JAK2 (IC50 = 2.8 nM); JAK1 (IC50 = 3.3 nM); Tyk2 (IC50 = 19 nM); JAK3 (IC50 = 428 nM)

Ruxolitinib 磷酸盐 (INCB018424) 以有效且特异的方式抑制 JAK2V617F 介导的信号传导和增殖。 Ruxolitinib 磷酸盐的 EC50 值为 186 nM，这意味着它抑制 HEL 细胞生长。 Ruxolitinib 磷酸盐可显着抑制原发性 MPN 患者样本中造血祖细胞的增殖并增加 Ba/F3-EpoR-JAK2V617F 细胞凋亡 [1]。

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INCB018424抑制白细胞介素-6信号传导（50%抑制浓度[IC50]=281nM）和JAK2V617F+Ba/F3细胞的增殖（IC50=127nM）。在原代培养中，INCB018424优先抑制JAK2V617F+真性红细胞增多症患者（IC50=67nM）与健康供体（IC50>400nM）的红系祖细胞集落形成。[1]

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此外，在用JAK1抑制剂ruxolitinib治疗后，具有活性JAK/STAT信号传导的HOXA9+患者来源的异种移植物（PDX）样本中，PIM1 RNA和蛋白质水平迅速下调（图6C）。这为JAK/STAT信号下游PIM1调控的功能信号网络提供了进一步的证据。利用这一观察结果，我们接下来试图确定PIM1和JAK1的双重抑制是否对JAK/STAT突变T-ALL样本有益。在这里，我们观察到在离体细胞培养中用JAK激酶抑制剂（ruxolitinib）与PIM1抑制剂（AZD1208）联合治疗JAK3突变T-ALL样品时出现了协同反应[3]。

在注射 JAK2V617F 表达细胞的小鼠中，磷酸卢福替尼（180 mg/kg，口服）可减轻肿瘤负荷，且不会导致贫血或淋巴细胞减少症 [1]。

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在JAK2V617F+MPN的小鼠模型中，口服INCB018424显著降低了脾肿大和循环中炎性细胞因子的水平，并优先消除了肿瘤细胞，从而显著延长了存活时间，而没有骨髓抑制或免疫抑制作用。初步临床结果支持这些临床前数据，并将INCB018424确立为治疗MPNs的有前景的口服药物。[1]

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JAK1/2抑制剂鲁索利替尼可降低CSF3RT618I小鼠的白细胞计数并减少脾肿大[2]
我们之前已经证明，激活CSF3R突变会导致通过JAK激酶的优先下游信号传导，一名携带JAK激活CSF3RT618I突变的CNL患者在服用JAK1/2抑制剂ruxolitinib后表现出明显的临床改善。1为了确定CSF3RT68I小鼠中观察到的粒细胞扩增是否依赖于JAK激酶途径，我们在第二组CSF3RT617I小鼠中测试了ruxolitnib的效果。移植后第12天开始口服ruxolitinib（90mg/kg 2×/d）或赋形剂，此时小鼠已经出现白细胞增多。鲁索利替尼治疗导致白细胞计数迅速减少，脾脏重量减少（图2A-C）。与改善骨髓纤维化疲劳和早期饱腹感等体质症状的能力一致，12,13鲁索利替尼治疗的小鼠与赋形剂治疗的小鼠相比体重增加（图2D）。这表明CSF3RT618I小鼠模型中粒细胞的病理扩张对JAK抑制敏感，并值得进一步研究JAK抑制剂在携带CSF3RT617I突变的CNL患者中的治疗应用。

生化测定[1]
用N-末端表位标签通过PCR克隆人JAK1（837-1142）、JAK2（828-1132）、JAK3（781-1124）和Tyk2（873-1187）的激酶结构域。使用Sf21细胞和杆状病毒载体表达重组蛋白，并用亲和层析纯化。JAK激酶测定使用肽底物（-EQUEDEPEGDYFEWLE）的均匀时间分辨荧光测定。用测试化合物或对照、JAK酶、500nM肽、三磷酸腺苷（ATP；1mM）和2.0%二甲基亚砜（DMSO）进行每种酶反应1小时。50%抑制浓度（IC50）计算为抑制50%荧光信号所需的化合物浓度。CHK2和c-MET酶的生化测定使用标准条件（Michaelis常数[Km]ATP）进行，具有来自每种蛋白质和合成肽底物的重组表达的催化结构域 使用标准条件（CEREP；www.CEREP.com）使用200nM INCB018424进行额外的激酶测定（Abl、Akt1、AurA、AurB、CDC2、CDK2、CDK4、CHK2、c-kit、c-Met、EGFR、EphB4、ERK1、ERK2、FLT-1、HER2、IGF1R、IKKα、IKKβ、JAK2、JAK3、JNK1、Lck、MEK1、p38α、p70S6K、PKA、PKCα、Src和ZAP70）。显著抑制被定义为与对照值相比大于或等于30%（重复测定的平均值）。

