Department of Pharmaceutics, Genentech, Inc,, 1 DNA Way, South San Francisco, CA 94080, USA.
Nanoscale Res Lett. 2014 Apr 1;9(1):156. doi: 10.1186/1556-276X-9-156.
Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.
紫杉醇是一种常见的化疗药物，对多种癌症有效。紫杉醇的水溶性差，需要在其商业制剂中加入大量的 Cremophor EL:乙醇（USP），这会导致患者产生过敏反应。我们评估了使用结晶纳米混悬剂与 USP 制剂将紫杉醇递送至荷瘤异种移植小鼠的效果。在静脉给予三个 20mg/kg 剂量的紫杉醇后，评估了抗肿瘤功效。评估了紫杉醇的药代动力学和组织分布，并观察到两种制剂之间存在差异。与接受 USP 制剂的小鼠相比，接受纳米混悬剂的小鼠的血浆清除率和组织与血浆的比值分别高约 33 倍和 11 倍。尽管纳米混悬剂治疗组的肿瘤与血浆的比值较高，但 USP 组的绝对紫杉醇肿瘤暴露量更高。因此，接受 USP 制剂给药的异种移植小鼠观察到更高的抗肿瘤效果（90%对 42%的肿瘤生长抑制）。这种纳米颗粒制剂活性降低似乎是由于体内溶解速度比预期的慢。这项研究说明了在将纳米混悬剂用作静脉给药方式之前，需要仔细考虑剂量和全身溶解度。
