboard and carries out cleavage reaction in synthesizer；After cutting, with rotation
Evaporimeter removes the TFA in cutting liquid；Due to containing arginine in polypeptide sequence, ice need to be carried out again and cut；Ice obtains after the completion of cutting
Obtain thick peptide；It is purified using RP HPLC after thick peptide drying, product after purification in -80 DEG C of low temperature refrigerator freeze overnights, is then used first
Freeze drier saves backup after being lyophilized into white powder in -20 DEG C of refrigerators, as synthesized polypeptide finished product.
The anti-angiogenesis polypeptide NR16 and its transformation peptide, as the application in tumor therapeutic agent, the tumour
Such as tumour caused by H22 liver cancer.
In the prior art, although polypeptide A S16 shows preferable tumor killing effect, but for being used as medicament reality, still
The defects of it is single that there are pharmacy types, and effect needs to be further increased.Polypeptide NR16 provided by the present invention and its transformation peptide [D-
Ala1] AR17, there is certain similar degree, while what is more important with polypeptide A S16 structures, equally shows preferably
Tumor killing effect, thus be that can preferably be used as the supplement of polypeptide A S16 even replacement more for its following application prospect
Peptide AS16's, while being also that the development of the following new oncology pharmacy, exploitation provide new reference and may.
Description of the drawings
Fig. 1 is the Mass Spectrometric Identification figure of AS16；
Fig. 2 is the Mass Spectrometric Identification figure of NR16；
Fig. 3 is [D-Ala1] AR17 Mass Spectrometric Identification figure；
Fig. 4 is polypeptide A S16, polypeptide NR16, polypeptide [D-Ala1] AR17 are to the growth curve charts of Balb/c mouse；
Fig. 5 is polypeptide A S16, polypeptide NR16, polypeptide [D-Ala1] AR17 are to the H22 knurl weights of Balb/c mouse；
Fig. 6 is polypeptide A S16, polypeptide NR16, polypeptide [D-Ala1] AR17 are to the tumour inhibiting rates of Balb/c mouse.
Specific implementation mode
With reference to embodiment the present invention will be further explained explanation.Before introducing specific embodiment, to the present invention
In sample segment, medicament and instrument and equipment used be briefly described as follows.
Experiment reagent
In Fomc Solid phase peptide synthssis, Wang resins and fmoc-protected L-type amino acid and D type amino acid are purchased from gill
It is biochemical（Shanghai）Co., Ltd；
In cell culture, RPMI-1640 culture mediums（500mL/ bottles）It is purchased from Beijing Solarbio companies；FBS（Tire ox blood
Clearly, 100mL/ bottles）It is purchased from Hangzhou Chinese holly biology Co., Ltd.
Mouse samples and cancer cell
Balb/c mouse, specific pathogen free animal（SPF）Grade, female, 18-20g are purchased from Beijing China Fukang biological medicine
Science and Technology Ltd.；
Kunming mice, cleaning grade, 18-20g, experimental animal center of henan province provide；
H22 murine hepatocarcinoma cells come from medical scientific institute of Henan Province.
The foundation of Balb/c mice-transplanted tumor models
It is as follows：
（1）Take out the H22 murine hepatocarcinoma cells cultivated in culture bottle, adjustment cell concentration to 1 × 107A/mL, it is conventional
Disinfection；0.2mL is drawn with 1mL syringes（Containing 2 × 106A cell）Tumour cell（H22 murine hepatocarcinoma cells）Suspension is injected into
Kunming mice it is intraperitoneal；
（2）By H22 murine hepatocarcinoma cells after the passage of abdominal cavity more than twice, ascites, 800r/min centrifugations are taken out
8min abandons supernatant, and physiological saline is resuspended, and draws re-suspension liquid and expects that blue dyeing, microscopically observation confirm cellular activities with 0.2%
It can further be applied when rate ＞ 95%.Cell concentration is adjusted to 1 × 107A/mL, routine disinfection are spare；
（3）Draw 0.2mL（Containing 2 × 106A cell）Tumour cell（H22 murine hepatocarcinoma cells）Suspension is injected into Balb/c
Mouse right upper extremity oxter establishes Balb/c mice-transplanted tumor models, and observes and records the growing state of tumour.