细胞增殖测定[1]
将细胞接种在2000/孔的白色底部96孔板上，用来自DMSO储备的化合物（0.2%的最终DMSO浓度）处理，并在37°C下用5%CO2孵育48小时。通过使用Cell Titer Glo萤光素酶试剂的细胞ATP测定或活细胞计数来测量存活率。将值转换为相对于车辆控制的抑制百分比，并根据使用PRISM GraphPad的数据的非线性回归分析拟合IC50曲线<小时> 细胞凋亡[1]

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膜联蛋白V染色。
将细胞处理20至24小时，并用膜联蛋白V和碘化丙啶染色，分别用于分析早期凋亡和死亡细胞。使用FACSCaliber流式细胞仪进行分析。 线粒体膜电位。将细胞处理24小时，然后与2μM染料JC-1一起孵育。使用488nm激发和530nm和585nm发射滤光片通过流式细胞术进行分析。JC-1在线粒体中表现出电位依赖性积累，其发射在红色光谱（590nM）中。从红色（590nM）到绿色（530nM）的荧光转移表明，由于线粒体膜电位的丧失，染料重新分布到细胞质中，线粒体膜电位是细胞凋亡的早期标志物<小时> 菌落形成测定[1]

In vivo treatment with INCB018424 in a myeloproliferative neoplasm mouse model [1]
Mice were fed standard rodent chow and provided with water ad libitum. Ba/F3-JAK2V617F cells (105 per mouse) were inoculated intravenously into 6- to 8-week-old female BALB/c mice. Survival was monitored daily, and moribund mice were humanely killed and considered deceased at time of death. Treatment with vehicle (5% dimethyl acetamide, 0.5% methocellulose) or INCB018424 began within 24 hours of cell inoculation, twice daily by oral gavage. Hematologic parameters were measured using a Bayer Advia120 analyzed, and statistical significance was determined using Dunnett testing.

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Histology and morphometric analysis [1]
Tissue samples of spleen were fixed in 10% neutral buffered formalin and processed through graded alcohols and a clearing agent, infiltrated and embedded in paraffin, sectioned at 5 μm, and stained with hematoxylin and eosin. To quantify the effects of INCB018424 on white pulp, a simple morphometric method using point-counts was devised. Images of spleen at 2 times magnification were overlaid with a standardized grid. Point counts were by made tabulating the grid intersects that overlaid total spleen and white pulp. Point counts for white pulps were summed for each group, that is, naive (N = 3), vehicle-treated (N = 6), and INCB018424-treated (N = 6), and mean values calculated. An approximate mean mass of white pulp was calculated using the mean weights of spleens for each group and the relative mean point counts for total spleen and white pulp. Photographic images were acquired with a Nikon Eclipse E800 microscope equipped with a Nikon 20×/0.75 Plan Apo objective, and a Nikon DXM1200 digital camera. Images were processed on a Dell computer with Nikon ACT/1 software and Adobe Photoshop 7.0.

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In Vivo and Ex Vivo Treatment of PDX Samples [3]
PDX samples were transplanted in 8-week-old NSG mice through tail-vein injection. Human leukemic cell expansion was monitored through human CD45 staining on blood samples. Single cells were isolated from the spleen, which at time of sacrifice contained >85% human CD45+ cells. Spleen cells were seeded in 96-well plate (5 × 105 cells/well) and incubated with vehicle (DMSO) or inhibitor. Cell viability was assessed at 48 hours using ATP-Lite. CompuSyn was used to calculate the combination index. For in vivo treatment studies, the XC65 was transduced overnight with lentivirus pCH-SFFV-eGFP-P2A-fLuc. The GFP-positive cells were then sorted using the S3 Sorter and retransplanted back into recipient NSG mice. Upon confirmation that XC65 was greater than >95% GFP positive, leukemic cells were isolated from the spleen and reinjected into a larger cohort of NSG mice for acute 7-day in vivo treatment. Ruxolitinib was dissolved in 0.5% methylcellulose, AZD1208 was dissolved in 50% PEG400/0.5% methylcellulose, and both were administered by oral gavage.

