Danhier Fabienne, Magotteaux Nicolas, Ucakar Bernard, Lecouturier Nathalie, Brewster Marcus, Préat Véronique
Université Catholique de Louvain, Unité de Pharmacie Galénique, Brussels B-1200, Belgium.
Eur J Pharm Biopharm. 2009 Oct;73(2):230-8. doi: 10.1016/j.ejpb.2009.06.015. Epub 2009 Jul 3.
Paclitaxel (PTX) is an effective anti-cancer drug currently used to treat a wide variety of cancers. Unfortunately, nonaqueous vehicle containing Cremophor EL is associated with serious clinical side effects. This work aimed to evaluate the ability of polymeric micelles to (i) solubilize PTX without Cremophor 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 (IC(50) 10.6 vs. 17.6 microg/ml). When solubilized in micelles, PTX induced apoptosis comparable with Taxol. The maximum tolerated doses (MTD) of PTX-loaded micelles and Taxol in mice were 80 mg/kg and 13.5mg/kg, respectively, after intraperitoneal administration; and 45 mg/kg and 13.5mg/kg, respectively, after intravenous administration. Similar anti-tumor efficacy of PTX-loaded micelles and Taxol was observed at the dose of 13.5mg/kg on TLT-tumor-bearing mice, while the body weight loss was only observed in Taxol 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, but significantly reduced the toxicity allowing the increase in the dose for better therapeutic response.
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，含有聚氧乙烯蓖麻油（Cremophor EL）的非水载体与严重的临床副作用相关。这项工作旨在评估聚合物胶束（i）在不含Cremophor EL的情况下增溶PTX的能力，并用作PTX的（ii）安全和（iii）有效递送系统。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。载有PTX的胶束显示PTX缓慢释放，无突释效应。通过MTT试验评估，载有PTX的胶束对HeLa细胞活力的抑制作用低于紫杉醇（IC（50）分别为10.6和17.6μg/ml）。当溶解在胶束中时，PTX诱导的细胞凋亡与紫杉醇相当。腹腔注射后，载有PTX的胶束和紫杉醇在小鼠中的最大耐受剂量（MTD）分别为80mg/kg和13.5mg/kg；静脉注射后分别为45mg/kg和13.5mg/kg。在携带TLT肿瘤的小鼠中，在13.5mg/kg的剂量下观察到载有PTX的胶束和紫杉醇具有相似的抗肿瘤疗效，而体重减轻仅在紫杉醇组中观察到。然而，由于能耐受更高的剂量（80mg/kg - 腹腔注射），载有PTX的胶束诱导了更高的生长延迟。这些结果表明，载有PTX的自组装胶束具有与紫杉醇相似的抗肿瘤疗效，但显著降低了毒性，从而可以增加剂量以获得更好的治疗反应。
