Novel self-assembling PEG-p-(CL-co-TMC) polymeric micelles as safe and effective delivery system for Paclitaxel
Novel self-assembling PEG-p-(CL-co-TMC) polymeric micelles as safe and effective delivery system for Paclitaxel
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DOI：
10.1016/j.ejpb.2009.06.015
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发表时间：
2009-10-01
影响因子：
4.9
通讯作者：
Preat, Veronique
中科院分区：
文献类型：
--
作者：
Danhier, Fabienne;Magotteaux, Nicolas;Preat, Veronique
紫杉醇（PTX）是一种有效的抗癌药物，目前用于治疗多种癌症。不幸的是，含有 Cremophor(R) EL 的非水载体会产生严重的临床副作用。这项工作旨在评估聚合物胶束 (i) 在没有 Cremophor(R) EL 的情况下溶解 PTX 的能力，以及用作 (ii) 安全且 (iii) 有效的 PTX 递送系统的能力。因此，我们开发了新型自组装聚(乙二醇)(750)-嵌段-聚(ε-己内酯-共-三亚甲基碳酸酯)(PEG-p-(CL-co-TMC)聚合物胶束，其在水溶液中自发形成胶束。PTX的溶解度增加了三个数量级。负载PTX的胶束表现出PTX的缓慢释放，没有爆发效应。MTT测试评估的HeLa细胞活力较低负载 PTX 的胶束的 IC50 值高于紫杉醇 (R) (IC50 10.6 vs. 17.6 μ g/ml)。当溶解在胶束中时，M 诱导的细胞凋亡与紫杉醇 (R) 相当。腹膜内给药后，负载 PTX 的胶束和紫杉醇 (R) 的最大耐受剂量 (MTD) 分别为 80 mg/kg 和 45。静脉注射后，13.5 mg/kg 剂量的 PTX 胶束和 Taxol(R) 分别具有相似的抗肿瘤功效，而仅在 Taxol(R) 组中观察到体重减轻。然而，由于耐受较高剂量（80 mg/kg-IP），负载 PTX 的胶束诱导了更高的生长延迟。负载 PTX 的自组装胶束具有与紫杉醇 (Taxol) 类似的抗肿瘤功效，但显着降低了毒性，允许增加剂量以获得更好的治疗反应 (C) 2009 Elsevier B.V. 保留所有权利。
Paclitaxel (PTX) is an effective anti-cancer drug currently used to treat a wide variety of cancers. Unfortunately, nonaqueous vehicle containing Cremophor(R) EL is associated with serious clinical side effects. This work aimed to evaluate the ability of polymeric micelles to (i) solubilize PTX without Cremophor(R) EL and to be used as a (ii) safe and (iii) effective delivery system for PTX. Hence, we developed novel self-assembling poly(ethyleneglycol)(750)-block-poly(epsilon-caprolactone-co-trimethylenecarbonate) (PEG-p-(CL-co-TMC) polymeric micelles which form micelles spontaneously in aqueous solution. The solubility of PTX increased up to three orders of magnitude. The PTX-loaded micelles showed a slow release of PTX with no burst effect. The HeLa cells viability assessed by the MTT test was lower for PTX-loaded micelles than for Taxol(R) (IC50 10.6 vs. 17.6 mu g/ml). When solubilized in micelles, M induced apoptosis comparable with Taxol(R). The maximum tolerated doses (MTD) of PTX-loaded micelles and Taxol(R) in mice were 80 mg/kg and 13.5 mg/kg, respectively, after intraperitoneal administration; and 45 mg/kg and 13.5 mg/kg, respectively, after intravenous administration. Similar anti-tumor efficacy of PTX-loaded micelles and Taxol(R) was observed at the dose of 13.5 mg/kg on TLT-tumor-bearing mice, while the body weight loss was only observed in Taxol(R) group. However, as higher dose was tolerated (80 mg/kg-IP), a higher growth delay was induced with PTX-loaded micelles. These results demonstrated that PTX-loaded self-assembling micelles present a similar anti-tumor efficacy as Taxol(R), but significantly reduced the toxicity allowing the increase in the dose for better therapeutic response. (C) 2009 Elsevier B.V. All rights reserved.