Tubulin

尽管卡铂和紫杉醇的标准初级治疗方案的初始反应率为80%，但大多数癌症卵巢患者将在五年内出现不治之症复发，并将接受多种连续姑息治疗。因此，对化疗药物的需求很大，化疗药物不仅在临床上有效，而且具有可接受的副作用。紫杉醇多颖壳（PPX）是一种最近开发的紫杉烷，其中紫杉醇与聚（l-谷氨酸）结合，使其水溶性，减少超敏反应，并优先将其靶向肿瘤[1]。

紫杉烷仍然是延长去势抵抗转移性前列腺癌症生存期的唯一药物，但它们对该疾病自然史的影响不大。我们试图检验这样一种假设，即通过使用雌二醇调节的紫杉醇大分子聚合物药物偶联物来增加紫杉烷化疗对肿瘤的输送，可以扩大这类药物的效用。尽管接受了标准激素治疗，但在含多西他赛的化疗后仍进展的前列腺转移性腺癌患者接受了为期4周的经皮雌二醇（0.2 mg/24小时）治疗，随后每28天接受一次相同剂量的经皮雌激素和紫杉醇聚晶（PPX；150 mg/m静脉注射）治疗。主要目的是确定使用一部分血清前列腺特异性抗原（PSA）下降50%或更多的患者测量的方案活性水平。一项旨在确定反应率≥25%的两阶段II期研究要求在第一阶段的21名患者中有3名反应者。在2007年3月至2008年5月期间，21名接受了两种早期化疗方案中位数的患者参加了这项试验。在仅使用雌二醇的治疗阶段，没有患者的PSA下降超过50%，五名患者的PSA降幅较小，范围在8.8%至34.1%之间。在添加PPX后，没有患者的PSA下降≥50%，可测量的疾病也没有反应。进展的中位时间为4周。总之，这种低剂量透皮雌二醇诱导和PPX方案在紫杉烷预处理的去势耐受性前列腺癌症患者中没有活性[2]。

Taxanes remain the only agents to extend survival in castration-resistant metastatic prostate cancer, but their impact on the natural history of this disease is modest. We sought to test the hypothesis that increased delivery of taxane chemotherapy to the tumor through the use of a macromolecular polymer-drug conjugate of paclitaxel modulated by estradiol could extend the utility of this class of drugs. Patients with metastatic adenocarcinoma of the prostate who progressed despite standard hormonal therapy and after docetaxel-containing chemotherapy were treated with transdermal estradiol (0.2 mg/24 h) for 4 weeks followed by the same dose of transdermal estradiol and paclitaxel poliglumex (PPX; 150 mg/m intravenous) every 28 days. The primary objective was to determine the level of activity of the regimen measured using a fraction of patients who experienced a confirmed decline in serum prostate-specific antigen (PSA) of 50% or more. A two-stage phase II study designed to identify a response rate of > or =25% required three responders among 21 patients in the first stage. Twenty-one patients who received a median of two earlier chemotherapy regimens were enrolled in the trial between March 2007 and May 2008. During the estradiol-only treatment phase, no patient had a PSA decline in excess of 50% and lesser PSA declines that ranged from 8.8 to 34.1% were seen in five patients. No patients achieved a > or =50% PSA decline following the addition of PPX and there were no responses in measurable disease. The median time to progression was 4 weeks. In conclusion, this regimen of low-dose transdermal estradiol induction followed by PPX does not have activity in taxane pretreated patients with castration-resistant prostate cancer.[2]

[1]. Paclitaxel poliglumex for ovarian cancer. Expert Opin Investig Drugs. 2011 Jun;20(6):813-21.
[2]. A phase II study of paclitaxel poliglumex in combination with transdermal estradiol for the treatment of metastatic castration-resistant prostate cancer after docetaxel chemotherapy. Anticancer Drugs. 2010 Apr;21(4):433-8.

Paclitaxel Poliglumex is the agent paclitaxel linked to a biodegradable, water-soluble polyglutamate polymer with antineoplastic properties. The polyglutamate residue increases the water solubility of paclitaxel and allows delivery of higher doses than those achievable with paclitaxel alone. Paclitaxel promotes microtubule assembly and prevents microtubule depolymerization, thus interfering with normal mitosis.

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Despite an 80% initial response rate to the standard primary regimen of carboplatin and paclitaxel, most women with ovarian cancer will experience recurrence with incurable disease within five years and will be treated with several successive palliative regimens. Consequently, a significant need exists for chemotherapeutic agents, which are not only clinically efficacious, but have acceptable side-effect profiles. Paclitaxel poliglumex (PPX) is a recently developed taxane in which paclitaxel is conjugated to poly(l-glutamic acid), which renders it water soluble, reduces hypersensitivity reactions and preferentially targets it to the tumor. Areas covered: This review covers pre-clinical pharmacokinetic data and key Phase I and II clinical trial results in ovarian cancer. Expert opinion: While PPX is active in ovarian cancer, it is unclear at present whether it offers significant benefit in terms of its side-effect profile or outcomes over a standard taxane-based regimen as first-line therapy, or what role it will have in maintenance therapy as studies are ongoing.[1]

C52H60N2O18

1001.04

853.33

C, 62.39; H, 6.04; N, 2.80; O, 28.77

263351-82-2

186040-50-6 (ceribate); 117527-50-1 (Paclitaxel-Succinic acid); 33069-62-4; 263351-82-2 (Poliglumex)

134715513

Typically exists as solid at room temperature

1.4±0.1 g/cm3

957.1±65.0 °C at 760 mmHg

532.6±34.3 °C

0.0±0.3 mmHg at 25°C

1.637

7.38

322Ų

7

19

18

72

1940

12

O1C[C@@]2([C@H]1C[C@@H]([C@@]1(C)C([C@@H](C3=C(C)[C@H](C[C@](C3(C)C)([C@H]([C@H]21)OC(C1C=CC=CC=1)=O)O)OC([C@@H]([C@H](C1C=CC=CC=1)NC(C1C=CC=CC=1)=O)O)=O)OC(C)=O)=O)O)OC(C)=O

ZPUHVPYXSITYDI-ZYOSQDPASA-N

InChI=1S/C47H51NO14.C5H9NO4/c1-25-31(60-43(56)36(52)35(28-16-10-7-11-17-28)48-41(54)29-18-12-8-13-19-29)23-47(57)40(61-42(55)30-20-14-9-15-21-30)38-45(6,32(51)22-33-46(38,24-58-33)62-27(3)50)39(53)37(59-26(2)49)34(25)44(47,4)56-3(5(9)10)1-2-4(7)8/h7-21,31-33,35-38,40,51-52,57H,22-24H2,1-6H3,(H,48,54)3H,1-2,6H2,(H,7,8)(H,9,10)/t31-,32-,33-,35-,36+,37+,38-,40-,45+,46-,47-3-/m00/s1

(2aS,4S,4aS,6R,9S,11R,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-3,4,4a,5,6,9,10,11,12,12a-decahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b(2aH)-diyl diacetate L-glutamate

PPX PG-TXL; Paclitaxel Poliglumex; CT-2103; CT2103; Paclitaxel Poliglumex; 263351-82-2; 2-aminopentanedioic acid;[(1R,4S,10S)-4,12-diacetyloxy-15-(3-benzamido-2-hydroxy-3-phenylpropanoyl)oxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate; PG-TXL; CT 2103; PPX; Opaxio; Xyotax

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。