CN105412930A - Application of TPO (thrombopoietin) receptor agonist in promoting homing of HSCs (hematopoietic stem cells) - Google Patents
Application of TPO (thrombopoietin) receptor agonist in promoting homing of HSCs (hematopoietic stem cells) Download PDFInfo
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Abstract
The invention discloses an application of a TPO (thrombopoietin) receptor agonist in promoting homing of HSCs (hematopoietic stem cells). The TPO receptor agonist can effectively promote homing of the HSCs after a bone marrow transplantation operation and further can be effectively used for preparation of a drug for promoting homing of the HSCs. The drug can increase the number of the homing HSCs and improve the homing efficiency of the HSCs and further can promote implantation of the HSCs and increase the success rate of transplantation of bone marrow HSCs.
Description
Priority information
The application's request on 08 07th, 2015 is submitted to China national Department of Intellectual Property, number of patent application is priority and the rights and interests of the patent application of 201510483901.5, and is incorporated to herein in full by referring to by it.
Technical field
The present invention relates to field of biological pharmacy, particularly, relate to the purposes of thrombopoietin receptor agonist in promoting hematopoietic stem cell to go back to the nest.
Background technology
Hematopoietic stem cell (Hematopoieticstemcells, HSC) is transplanted has become one of important means of the multiple malignant hematologic disease of clinical treatment, immunodeficiency diseases etc.After hematopoietic stem cell transplantation, go back to the nest in receptor hematopoieticmicroenviron-ment through blood circulation, carry out breeding, breaking up, rebuild hemopoietic and the immune system of receptor, thus reach the object for the treatment of.Hematopoietic stem cell is implanted for a long time in recipient's body, is subject to the impact of many factors, and wherein the hematopoietic stem cell efficiency of going back to the nest in bone marrow is an important influence factor.In 24 hours after transplanted cells, by effective short medicine of going back to the nest be used for reach the object increasing the hematopoietic stem cell quantity of going back to the nest, significant for the implantation efficiency improving hematopoietic stem cell.
But the medicine promoting hematopoietic stem cell to go back to the nest after not still being applied to transplantation of hematopoietic stem cell clinically at present, the medicine for this field needs to be studied further.
Summary of the invention
The present invention is intended at least to solve one of technical problem existed in prior art.For this reason, one object of the present invention is to propose thrombopoietin receptor agonist for the preparation of promoting the purposes that hematopoietic stem cell is gone back to the nest in medicine in transplantation of hematopoietic stem cell.
It should be noted that, the present invention completes based on the following work of inventor:
Recombined human thrombopoietin (rhTPO) is clinically for platelet reconstitution after thrombocytopenia, idiopathic thrombocytopenic purpura and hematopoietic stem cell transplantation caused after chemotherapy.Thrombopoietin action target spot is the c-MPL receptor of cell surface.Hematopoietic stem cell and megalokaryocyte surface expression c-MPL.Thrombopoietin and receptors bind, have activated downstream signaling pathway, have adjusted hematopoietic stem cell and the biological behaviour such as Megakaryocytic amplification and differentiation.
Based on people's recombinant platelet generate element can safely, be effectively applied to the clinical treatment of the postoperative thrombocytopenia of Allogeneic Hematopoietic Stem Cell Transplantation, inventor studies further and finds that thrombopoietin and thrombopoietin receptor (c-MPL) agonist all play an important role to going back to the nest of hematopoietic stem cell, obviously can increase hematopoietic stem cell goes back to the nest to the quantity of bone marrow, and then promote the implantation of hematopoietic stem cell, improve the transplanting succeed rate of hematopoietic stem cell.