Embodiment 1
Anti-angiogenesis polypeptide NR16 and its transformation peptide, the polypeptide NR16 provided herein contains 16 amino
Acid, molecular weight 1683.0, specific amino acid sequence are：
Asn-Leu-Leu-Met-Ala-Ala-Ser-Ala-Ala-Ala-Thr-Trp-Leu-Pro-Pro-Arg, i.e.,
NLLMAASAAATWLPPR；
Peptide is transformed in the NR16, is named as [D-Ala1] AR17, including 17 amino acid, molecular weight 1754.1, tool
Body amino acid sequence is：
D-Ala-Asn-Leu-Leu-Met-Ala-Ala-Ser-Ala-Ala-Ala -Thr-Trp-Leu-Pro-Pro-
Arg, i.e.,
D-ANLLMAASAAATWLPPR；
The NR16 transformation peptides [D-Ala1] AR17, it is realized by increasing a D-Ala in NR16 peptide N-terminals；
Described D-Ala, D-A represent in the polypeptide sequence first amino acid alanine as D-form.
AS16 is published in existing patent（Application number：2010101722261, publication number：CN101830971A, one
Kind novel antiangiogenic polypeptide, is in that patent V3 peptides）Polypeptide sequence, compared with existing polypeptide sequence, polypeptide
It is reverse that NR16 is that the order of connection of ATWLPPR peptide fragments and NLLMAAS peptide fragments has occurred with its main distinction in structure.
Polypeptide NR16 is prepared using Fomc solid phase polypeptide synthesis, and specific preparation process is as follows：
（1）Swellable resins, weigh the Wang resins of 0.3g, then load weighted Wang resins are poured into wash clean and drying
In Peptide synthesizer, DMF 5 mL, swellable resins 30min is added later will be in Peptide synthesizer with vacuum pump after being swollen
DMF is extracted out；
（2）The addition of first amino acid,
Arginine 462.0mg, HOBT (1- hydroxyl azimidobenzenes are weighed by the calculating of formula I）101.4mg、DIC（N, N- bis- is different
Propyl diimine）94.7 μ L,
The formula I is：The relative molecular mass of m=resin quality × 2.5 times equivalent × tie substance；
DMAP is weighed by the calculating of formula II（To lutidines）9.162mg
The formula II is：The relative molecular mass of the quality of DMAP=resin quality × 0.25 times equivalent × DMAP；
DMF is added first into beaker and comes Dissolved Amino Acids and HOBT, after amino acid and HOBT dissolvings, is poured into dress
In the Peptide synthesizer for having the resin being swollen, DIC is then directly added in synthesizer, 10min is stirred on shaking table；It adds
DMAP, shaking table stir 2.5h；
Then in the following order and number washed, DMF twice → MeOH (methanol) three times → DCM（Dichloromethane）Three
Secondary → DMF twice, vibrates washing, washs 2min every time, drained liquid with vacuum pump at the end of washing in shaking table；
It is first amino acid and the case where resin-bonded at 290nm with spectrophotometric determination wavelength, according to formula meter
Substitution value is calculated, seals up first liquid end socket twice, each 20min is vibrated in shaking table, is washed out, the same step of washing methods（2）In
Washing requirement；
Substitution value calculation formula is：Substitution value=sample OD values/（1.65 × resin quality）；
（3）The addition of second amino acid, that is, alanine,
Synthesis is carried out from the C-terminal of peptide chain to N-terminal direction, to step（2）In resin remove-insurance after an amino acid adding
Twice, deprotection is that 3 ~ 5mL deprotection liquid is added in synthesizer to shield（The volume ratio of piperidines and DMF are 1:3）, stirred in shaking table
Reaction 20min is mixed, vacuum pump is drained；
It is washed out, washing methods and the same step of step（2）Middle washing；
After washing, picking resin carries out indenes inspection, when indenes inspection is in blue（If previous amino acid is proline, serine
With when histidine then indenes inspection be in rufous, other amino acid then be blue）, second amino acid dried meat ammonia is weighed by the calculating of formula III
The amount of acid, HOBT, DIC, respectively 261.9mg, 63.8mg, 59.56 μ L,
The formula III is：Relative molecular mass × substitution value of m=resin quality × 2.5 times equivalent × tie substance；
DMF is added first into beaker and comes Dissolved Amino Acids and HOBT, after amino acid and HOBT dissolvings, is poured into dress
In the Peptide synthesizer for having the resin being swollen, DIC is then directly added in synthesizer, 2.5h is stirred to react on shaking table；
Step is pressed after reaction（2）Method wash resin, the inspection of picking resin indenes is in colourless after washing；
（4）The addition of subsequent amino-acid,
The method of addition with above-mentioned second amino acid adding procedure, until add all amino acid；
（5）The cutting of polypeptide,
