DNA Alkylator
Alkylating agent . [1]

Treosulfan 是一种烷基化剂。 Treosulfan 在 100 μg/mL 浓度下对多种癌细胞系（包括 Panc-1、Miapaca-2 和 Capan-2 细胞）表现出近 100% 的细胞毒性，IC50 分别为 3.6 μg/mL、1.8 μg/mL 和 2.1 μg /mL，分别。与 LY 188011 结合使用时，三硫丹 (0.1-100 μg/mL) 显示出更强的抗癌细胞活性。另一方面，Treosulfan（1、2.5 和 5 μg/ml）与 5-FU（0.1、0.25 和 0.5 μg/ml）组合在所有剂量下对 Miapaca-2 细胞和 Panc-1 表现出拮抗作用中浓度和高浓度的细胞[1]。 Treosulfan (800 µg/mL) 显着降低红细胞前向散射并提高 ROS、[Ca²⁺]_i 和膜联蛋白-V 结合细胞的比例。当细胞外 Ca²⁺ 被去除后，Treosulfan 对膜联蛋白-V 结合的影响就会被抵消[2]。

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Alamar Blue检测结果显示，Treosulfan 在72小时暴露后，对三种人胰腺导管癌细胞系（Panc-1、MIA PaCa-2和Capan-2）均表现出强效的剂量依赖性细胞毒性。在100 μg/ml浓度下，其细胞毒性接近100%。对Panc-1、MIA PaCa-2和Capan-2细胞的IC50值分别为3.6 μg/ml、1.8 μg/ml和2.1 μg/ml。[1]
流式细胞术分析（Annexin V/7-AAD染色）证实，用10-100 μg/ml的 treosulfan 处理会导致晚期凋亡和坏死细胞群呈强剂量依赖性增加。台盼蓝拒染法也证实了其剂量依赖性的细胞杀伤作用。[1]
Treosulfan 与吉西他滨联用，对Panc-1和MIA PaCa-2细胞系显示出强烈的协同细胞毒作用，且该协同作用与给药顺序（同时给药或间隔12小时序贯给药）无关。对于Panc-1细胞，在所有测试剂量下联合指数（CI）值在0.17至0.68之间，表明具有协同作用。对于MIA PaCa-2细胞，在中高浓度下观察到协同作用（CI值0.66-0.74）。[1]
Treosulfan 与放射治疗（1-10 Gy）联用，在Panc-1和MIA PaCa-2细胞中产生协同至相加的细胞毒作用，CI值范围在0.7至1.1之间。该协同作用也与给药顺序无关。[1]
Treosulfan 与5-氟尿嘧啶（5-FU）联用，在MIA PaCa-2细胞的所有测试剂量下（CI 1.16-1.28）以及在Panc-1细胞的中高浓度下（CI 1.6-2.1）均表现出拮抗作用。[1]

Treosulfan（1.5 g/kg/天）导致小鼠快速进行清髓并失去所有脾脏 B 和 T 细胞。 Treosulfan（1.5 g/kg/天）会短暂增加脾细胞中白细胞介素 2 的产生，但对小鼠肿瘤坏死因子-α 和/或 IFN-γ 的合成没有明显影响[3]。

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用 treosulfan（1.5 g/kg/天，连续3天）处理BALB/c小鼠，诱导了快速、强烈且持久的骨髓清除。骨髓中的粒细胞-巨噬细胞集落形成单位 (CFU-GM) 计数在最后一次给药后第1天即达到最低点，并在此低水平维持到观察期结束（第12天）。这种骨髓清除效应与白消安相当，且比环磷酰胺的更持久。[3]
用 treosulfan 处理导致脾脏中B细胞 (CD19+) 和T细胞 (CD3+) 的快速且显著耗竭。最低点（B细胞为对照的12.5%，T细胞为25%）从处理后第1天持续到第12天。这种耗竭比环磷酰胺或白消安诱导的更强、更持久。CD4+ 和 CD8+ T细胞亚群均被同等程度地耗竭。[3]
对经PMA/离子霉素体外刺激后的脾脏T细胞进行细胞因子产生分析显示，treosulfan 处理在第1至第3天诱导了产生IL-2的细胞百分比短暂增加，随后在第6至第12天降至对照水平的50%。产生TNF-α的细胞百分比与对照组相比无显著变化，而产生IFN-γ的细胞百分比从第1天到第12天普遍降低。[3]