Further, inventor is found by a series of research, and eltrombopag olamine, by lowering the expression of mmp-9 gene in Mice Body, reduces MMP9 protein excretion, suppresses SDF-1 α degraded, regulates hematopoietic stem/progenitor cells homing by upsetting SDF-1 α/CXCR4 functional shaft.And traditional thrombopoietin research is thought, the activation of TPO receptor (c-Mpl) can regulate hematopoietic stem cell to Meloid progenitor → megakaryoblast → platelet differentiation by signal paths such as Jak/STAT, PI3K/AKT, Ras/MAPK.Obviously, two kinds of effects of TPO receptor stimulating agent, regulatory mechanism has essential distinction.And then according to an aspect of the present invention, the invention provides thrombopoietin receptor agonist and preparing the purposes in medicine, described medicine promotes that hematopoietic stem cell is gone back to the nest.
The discovery that inventor is surprised, medicine prepared by application thrombopoietin receptor agonist, going back to the nest of hematopoietic stem cell can be promoted in transplantation of hematopoietic stem cell, increase the quantity of the hematopoietic stem cell of going back to the nest, improve hematopoietic stem cell to go back to the nest efficiency, and then improve the transplanting succeed rate of marrow hemopoietic stem cells.
According to embodiments of the invention, described thrombopoietin receptor agonist is for being selected from least one in eltrombopag olamine, Luo meter Si booth, AKR-501, AS1070542, MA01G4G344 and VB22Bsc (Fv) 2, preferred eltrombopag olamine (SB-497115; Eltrombopag).Thus, utilize described medicine can significantly improve hematopoietic stem cell to go back to the nest efficiency.
According to a further aspect in the invention, the invention provides a kind of medicine for promoting hematopoietic stem cell to go back to the nest.According to the embodiment of the present invention, this pharmaceutical pack is containing thrombopoietin receptor agonist.
The discovery that inventor is surprised, this medicine can promote going back to the nest of hematopoietic stem cell in transplantation of hematopoietic stem cell, increases the quantity of hematopoietic stem cell of going back to the nest, and improves hematopoietic stem cell and to go back to the nest efficiency, and then improve the transplanting succeed rate of marrow hemopoietic stem cells.
According to embodiments of the invention, described thrombopoietin receptor agonist is for being selected from least one in eltrombopag olamine, Luo meter Si booth, AKR-501, AS1070542, MA01G4G344 and VB22Bsc (Fv) 2, preferred eltrombopag olamine.Thus, in transplantation of hematopoietic stem cell, utilize described medicine, hematopoietic stem cell can be significantly improved and to go back to the nest efficiency.According to the embodiment of the present invention, described medicine is at least one being selected from injection, granule, Tablet and Capsula agent, optimizing injection.
According to the embodiment of the present invention, described medicine adopts normal saline or PBS to dilute.
According to the embodiment of the present invention, described medicine carries out administration in 24 hours clear marrow pre-irradiation 24 is little after bone marrow transplantation.According to concrete examples more of the present invention, described medicine carries out administration in 4 hours clear marrow pre-irradiation 24 is little after bone marrow transplantation.Thus, it is effective that medicine promotes that hematopoietic stem cell is gone back to the nest, and then promote the early stage implantation of hematopoietic stem cell.
According to the embodiment of the present invention, the route of administration of described medicine is at least one being selected from subcutaneous injection, intramuscular injection, intravenous injection and oral administration gavage.According to concrete examples more of the present invention, preferred oral gastric infusion.Thus, the good absorbing effect of medicine.
According to the embodiment of the present invention, the dosage of described medicine is 10-400mg/kg.Thus, the good effect of medicine.
Additional aspect of the present invention and advantage will part provide in the following description, and part will become obvious from the following description, or be recognized by practice of the present invention.
Accompanying drawing explanation
Above-mentioned and/or additional aspect of the present invention and advantage will become obvious and easy understand from accompanying drawing below combining to the description of embodiment, wherein:
Fig. 1 shows according to one embodiment of the invention, utilizes Flow cytometry donor mouse hematopoietic stem cell (CD45.1/LSK) to go back to the nest in recipient's body the schematic diagram of ratio;
Fig. 2 and Fig. 3 shows according to one embodiment of the invention, utilizes the method for Colony cultivation to detect the schematic diagram of the go back to the nest quantity of donor mouse hematopoietic stem cell in recipient's body.