Step（4）In prepared polypeptide still adhere to and is incorporated on resin, thus it is still necessary to further cut, purify；
The proportioning of cutting reagent is as follows：TFA 4.95mL, tri-distilled water 0.3mL, thioanisole 0.3mL, 1,2- ethylene dithiol
Alcohol 0.3mL, phenol 0.3mL；
Detailed process is as follows：
Suitable deprotection liquid is added into the Peptide synthesizer equipped with resin, deprotection is twice；Again in the following order into
Row washing, DMF twice → MeOH three times → DCM three times → DMF is primary → DCM twice, two minutes every time；
In draught cupboard, the cutting reagent configured is poured into synthesizer, then blender is put into synthesizer and is started
Carry out cleavage reaction 3h；
It after cutting, is filtered out in cutting liquid to balloon flask with vacuum filtration pumping, DCM is used in combination to rinse to filtering out
Until liquid color is transparent；
The TFA in cutting liquid is removed with Rotary Evaporators, Rotary Evaporators temperature is adjusted to 65 DEG C, rotary evaporation 10 ~
20min；
Due to containing arginine in polypeptide sequence, ice need to being carried out again and being cut, 5mL TFA are added into bottle, are placed in ice, shaking table
On shake 30min；Ether re-evaporation is added in balloon flask 4 ~ 6 times, is eventually adding ice ether and stands 30min on ice, in vain
Color precipitation is the thick peptide being precipitated；
After precipitation is complete, draws precipitation ether mixed liquor with suction pipe and be placed in 15mL centrifuge tubes, later 2000r/min, from
Heart 2min；Supernatant is abandoned after centrifugation and collects precipitation, continues to draw the precipitation that precipitation ether mixed liquor is resuspended in centrifuge tube later, then
Continue to centrifuge；Until collecting all precipitations, washing precipitation is resuspended in absorption ice ether later, repeated washing centrifuges 5-7 times；
Obtained thick peptide is dried in 37 DEG C of baking ovens；
Thick peptide is purified using RP HPLC, purification condition is：
Mobile phase A：Water+0.1%TFA；
Mobile phase B：Acetonitrile+0.1%TFA；
The linear gradient of Mobile phase B：20~60%；Flow velocity：5min/mL；Run time：40min；Applied sample amount：4mL；Detection
Wavelength：228nm；
By collected product first in -80 DEG C of low temperature refrigerator freeze overnights, then white is lyophilized into freeze drier
It is saved backup in -20 DEG C of refrigerators after powder.
[D-Ala1] AR17 be NR16 transformation peptide, compared with NR16 polypeptide sequences, the main distinction is the N in NR16
One D-form alanine of end addition.Polypeptide [D-Ala1] AR17 equally carries out synthesis system using Fomc solid phase polypeptide synthesis
Standby, preparation process is same as above the preparation process of NR16, it should be noted that in addition to the last one amino acid is changed to D types third when preparation
Outside propylhomoserin, other amino acid are L-type amino acid.
There is provided polypeptide NR16 and its transformation peptide [D-Ala to illustrate the invention1] AR17 tumor killing effect, the present invention is same
It is prepared for polypeptide A S16 as a contrast, the preparation of polypeptide A S refers to the prior art（Application number：2010101722261, publication number：
CN101830971A, a kind of novel antiangiogenic polypeptide are in that patent V3 peptides）, equally more using Fomc solid phases
Method of peptide synthesis is synthetically prepared.
To prepared polypeptide A S16, polypeptide NR16, NR16 transformation peptide [D-Ala1] AR17 Mass Spectrometric Identification result difference
Referring to Fig. 1, Fig. 2, Fig. 3.
From its Mass Spectrometric Identification interpretation of result can be seen that using prepared by Fomc solid phase polypeptide synthesis polypeptide A S16,
Polypeptide NR16, NR16 transformation peptide [D-Ala1] AR17 meets theoretical value, explanation is successfully prepared.
Embodiment 2
The present embodiment is mainly introduced with Balb/c mice-transplanted tumor models（Load H22 murine hepatocarcinoma cells）For organism material
Expect the related inhibiting tumor assay carried out.Related experiment situation is described in detail as follows.
The male mouse in Balb/c mice-transplanted tumor models is taken, is randomly divided into 8 groups, every group 6.8 groups are specially：It is negative
Control group（Physiological saline NS）, AS16 high dose groups（2mg/kg/d）, AS16 low dose groups（0.5mg/kg/d）, NR16 high doses
Group（2mg/kg/d）, NR16 low dose groups（0.5mg/kg/d）、[D-Ala1] AR17 high dose groups（2mg/kg/d）、[D-Ala1]
AR17 low dose groups（0.5mg/kg/d）, positive control 5-Fu（1mg/kg/d）Group.