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Dissolved in 5% dimethyl acetamide, 0.5% methocellulose; 180 mg/kg/day; Oral gavage

JAK2V617F-driven mouse model

Absorption, Distribution and Excretion
Following oral administration, ruxolitinib undergoes rapid absorption and the peak concentrations are reached within one hour after administration. Over a single-dose range of 5 mg to 200 mg, the mean maximal plasma concentration (Cmax) increases proportionally. Cmax ranged from 205 nM to 7100 nM and AUC ranged from 862 nM x hr to 30700 nM x hr. Tmax ranges from one to two hours following oral administration. Oral bioavailability is at least 95%.
Following oral administration of a single radiolabeled dose of ruxolitinib, the drug was mainly eliminated through metabolism. About 74% of the total dose was excreted in urine and 22% was excreted in feces, mostly in the form of hydroxyl and oxo metabolites of ruxolitinib. The unchanged parent drug accounted for less than 1% of the excreted total radioactivity.
The mean volume of distribution (%coefficient of variation) at steady-state is 72 L (29%) in patients with myelofibrosis and 75 L (23%) in patients with polycythemia vera. It is not known whether ruxolitinib crosses the blood-brain barrier.
Ruxolitinib clearance (% coefficient of variation) is 17.7 L/h in women and 22.1 L/h in men with myelofibrosis. Drug clearance was 12.7 L/h (42%) in patients with polycythemia vera and 11.9 L/h (43%) in patients with acute graft-versus-host disease.
Following oral administration, absorption of ruxolitinib is approximately 95%, and mean systemic bioavailability is estimated to be about 80%. Following oral administration of ruxolitinib, peak plasma concentrations are achieved within 1-2 hours. ... Following administration of a single oral dose of radiolabeled ruxolitinib in healthy individuals, elimination was predominantly through metabolism with 74 and 22% of radioactivity excreted in urine and feces, respectively. Unchanged drug accounted for less than 1% of the excreted total radioactivity.

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Metabolism / Metabolites
More than 99% of orally-administered ruxolitinib undergoes metabolism mediated by CYP3A4 and, to a lesser extent, CYP2C9. The major circulating metabolites in human plasma were M18 formed by 2-hydroxylation, and M16 and M27 (stereoisomers) formed by 3-hydroxylation. Other identified metabolites include M9 and M49, which are formed by hydroxylation and ketone formation. Not all metabolite structures are fully characterized and it is speculated that many metabolites exist in stereoisomers. Metabolites of ruxolitinib retain inhibitory activity against JAK1 and JAk2 to a lesser degree than the parent drug.
Cytochrome P-450 (CYP) isoenzyme 3A4 is the major enzyme responsible for metabolism of ruxolitinib. Two major active metabolites were identified in the plasma of healthy individuals; all active metabolites contribute 18% of the overall pharmacodynamic activity of ruxolitinib.
Ruxolitinib is metabolized mainly by cytochrome P-450 (CYP) isoenzyme 3A4.

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Biological Half-Life
The mean elimination half-life of ruxolitinib is approximately 3 hours and the mean half-life of its metabolites is approximately 5.8 hours.
The mean half-life of ruxolitinib following a single oral dose is approximately 3 hours, and the mean half-life of ruxolitinib and its metabolites is approximately 5.8 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of ruxolitinib during breastfeeding. Because ruxolitinib is 97% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during ruxolitinib therapy and for 2 weeks after the last dose for the oral tablets and for 4 weeks after the last dose for the topical cream.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood, 2010, 115(15), 3109-3117.

[2]. The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition. Blood. 2013 Nov 21;122(22):3628-31.

[3]. HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development. Cancer Discov. 2018 May;8(5):616-631.

Ruxolitinib phosphate is a phosphate salt obtained by reaction ruxolitinib with one equivalent of phosphoric acid. Used for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. It has a role as an antineoplastic agent and an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor. It contains a ruxolitinib.
Ruxolitinib Phosphate is the phosphate salt form of ruxolitinib, an orally bioavailable Janus-associated kinase (JAK) inhibitor with potential antineoplastic and immunomodulating activities. Ruxolitinib specifically binds to and inhibits protein tyrosine kinases JAK 1 and 2, which may lead to a reduction in inflammation and an inhibition of cellular proliferation. The JAK-STAT (signal transducer and activator of transcription) pathway plays a key role in the signaling of many cytokines and growth factors and is involved in cellular proliferation, growth, hematopoiesis, and the immune response; JAK kinases may be upregulated in inflammatory diseases, myeloproliferative disorders, and various malignancies.
See also: Ruxolitinib (has active moiety).