Detailed description of the invention
Be described below in detail embodiments of the invention, the example of described embodiment is shown in the drawings.Being exemplary below by the embodiment be described with reference to the drawings, only for explaining the present invention, and can not limitation of the present invention being interpreted as.
According to an aspect of the present invention, the invention provides thrombopoietin receptor agonist and preparing the purposes in medicine, described medicine promotes that hematopoietic stem cell is gone back to the nest.
The discovery that inventor is surprised, medicine prepared by application thrombopoietin receptor agonist, going back to the nest of hematopoietic stem cell can be promoted in transplantation of hematopoietic stem cell, increase the quantity of the hematopoietic stem cell of going back to the nest, improve hematopoietic stem cell to go back to the nest efficiency, and then improve the transplanting succeed rate of marrow hemopoietic stem cells.
According to embodiments of the invention, the kind of described thrombopoietin receptor agonist is not particularly limited, such as eltrombopag olamine, Luo meter Si booth (Romiplostim), AKR-501, AS1070542, MA01G4G344, VB22Bsc (Fv) 2 etc., as long as it possesses thrombopoietin receptor agonist function, effectively thrombopoietin receptor can be activated.According to concrete examples more of the present invention, preferably, described thrombopoietin receptor agonist is eltrombopag olamine.Thus, utilize described medicine can significantly improve hematopoietic stem cell to go back to the nest efficiency.
According to a further aspect in the invention, the invention provides a kind of medicine for promoting hematopoietic stem cell to go back to the nest.According to the embodiment of the present invention, this pharmaceutical pack is containing thrombopoietin receptor agonist.
The discovery that inventor is surprised, this medicine can promote going back to the nest of hematopoietic stem cell in transplantation of hematopoietic stem cell, increases the quantity of hematopoietic stem cell of going back to the nest, and improves hematopoietic stem cell and to go back to the nest efficiency, and then improve the transplanting succeed rate of marrow hemopoietic stem cells.
As previously mentioned, the kind of thrombopoietin receptor agonist is not particularly limited.According to some embodiments of the present invention, described thrombopoietin receptor agonist is for being selected from least one in eltrombopag olamine, Luo meter Si booth, AKR-501, AS1070542, MA01G4G344 and VB22Bsc (Fv) 2, preferred eltrombopag olamine (Eltrompobag).Thus, in transplantation of hematopoietic stem cell, utilize described medicine, hematopoietic stem cell can be significantly improved and to go back to the nest efficiency.According to the embodiment of the present invention, described medicine is at least one being selected from injection, granule, Tablet and Capsula agent, optimizing injection.
According to the embodiment of the present invention, described medicine adopts normal saline or PBS (i.e. phosphate buffer, pH=7.4) to dilute.
According to the embodiment of the present invention, described medicine carries out administration in 24 hours clear marrow pre-irradiation 24 is little after bone marrow transplantation.According to concrete examples more of the present invention, described medicine carries out administration in 4 hours clear marrow pre-irradiation 24 is little after bone marrow transplantation.Thus, it is effective that medicine promotes that hematopoietic stem cell is gone back to the nest, and effectively can improve curative effect of medication.
According to the embodiment of the present invention, the route of administration of described medicine is not particularly limited, such as, can pass through intravenous administration, administered intramuscular, intravenous administration or oral administration gavage administration.According to concrete examples more of the present invention, preferably by oral administration gavage administration.Thus, the good absorbing effect of medicine.
According to the embodiment of the present invention, the effective dosage scope of described safety of medicine can reach 10-400mg/kg, according to medication demand and treatment individual variation, suitably can adjust according to clinical experience.According to concrete example of the present invention, for 6-8 week age, 20g body weight, male C57BL/45.1 Strains of Mouse, is carrying out Co
60roentgenization, dosage 9.5Gy, irradiated after 20-22 hour, and the dosage of described medicine is 100mg/kg.Thus, the good effect of medicine.