在 96 孔组织培养板中，细胞以每孔 100 μL 体积生长，并以 1×10⁴ 细胞/mL 铺板用于细胞毒性测定。让细胞粘附一整夜后，将它们与不同浓度的 Treosulfan 单独培养或与 LY 188011 联合培养。药物组合可按顺序引入（第二种药物在第一种药物后 12 小时添加）或同时引入细胞培养物。 72 小时孵育期后，将 Alamar Blue® 溶液添加到孔中，然后再进行过夜孵育。接下来，使用分光光度计测定吸光度，并计算药物细胞毒性和细胞增殖。此外，在某些实验中，使用台盼蓝排除法测定增殖和细胞毒性，并使用改进的Neubauer血细胞计数器对细胞进行计数。通过用 7-氨基放线菌素 D（终浓度 200 μg/mL）和膜联蛋白-V 对细胞进行染色，然后使用 FACS 扫描流式细胞仪进行流式细胞术分析来评估细胞活力[1]。

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细胞毒性实验（Alamar Blue法）： 将细胞（Panc-1、MIA PaCa-2、Capan-2）以1x10^4 细胞/ml的密度（100 μl/孔）接种于96孔板中，过夜贴壁。随后，用不同浓度的 treosulfan 单独或与其他药物（吉西他滨、5-FU）联合处理72小时。对于联合研究，药物同时加入或序贯加入（第一种药物加入12小时后再加入第二种药物）。孵育后，加入Alamar Blue溶液，将板继续孵育过夜。使用分光光度计测量吸光度，并计算细胞增殖/细胞毒性。[1]
细胞活力评估（流式细胞术）： 为了区分增殖抑制和细胞死亡，用 treosulfan 处理过的细胞用Annexin-V和7-氨基放线菌素D（7-AAD）染色，并使用流式细胞仪进行分析，以鉴定凋亡和坏死细胞群。[1]
细胞活力评估（台盼蓝拒染法）： 也使用台盼蓝拒染法，随后用血细胞计数器进行细胞计数来评估细胞活力。[1]

Mice: At 10 to 12 weeks of age, female BALB/c mice weighed about 20 g. Standard pelleted feed and unlimited water are provided to the animals. They are kept in a climate-controlled room with a 12-hour light/dark cycle. There are four groups that they are split up into: one group gets treated with liposomal NCI C01592 (37 mg/kg/day) for four days straight; another group receives NSC-26271 (0.1 g/kg/day) for two days straight; a control group does not receive any treatment. To sustain the animals' survival in the absence of bone marrow support, sublethal doses of NSC-26271, NCI C01592, and treosulfan are administered. Days 1, 3, 6, 9, and 12 following the final treatment dose are dedicated to animal sacrifice, during which the femurs and spleen are extracted. Two control and six treated animals are included at each time point [3].

