Tumor targeting by conjugation of DHA to paclitaxel
Tumor targeting by conjugation of DHA to paclitaxel
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DOI：
10.1016/s0168-3659(01)00321-2
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发表时间：
2001-07-06
影响因子：
10.8
通讯作者：
Donehower, RC
中科院分区：
文献类型：
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作者：
Bradley, MO;Swindell, CS;Donehower, RC
将抗癌药物靶向肿瘤应增加肿瘤中的药物浓度-时间曲线下面积 (AUC)，同时减少正常细胞中的 AUC，因此应增加该药物的治疗指数。抗肿瘤药物的半衰期通常远短于大多数肿瘤细胞的细胞周期通过时间。肿瘤靶向，伴随着较长的肿瘤暴露时间。当药物浓度高时，会增加进入周期的细胞比例，这会导致更多的肿瘤细胞死亡。为了验证这一假设，我们通过酯键将天然脂肪酸二十二碳六烯酸 (DHA) 与紫杉醇 2'-氧缀合。所得紫杉醇脂肪酸缀合物（DHA-紫杉醇）不会组装微管且无毒。在 M109 小鼠肿瘤模型中，DHA-紫杉醇的毒性低于紫杉醇，治愈 10/10 的肿瘤动物，而紫杉醇治愈 0/10。对于该缀合物具有较高治疗指数的一种解释是，脂肪酸改变了药物的药代动力学，增加了其在肿瘤中的 AUC，并降低了其在正常细胞中的 AUC。为了测试这种可能性，我们比较了 DHA-紫杉醇和紫杉醇在带有类似 125 mg sc M109 肿瘤的 CD2F1 小鼠中的药代动力学。在零时间向小鼠注射 DHA-紫杉醇或以 10% cremophor/10% 乙醇/80% 盐水配制的紫杉醇推注。根据14天的时间函数处死动物。冷冻并储存肿瘤和血浆。通过LC/MS/MS分析紫杉醇和DHA-紫杉醇的浓度。结果表明，DHA 将紫杉醇靶向肿瘤：在等毒剂量下，DHA-紫杉醇的肿瘤 AUC 比紫杉醇高 61 倍，在等摩尔剂量下高 8 倍。同样，在等毒剂量下，静脉注射紫杉醇的肿瘤 AUC DHA-紫杉醇比静脉注射紫杉醇高 6.1 倍。紫杉醇。静脉注射紫杉醇的肿瘤浓度紫杉醇迅速下降，因此到 16 小时时，它已降至与 DHA-紫杉醇等毒浓度后相同的浓度 (2.8 μM)。在血浆中，DHA-紫杉醇MTD剂量后的紫杉醇AUC约为DHA-紫杉醇AUC的0.5%。因此，在M109小鼠肿瘤模型中，施用DHA-紫杉醇后肿瘤AUC和紫杉醇有限血浆AUC的增加与DHA-紫杉醇相对于紫杉醇的治疗指数的增加一致。约翰·霍普金斯医院已完成一项 I 期临床研究，以评估 DHA-紫杉醇对多种实体瘤患者的安全性。迄今为止，已有 21 名患者接受治疗。推荐的II期剂量为1100 mg/m(2)，相当于最大批准紫杉醇摩尔剂量的4.6倍。未观察到脱发或明显的周围神经病变、恶心或呕吐。无症状、短暂性中性粒细胞减少症是主要副作用。 22 名可评估的 I 期患者中有 11 名从进展期疾病转变为稳定期疾病。通过后续 CT 评估。人们观察到生活质量显着改善。因此。 DHA-紫杉醇在患者中具有良好的耐受性，并通过将药物靶向肿瘤来治愈小鼠的肿瘤。 (C) 2001 年由 Elsevier Science B.V. 出版
Targeting an anti-cancer drug to tumors should increase the Area Under the drug concentration-time Curve (AUC) in tumors while decreasing the AUC in normal cells and should therefore increase the therapeutic index of that drug. Anti-tumor drugs typically have half-lives far shorter than the cell cycle transit times of most tumor cells. Tumor targeting, with concomitant long tumor exposure times. will increase the proportion of cells that move into cycle when the drug concentration is high, which should result in more tumor cell killing. In an effort to test that hypothesis, we conjugated a natural fatty acid, docosahexaenoic acid (DHA), through an ester bond to the paclitaxel 2 ' -oxygen. The resulting paclitaxel fatty acid conjugate (DHA-paclitaxel) does not assemble microtubules and is non-toxic. In the M109 mouse tumor model, DHA-paclitaxel is less toxic than paclitaxel and cures 10/10 tumored animals, whereas paclitaxel cures 0/10. One explanation for the conjugate's greater therapeutic index is that the fatty acid alters the pharmacokinetics of the drug to increase its AUC in tumors and decrease its AUC in normal cells. To test that possibility, we compared the pharmacokinetics of DHA-paclitaxel with paclitaxel in CD2F1 mice bearing similar to 125 mg sc M109 tumors, The mice were injected at zero time with a bolus of either DHA-paclitaxel or paclitaxel formulated in 10% cremophor/10% ethanol/80% saline. Animals were sacrificed as a function of time out to 14 days. Tumors and plasma were frozen and stored. The concentrations of paclitaxel and DHA-paclitaxel were analyzed by LC/MS/MS. The results show that DHA targets paclitaxel to tumors: tumor AUCs are 61-fold higher for DHA-paclitaxel than for paclitaxel at equitoxic doses and eight-fold higher at equimolar doses. Likewise, at equi-toxic doses, the tumor AUCs of paclitaxel derived from i.v. DHA-paclitaxel are 6.1-fold higher than for paclitaxel derived from i.v. paclitaxel. The tumor concentration of paclitaxel derived from i.v. paclitaxel drops rapidly, so that by 16 h it has fallen to the same concentration (2.8 muM) as after an equi-toxic concentration of DHA-paclitaxel. In plasma, paclitaxel AUC after an MTD dose of DHA-paclitaxel is approximately 0.5% of DHA-paclitaxel AUC. Thus, the increase in tumor AUC and the limited plasma AUC of paclitaxel following DHA-paclitaxel administration are consistent with the increase in therapeutic index of DHA-paclitaxel relative to paclitaxel in the M109 mouse tumor model. A phase I clinical study has been completed at The Johns Hopkins Hospital to evaluate the safety of DHA-paclitaxel in patients with a variety of solid tumors. Twenty-one patients have been treated to date. The recommended phase II dose is 1100 mg/m(2), which is equivalent to 4.6 times the maximum approved paclitaxel dose on a molar basis. No alopecia or significant peripheral neuropathy, nausea, or vomiting have been observed. Asymptomatic, transient neutropenia has been the primary side effect. Eleven of 22 evaluable phase I patients transitioned from progressive to stable disease. as assessed by follow-up CT. Significant quality of life improvements have been observed. Thus. DHA-paclitaxel is well tolerated in patients and cures tumors in mice by targeting drug to tumors. (C) 2001 Published by Elsevier Science B.V.