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Drug Indication
Opzelura is indicated for the treatment of non-segmental vitiligo with facial involvement in adults and adolescents from 12 years of age.
Myelofibrosis (MF)Jakavi is indicated for the treatment of disease related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis. Polycythaemia vera (PV)Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Graft versus host disease (GvHD)Jakavi is indicated for the treatment of patients aged 12 years and older with acute graft versus host disease or chronic graft versus host disease who have inadequate response to corticosteroids or other systemic therapies (see section 5. 1).
Treatment of atopic dermatitis
Treatment of chronic Graft versus Host Disease (cGvHD)
Treatment of acute graft-versus-host disease (aGvHD)
Treatment of vitiligo.

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Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC(50)] = 281nM), and proliferation of JAK2V617F(+) Ba/F3 cells (IC(50) = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F(+) polycythemia vera patients (IC(50) = 67nM) versus healthy donors (IC(50) > 400nM). In a mouse model of JAK2V617F(+) MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs. [1]

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We have recently identified targetable mutations in CSF3R (GCSFR) in 60% of chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL-negative) chronic myeloid leukemia (aCML) patients. Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model. Mice transplanted with CSF3R T618I-expressing hematopoietic cells developed a myeloproliferative disorder characterized by overproduction of granulocytes and granulocytic infiltration of the spleen and liver, which was uniformly fatal. Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced spleen weight. This demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. This murine model is an excellent tool for the further study of neutrophilic myeloproliferative neoplasms and implicates the clinical use of JAK inhibitors for this disease. [2]

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Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared with JAK3 or HOXA9 alone. Integrated RNA sequencing, chromatin immunoprecipitation sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) revealed that STAT5 and HOXA9 have co-occupancy across the genome, resulting in enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9-expressing cells.Significance: The mechanism of oncogene cooperation in cancer development remains poorly characterized. In this study, we model the cooperation between activated JAK/STAT signaling and ectopic HOXA9 expression during T-cell leukemia development. We identify a direct cooperation between STAT5 and HOXA9 at the transcriptional level and identify PIM1 kinase as a possible drug target in mutant JAK/STAT/HOXA9-positive leukemia cases. [3]

C₁₇H₂₁N₆O₄P

404.36

404.136

1092939-17-7

Ruxolitinib;941678-49-5;Ruxolitinib (S enantiomer);941685-37-6;Ruxolitinib sulfate;1092939-16-6

25127112

Typically exists as white to gray solids at room temperature

2.537

170.75

4

8

4

28

503

1

N#CC[C@H](C1CCCC1)N2N=CC(C3=C4C=CNC4=NC=N3)=C2.O=P(O)(O)O

JFMWPOCYMYGEDM-XFULWGLBSA-N

InChI=1S/C17H18N6.H3O4P/c18-7-5-15(12-3-1-2-4-12)23-10-13(9-22-23)16-14-6-8-19-17(14)21-11-20-16;1-5(2,3)4/h6,8-12,15H,1-5H2,(H,19,20,21);(H3,1,2,3,4)/t15-;/m1./s1

(3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile;phosphoric acid

INCB-018424 phosphate, INCB 018424, INCB018424; INC424, INC424, INC-424; INCB18424, INCB 18424, 1092939-17-7; (R)-3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate; OPZELURA; Ruxolitinib (phosphate); ruxolitinib monophosphate; INCB-18424; Jakafi and Jakavi (trade name)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.75 mg/mL (6.80 mM) (饱和度未知) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.75 mg/mL (6.80 mM) (饱和度未知) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (5.14 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 4 中的溶解度: ≥ 2.08 mg/mL (5.14 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100μL 20.8mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 5 中的溶解度: ≥ 2.08 mg/mL (5.14 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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配方 6 中的溶解度: 2% DMSO+30% PEG 300+ddH2O:5mg/mL

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配方 7 中的溶解度: 10 mg/mL (24.73 mM) in 0.5% MC 0.5% Tween-80 (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。