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Myeloablative and Immunosuppressive Study in Mice: Female BALB/c mice (10-12 weeks old) were divided into groups. The treosulfan treatment group received intraperitoneal injections of treosulfan at a dose of 1.5 g/kg/day for 3 consecutive days. This dose was sublethal, allowing survival without bone marrow support. Control groups received either cyclophosphamide (0.1 g/kg/day for 2 days), liposomal busulfan (37 mg/kg/day for 4 days), or no treatment. Animals were sacrificed on days 1, 3, 6, 9, and 12 after the last drug dose. Bone marrow (from femurs) and spleens were collected for clonogenic assays and immunological analyses (flow cytometry, cytokine analysis, MLR). [3]

Absorption, Distribution and Excretion
In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. ... The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 + or - 0.18 (mean + or - SD) using the values AUC oral = 82.1 + or- 39.4 ug/ml hr and AUC i.v. = 85.4 + or - 30.3 ug/ml hr. The peak plasma concentration cmax (29 + or - 14 ug/ml vs 65 + or - 23 ug/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 + or - 0.34 hr. The terminal half-life of treosulfan was about 1.8 hr. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 hr (range 6-26%). ... A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.

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In clinical high-dose chemotherapy regimens, plasma concentrations of treosulfan exceeding 500 μg/ml can be achieved. [1]

dog\tLDLo\tintravenous\t222 mg/kg\tGASTROINTESTINAL: OTHER CHANGES; BLOOD: LEUKOPENIA; BLOOD: OTHER CHANGES\tCancer Chemotherapy Reports, Part 2., 2(203), 1965
\nmonkey\tLDLo\tintravenous\t222 mg/kg\tBLOOD: LEUKOPENIA; BLOOD: AGRANULOCYTOSIS; BLOOD: OTHER CHANGES\tCancer Chemotherapy Reports, Part 2., 2(203), 1965\n

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\nInteractions\n
\nL-buthionine-[S,R]-sulfoximine had minor effects on the toxicity of doxorubicin, ACNU (1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosou rea, nimustine) and vincristine. L-buthionine-[S,R]-sulfoximine failed to alter teniposide or cytarabine toxicity. L-buthionine-[S,R]-sulfoximine induced prominent sensitization to the alkylating agent, treosulfan, in both cell lines, as assessed by viability assays, in situ DNA end labeling and quantitative DNA fragmentation. Treosulfan is thought to mediate toxicity via formation of reactive epoxides.\nPMID:9484802\n

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\n\nAntidote and Emergency Treatment\n
\nBasic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/\n
\nAdvanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: \"To keep open\", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/\n

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\nHuman Toxicity Excerpts\n
\n... Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 hr at escalating doses from 20 to 56 g/sq m, and pharmacokinetic parameters were analyzed. At 56 g/sq m, three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/sq m treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/sq m. A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile.\n
\nVenous blood was taken from apparently healthy volunteers and patients with cancer, the latter both before and at intervals after treatment with single cytotoxic drugs. Cells from untreated individuals were exposed to a range of concentrations of drugs in culture medium. Chlorambucil, treosulfan and cyclophosphamide (activated by hepatic microsomes) significantly increased the numbers of SCEs, both in vitro and in the lymphocytes of patients. While methotrexate and 5-fluorouracil had no effect, bleomycin slightly increased the number of SCEs, but only in vitro. Although the in vitro dose-effect relationship indicated which drugs would increase the frequency of SCE in vivo, the magnitude of the response tended to be overestimated. When patients were treated with drugs the frequency of SCE increased, then declined with time. Though this complicates the quantitative relationship between dose and damage, SCEs may be useful to monitor the effects of alkylating agents on normal tissues.\nPMID:6891648\n