Each group is all made of subcutaneous administrations, and administered volume is carried out according to 0.1mL/10g.Start to be administered within the 3rd day after lotus knurl,
It is administered 7 days altogether.Mouse ad lib is intake during experiment.
Tumour major diameter is measured since being administered second day（a）And minor axis（b）, gross tumor volume is calculated as follows and draws
Gross tumor volume growth curve,
Gross tumor volume=（π/6）×a×b2。
Administration puts to death mouse after 7 days, divests tumour and claims knurl weight, tumour inhibiting rate（Inhibition rate of tumor growth, Inhibition
Rate, IR）It is calculated as follows,
Inhibition rate of tumor growth=（1- administration groups average knurl weight/negative control group average knurl weight）×100%.
Gross tumor volume growth curve is as shown in figure 4, tumour knurl weight and each group tumour inhibiting rate are as shown in Figure 5, Figure 6.
Polypeptide NR16, NR16 transformation peptide [D-Ala is can be seen that from result shown in Fig. 4 ~ 61] AR17 and polypeptide A S16 mono-
Sample shows preferable tumor killing effect.AS16 (2mg/kg) group, AS16 (0.5mg/kg) group, NR16 (2mg/kg) group, NR16
(0.5mg/kg) group, [D-Ala1] AR17 (2mg/kg) group, [D-Ala1] AR17 (0.5mg/kg) group, 5Fu (1mg/kg) are organized
Tumour inhibiting rate is respectively 34.29%, 32.33%, 11.88%, 36.99%, 37.89%, 26.47%, 32.78%.NR16 (0.5mg/kg) is low
The tumor killing effect of dosage group and [D-Ala1] AR17 (2mg/kg) high dose group is slightly better than AS16 groups.It is thus preferably to make
For polypeptide A S16 supplement with even substituting polypeptide A S16, thus be that there is preferably application value.
SEQUENCE LISTING
<110>Zhengzhou University
<120>A kind of the polypeptide NR16 and its transformation peptide of anti-angiogenesis
<130> none
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 16
<212> PRT
<213>Artificial sequence
<400> 1
Asn Leu Leu Met Ala Ala Ser Ala Ala Ala Thr Trp Leu Pro Pro Arg
1 5 10 15
<210> 2
<211> 17
<212> PRT
<213>Artificial sequence
<400> 2
Ala Asn Leu Leu Met Ala Ala Ser Ala Ala Ala Thr Trp Leu Pro Pro
1 5 10 15
Arg
Claims (4)
1. a kind of anti-angiogenesis polypeptide NR16, which is characterized in that contain 16 amino acid, molecular weight 1683.0, sequence is such as
Shown in SEQ ID NO.1, specific amino acid sequence is：
Asn-Leu-Leu-Met-Ala-Ala-Ser-Ala-Ala-Ala-Thr-Trp-Leu-Pro-Pro-Arg,
I.e.：NLLMAASAAATWLPPR.
2. peptide [D-Ala is transformed in anti-angiogenesis polypeptide NR16 described in claim 11] AR17, which is characterized in that include 17 ammonia
Base acid, molecular weight 1754.1, as shown in SEQ ID NO.2, specific amino acid sequence is sequence：
D-Ala-Asn-Leu-Leu-Met-Ala-Ala-Ser-Ala-Ala-Ala-Thr-Trp-Leu-Pro-Pro-Arg,
I.e.：D-ANLLMAASAAATWLPPR；
Described D-Ala, D-A represent in the polypeptide sequence first amino acid alanine as D-form.
3. peptide [D-Ala is transformed in polypeptide NR16 described in anti-angiogenesis polypeptide NR16 or claim 2 described in claim 11]AR17
Preparation method, which is characterized in that be all made of Fomc solid phase polypeptide synthesis and be prepared.
4. peptide [D-Ala is transformed in polypeptide NR16 described in anti-angiogenesis polypeptide NR16 or claim 2 described in claim 11]AR17
As the application in tumor therapeutic agent.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830971A (en) * | 2010-05-14 | 2010-09-15 | 郑州大学 | Novel antiangiogenic polypeptide |
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| EP2224961A1 (en) * | 2007-11-26 | 2010-09-08 | The Research Foundation of the State University of New York | Small molecule cancer treatments that cause necrosis in cancer cells but do not affect normal cells |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830971A (en) * | 2010-05-14 | 2010-09-15 | 郑州大学 | Novel antiangiogenic polypeptide |
Non-Patent Citations (1)
| Title |
|---|
| 人血清白蛋白融合技术在药物长效化改造中的应用;王芙蓉等;《生命科学》;20150930;第27卷(第9期);1197-1205 * |
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