According to the embodiment of the present invention, described medicine can single or multiple administration, according to medication demand and treatment individual variation, suitably can adjust according to clinical experience.According to the concrete example of the present invention, for 6-8 week age, 20g body weight, male C57BL/45.1 Strains of Mouse, is carrying out Co
60roentgenization, dosage 9.5Gy, irradiated after 20-22 hour, can based on the dosage determined by single-dose or twice administration.Thus, the good effect of medicine.
Below in conjunction with embodiment, the solution of the present invention is made an explanation.It will be understood to those of skill in the art that the following examples only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted concrete technology or condition in embodiment, according to the technology described by the document in this area or condition or carry out according to product description.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
Embodiment 1
According to following steps, detect the impact that thrombopoietin receptor agonist eltrombopag olamine is gone back to the nest on hematopoietic stem cell after bone marrow cell transplantation:
1, separating mouse medullary cell
C57BL/45.1 Strains of Mouse purchased from Beijing China Fukang bio tech ltd, 6-8 week age, 18-22g body weight, male, this batch of mice is as bone marrow cell transplantation donor.The early stage hematopoietic stem/progenitor cells of this mice and leukocyte surface stably express CD45.1, be used from competitive transplantation experiments with C57BL/45.2 Strains of Mouse one.Mice steady statue more than one week, vertebra dislocation is put to death, and takes out femur and tibia, and repeatedly rinses medullary cavity with PBS, and the cell suspension of acquisition centrifugal 5 minutes with 600g, then adds erythrocyte cracked liquid (BDFACS according to every mice 2ml
tMlysingSolution, CAT.No:55899, with deionized water 1:10 dilution before using), add equal-volume PBS after 2 minutes, the centrifugal 5min of 600g, and wash 2 times, obtain bone marrow cells in mice suspension, for subsequent use.
2, thrombopoietin receptor agonist eltrombopag olamine promotes the experiment that mouse hematopoetic cell is gone back to the nest
C57BL/45.2 Strains of Mouse purchased from Beijing Military Medical Science Institute Experimental Animal Center, 6-8 week age, 18-22g body weight, male.Mice steady statue, after one week, is carried out
60co gamma-rays irradiates (cobalt source is provided by Academy of Military Medicine, PLA), dosage 9.5Gy.This batch connects irradiated mice will as bone marrow cell transplantation receptor, that the mice of marrow hemopoietic stem cells removing is (because the hemopoietic tissue such as bone marrow are extreme spoke sensitive organization, be subject to the hemopoietic tissue heavy damage of mice after the radiation of doses, 9.5Gy radiation can cause the hematopoietic stem/progenitor of mouse bone marrow cells and the irreversible damage of hematopoieticmicroenviron-ment, if can not get rational treatment, most (>=95%) mice can be dead after 6 ~ 7 days after exposure).
After mice irradiation 20 hours, the medullary cell of the C57BL6J/CD45.1 mice of the fresh separated obtained by tail vein transplantation above-mentioned steps 1, often only transplanted 4 × 10
7cell.After mice is irradiated and/or after completing cell transplantation, carry out the following step (completing in 4 hours after being preferable over cell transplantation) immediately: experimental mice oral administration gavage gives the thrombopoietin receptor stimulating agent eltrombopag olamine (Eltrompobag of 100mg/kg, Beijing Chemsun Pharmaceutical Technology Co., Ltd., article No.: normal saline solution 20140425), matched group oral administration gavage gives isopyknic normal saline, often organizes 5 mices.