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\n\nNon-Human Toxicity Excerpts\n
\nThe cytotoxicity and mutagenicity of the human carcinogen, treosulphan, and its hydrolysis product, dl-1,2:3,4-diepoxybutane (DEB), were studied in Chinese hamster ovary, AS52, cells. Treosulphan (0.1-1.0 mM) is toxic and mutagenic at the gpt locus. A strong pH dependence was noted. dl-1,2:3,4-diepoxybutane is cytotoxic and mutagenic at a much lower dose (0.025 mM), but these effects were not affected by pH. The results suggest that the toxic and mutagenic effects of treosulphan are mediated by its hydrolysis product DEB, and that the conversion of treosulphan to DEB is highly pH-dependent.\nPMID:8419160\n
\nTwo human carcinogens, 4-aminobiphenyl (4AB) and treosulphan (Treo), were tested in male B6C3F1 mice for the induction of micronuclei in bone marrow and peripheral blood cells by 1-, 2- and 3-exposure protocols. Both compounds tested positive. The magnitude of response with respect to the incidence of micronucleated polychromatic erythrocytes by 2- and 3-exposure protocols was considerably higher than by the single-exposure protocol. The peripheral blood results for Treo were as typically seen with a 24-h delay when compared to the bone marrow. The peripheral blood results for 4AB, however, differed from those expected. The incidence of MN-PCE in peripheral blood of animals exposed to 4AB was significantly greater than seen in the bone marrow in 2- and 3-exposure protocols. There was also an increase in the % PCE at the 60 mg/kg dose level as a function of time. Based on these studies, it is concluded that a step-wise scoring scheme may be the best protocol for rodent micronucleus assay, involving a 3-exposure protocol with single sampling of bone marrow (24 h after the last treatment) and two samplings of peripheral blood (24 h and 48 h after the first treatment). This approach is cost-effective, it limits the number of animals required and provides maximum sensitivity.\n

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Treosulfan triggers eryptosis, the suicidal death of erythrocytes, characterized by cell shrinkage and phosphatidylserine exposure on the cell surface. [2]
The stimulation of eryptosis by treosulfan is identified as a potential mechanism contributing to the anemia commonly observed in patients treated with this drug. The concentrations required to stimulate eryptosis in vitro (800 μg/ml) are within the range achieved in vivo during clinical use. [2]
Excessive stimulation of eryptosis may lead to adhesion of erythrocytes to the vascular wall and stimulation of blood clotting, potentially fostering vascular occlusion and thrombosis, which have been observed under treosulfan therapy. [2]

[1]. Synergistic cytotoxic activity of treosulfan and LY 188011 in pancreatic cancer cell lines. Anticancer Res. 2014 Apr;34(4):1779-84.

[2]. Programmed erythrocyte death following in vitro Treosulfan treatment. Cell Physiol Biochem. 2015;35(4):1372-80.

[3]. Myeloablative and immunosuppressive properties of treosulfan in mice. Exp Hematol. 2006 Jan;34(1):115-21.

Treosulfan can cause cancer according to California Labor Code.
Treosulphan is an odorless white crystalline powder. (NTP, 1992)
Treosulfan is a methanesulfonate ester.
Treosulfan is under investigation in Allogeneic Haematopoietic Stem Cell Transplantation. Treosulfan has been investigated for the treatment of Lymphoblastic Leukemia, Acute, Childhood.
Treosulfan is the prodrug of a bifunctional sulfonate alkylating agent with myeloablative, immunosuppressive, and antineoplastic activities. Under physiological conditions, treosulfan converts nonenzymatically to L-diepoxybutane via a monoepoxide intermediate. The monoepoxide intermediate and L-diepoxybutane alkylate DNA at guanine residues and produce DNA interstrand crosslinks, resulting in DNA fragmentation and apoptosis. In escalated doses, this agent also exhibits myeloablative and immunosuppressive activities.

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Drug Indication
Treosulfan in combination with fludarabine is indicated as part of conditioning treatment prior to allogeneic haematopoietic stem cell transplantation (alloHSCT) in adult patients and in paediatric patients older than one month with malignant and non-malignant diseases.
Conditioning treatment prior to haematopoietic-progenitor-cell transplantation

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Mechanism of Action
The anti-tumour drug treosulfan (L-threitol 1,4-bismethanesulphonate, Ovastat) is a prodrug for epoxy compounds by converting non-enzymatically to L-diepoxybutane via the corresponding monoepoxide under physiological conditions. The present study supports the hypothesis that this conversion of treosulfan is required for cytotoxicity in vitro. DNA alkylation and interstrand cross-linking of plasmid DNA is observed after treosulfan treatment, but this is again produced via the epoxide species. Alkylation occurs at guanine bases with a sequence selectivity similar to other alkylating agents such as the nitrogen mustards. In treosulfan-treated K562 cells, cross-links form slowly, reaching a peak at approximately 24 h. Incubation of K562 cells with preformed epoxides shows faster and more efficient DNA cross-linking.