For above-mentioned each group of mice, 18-20 hour after completing cell transplantation, mice is put to death in vertebra dislocation, and take out femur and tibia, repeatedly rinse medullary cavity to turning white with PBS, the centrifugal 5min of 600g, abandons supernatant.Then 10ml erythrocyte cracked liquid (BDFACS is added
tMlysingSolution, CAT.No:55899, with deionized water 1:10 dilution before using), add equal-volume PBS stopped reaction after 2 minutes, the centrifugal 5min of 600g, abandons supernatant, identical centrifugal condition 20mlPBS washes 2 times, obtain Recipient mice medullary cell, then carry out following experiment: flow cytometry and hematopoietic colonies cultural method detect the ratio of the hematopoietic cell of going back to the nest in recipient's body, specific as follows:
2.1 Flow cytometry:
According to following steps, Flow cytometry is utilized to go back to the nest the ratio of the hematopoietic cell in recipient's body:
(1) for each mice in above-mentioned two groups of mices, its medullary cell is resuspended in the PBS of 100 μ l, obtaining concentration is 1 × 10
6the cell suspension of/ml;
(2) in above-mentioned cell suspension, add anti-mouse CD45.2, each 1 μ l of Sca-1, c-Kit antibody, Lineage antibody 0.3 μ l, after concussion mixing, put on the runner of 4 degrees Celsius of refrigerators, hatch 40min;
(3) cell after hatching is carried out centrifugal, 600g, 5min;
(4) the cell PBS after centrifugal is washed twice, be settled to 200 μ l, carry out flow cytometer detection, the results are shown in Figure 1.
2.2 hematopoietic colonies cultural methods detect:
According to following steps, hematopoietic colonies cultural method is utilized to detect the ratio of the hematopoietic cell of going back to the nest in recipient's body:
For each mice in above-mentioned two groups of mices, get 1 × 10
4medullary cell, by it, (formula is: 0.9% methylcellulose, 15% hyclone with 500 μ L mouse hematopoetic cell semisolid culturemediums, 100U/ml penicillin/streptomycin, 1mM Sodium Pyruvate, 2mM glutamine, 2mMPFHM II, 200 μ g/ml transferrins, 1 volume %BSA, 0.45mMMTG, 30 volume %IMDM, 50ng/mlSCF, 10ng/mlTPO, 10ng/mlIL-3,10ng/mlIL-11,10ng/mlGM-CSF, 3U/mlEPO) mixing, be placed in 37 DEG C, 5%CO
2cultivate in incubator after 4 days, erythroid hematopoiesis colony forming unit (CFU-E) is counted, cultivate after 4 days respectively to sudden and violent formula erythroid hematopoiesis colony forming unit (BFU-E), grain system-monokaryon system hematopoietic colonies forms unit (CFU-GM) and polyphyly hematopoietic colonies formation unit (CFU-GEMM) counts, and the results are shown in Figure 2 and Fig. 3.
Experimental result shows, the hematopoietic stem/progenitor (CD45.1 of donor source in the Recipient mice medullary cavity that oral platelet generates plain receptor stimulating agent eltrombopag olamine
+cD45.2
-l
-s
+k
+) ratio obviously rises (concrete outcome is shown in Fig. 1), illustrates that the go back to the nest ratio of the hematopoietic stem/progenitor of donor bone marrow in Recipient mice bone marrow significantly raises.As shown in Figure 1, left side is little by figure: CD45.1
+cD45.2
-represent the ratio of the hemocyte in donor mice source, middle little figure: represent from left side CD45.1
+cD45.2
-continue in cell mass to analyze Lin
-the ratio of cell mass, this group of cells represent donor Mouse Blood pedigree mark and are expressed as negative hematopoietic cell; The little figure in right side: represent from upper level Lin
-continue in cell mass to analyze Sca-1
+c-kit
+the ratio of cell, i.e. LSK cell (Lin
-sca-1
+c-kit
+; L
-s
+k
+) represent mouse hemopoietic ancestral cells.In figure, three streaming figure of matched group and administration group respectively show donor-derived cells (CD45.1 in recipient mice medullary cavity
+cD45.2
-) and wherein blood lineage negative cells, hematopoietic stem/progenitor (Lin
-, Lin
-sca-1
+c-kit
+) ratio.
In addition, the hematopoietic colonies total quantity that administration group bone marrow cells in mice is formed is obviously more than matched group about 1 times, illustrate that the hematopoietic stem/progenitor cells homing of more donor mice is in Recipient mice medullary cavity, and have the potentiality (concrete outcome is shown in Fig. 2-3) playing hematopoietic reconstitution function further.As shown in Figure 3, CFU-GM represents that grain system-monokaryon system hematopoietic colonies forms unit, and CFU-E represents erythroid hematopoiesis colony forming unit, and BFU-E represents sudden and violent formula erythroid hematopoiesis colony forming unit, and CFU-GEMM represents that mixed stocker hematopoietic colonies forms unit.As can be seen from the figure, the hematopoietic colonies total quantity that administration group bone marrow cells in mice is formed, especially red system and mixed stocker hematopoietic colonies quantity, comparatively matched group has and significantly increases.
The above results shows that thrombopoietin receptor agonist eltrombopag olamine can promote donor hematopoietic stem/progenitor cells homing, improve the quantity of the hematopoietic stem cell of going back to the nest, promote the hemopoietic system after damage and reconstruction, for the better rehabilitation faster of body provides basis.
By real-time quantitative PCR and Western-Blotting experiment, inventor find eltrombopag olamine can reduce mice mmp-9 gene expression, suppress its protein expression, and mmp-9 has Degradation for SDF-1 α, latter plays a significant role in hematopoietic stem/progenitor cells homing process.Therefore, inventor's research thinks that eltrombopag olamine passes through to lower the expression of mmp-9 gene in Mice Body, reduces MMP9 protein excretion, regulates hematopoietic stem/progenitor cells homing further by SDF-1 α/CXCR4 functional shaft.And traditional thrombopoietin research is thought, the activation of TPO receptor (c-Mpl) can regulate hematopoietic stem cell to Meloid progenitor → megakaryoblast → megakaryoblast → platelet differentiation by signal paths such as Jak/STAT, PI3K/AKT, Ras/MAPK, and the two has essential distinction on regulatory mechanism.
In the description of this description, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.
Although illustrate and describe embodiments of the invention, those having ordinary skill in the art will appreciate that: can carry out multiple change, amendment, replacement and modification to these embodiments when not departing from principle of the present invention and aim, scope of the present invention is by claim and equivalents thereof.
Claims (10)
1. thrombopoietin receptor agonist is preparing the purposes in medicine, and described medicine is for promoting that hematopoietic stem cell is gone back to the nest.
2. purposes according to claim 1, described thrombopoietin receptor agonist is for being selected from least one in eltrombopag olamine, Luo meter Si booth, AKR-501, AS1070542, MA01G4G344 and VB22Bsc (Fv) 2, preferred eltrombopag olamine.
3. the medicine for promoting hematopoietic stem cell to go back to the nest, is characterized in that, comprises thrombopoietin receptor agonist.
4. medicine according to claim 3, it is characterized in that, described thrombopoietin receptor agonist is for being selected from least one in eltrombopag olamine, Luo meter Si booth, AKR-501, AS1070542, MA01G4G344 and VB22Bsc (Fv) 2, preferred eltrombopag olamine.
5. medicine according to claim 3, is characterized in that, described medicine is at least one being selected from injection, granule, Tablet and Capsula agent, is preferably injection.
6. medicine according to claim 3, is characterized in that, described medicine adopts normal saline or PBS to dilute.
7. medicine according to claim 3, is characterized in that, described medicine carries out administration in 24 hours clear marrow pre-irradiation 24 is little after bone marrow transplantation.
8. medicine according to claim 7, is characterized in that, described medicine carries out administration in 4 hours clear marrow pre-irradiation 24 is little after bone marrow transplantation.
9. medicine according to claim 3, is characterized in that, the route of administration of described medicine is at least one being selected from subcutaneous injection, intramuscular injection, intravenous injection and oral administration gavage, preferred oral gastric infusion.
10. medicine according to claim 3, is characterized in that, the dosage of described medicine is 10-400mg/kg.
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| CN112022825A (en) * | 2020-08-24 | 2020-12-04 | 瑞阳制药有限公司 | Alvatripopa maleate tablet and preparation method thereof |
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| CN104232582A (en) * | 2014-08-27 | 2014-12-24 | 军事医学科学院华南干细胞与再生医学研究中心 | Application of poloxamer in inducing haemopoietic stem progenitor cell proliferation and/or meganucleus differentiation |
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