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Efficacy and Safety
Efficacy was evaluated in MC-FludT.14/L Trial II (NCT00822393), a randomized active-controlled trial comparing treosulfan to busulfan with fludarabine as a preparative regimen for allogeneic transplantation. Eligible patients included adults 18 to 70 years old with AML or MDS, Karnofsky performance status ≥ 60%, and age ≥ 50 years or hematopoietic cell transplantation comorbidity index [HCTCI] score > 2. There were 570 patients randomized to treosulfan (n=280) or busulfan (n=290).
The major efficacy outcome measure was overall survival (OS), defined as the time from randomization until death from any cause. The hazard ratio for OS (stratified by donor type and risk group) compared to busulfan was 0.67 (95% CI: 0.51, 0.90) in the randomized population, 0.73 (95% CI: 0.51, 1.06) in patients with AML, and 0.64 (95% CI: 0.40, 1.02) in patients with MDS.
The most common adverse reactions (≥20%) were musculoskeletal pain, stomatitis, pyrexia, nausea, edema, infection, and vomiting. Selected Grade 3 or 4 nonhematological laboratory abnormalities were increased GGT, increased bilirubin, increased ALT, increased AST, and increased creatinine.
Recommended Dose
The recommended treosulfan dose is 10 g/m2 daily on days -4, -3, and -2 in combination with fludarabine 30 mg/m2 daily on days -6, -5, -4, -3, and -2, and allogeneic hematopoietic stem cell infusion on day 0.

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Treosulfan is an alkylating agent with known clinical activity in ovarian cancer and other solid tumors. This study is the first to report its activity against pancreatic carcinoma cell lines. [1]
The synergistic activity of treosulfan with gemcitabine and irradiation, which is independent of the administration sequence, warrants further investigation for the treatment of pancreatic cancer. [1]

C6H14O8S2

278.30056

278.013

C, 25.89; H, 5.07; O, 45.99; S, 23.04

299-75-2

299-75-2 (Treosulfan); 55-98-1 (Busulfan); 52-24-4 (Thiotepa, Girostan; AI3-24916; NSC-6396)

9882105

White to off-white solid powder

1.6±0.1 g/cm3

607.0±55.0 °C at 760 mmHg

216 °F (NTP, 1992)

320.9±31.5 °C

0.0±3.9 mmHg at 25°C

1.518

-1.64

143.96

2

8

7

16

345

2

O[C@H]([C@@H](O)COS(C)(=O)=O)COS(C)(=O)=O

YCPOZVAOBBQLRI-WDSKDSINSA-N

InChI=1S/C6H14O8S2/c1-15(9,10)13-3-5(7)6(8)4-14-16(2,11)12/h5-8H,3-4H2,1-2H3/t5-,6-/m0/s1

[(2S,3S)-2,3-dihydroxy-4-methylsulfonyloxybutyl] methanesulfonate

NSC-39069; Treosulfan; NSC 39069; Treosulphan; Ovastat; Dihydroxybusulfan; threosulphan; Treosulfano; Treosulfanum; NSC39069; (2S,3S)-2,3-Dihydroxybutane-1,4diyl dimethanesulfonate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: ~56 mg/mL (~201.2 mM)
Water: ~56 mg/mL

配方 1 中的溶解度: ≥ 2.5 mg/mL (8.98 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 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；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 2 中的溶解度: ≥ 2.5 mg/mL (8.98 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 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，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 3 中的溶解度: ≥ 2.5 mg/mL (8.98 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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 16.67 mg/mL (59.90 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 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。