Peripheral neuropathy is a common side effect of paclitaxel. Clinical studies suggest that different paclitaxel formulations influence the severity and time course of paclitaxel-induced peripheral neuropathy. We compared two paclitaxel formulations, nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and Cremophor EL paclitaxel (CreEL-paclitaxel), for their toxicity, distribution, and clearance in the peripheral nervous system. Neuronal F11 cells were used to detect changes in morphology, cell nuclei size, and cell viability after nab- or CreEL-paclitaxel treatment via MTT Assay and immunohistochemistry. C57BL/6 mice were treated with 50 mg/kg of nab-paclitaxel or CreEL-paclitaxel. Paclitaxel levels in serum, liver, dorsal root ganglia (DRG), and sciatic nerve (SCN) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Accumulation of paclitaxel in DRG neurons and SCN was visualized by immunostainings. Neurotoxicity was evaluated after a 4-week treatment regime with nab- or CreEL-paclitaxel by nerve morphology, behavioral, and functional assays. In vitro cell nuclei size and morphology were similar between the two treatment groups. Viability was increased in neurons exposed to nab-paclitaxel compared to CreEL-paclitaxel. In vivo paclitaxel mostly accumulated in DRG. SCN displayed lower paclitaxel uptake. The two paclitaxel formulations mainly accumulated in neurofilament 200-positive large-caliber neurons and less in Isolectin B4-, or calcitonin gene-related peptide-positive small-caliber neurons. Sensory nerve conduction studies demonstrated increased sensory latencies after 11 days in nab-paclitaxel treated animals, while an increase occurred after 22 days in CreEL-paclitaxel treated animals. Behavioral testing did not reveal significant differences between the different groups. Skin denervation, axon count, myelin thickness, and F4/80-positive cell accumulation were comparable between the two treatment groups. Our findings indicate that different drug formulations impact the severity of neuropathy induced by paclitaxel via different tissue uptake. Neurotoxicity was comparable between the two paclitaxel formulations.

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药物配方对紫杉醇诱导神经病变临床前模型动力学和毒性的影响

周围神经病变是紫杉醇的常见副作用。临床研究表明，不同的紫杉醇制剂会影响紫杉醇诱导的周围神经病变的严重程度和时间进程。我们比较了两种紫杉醇制剂，纳米颗粒白蛋白结合紫杉醇 (nab-paclitaxel) 和 Cremophor EL 紫杉醇 (CreEL-paclitaxel)，它们在周围神经系统中的毒性、分布和清除率。神经元 F11 细胞用于通过 MTT 分析和免疫组织化学检测 nab 或 CreEL 紫杉醇处理后形态、细胞核大小和细胞活力的变化。用 50 mg/kg nab-紫杉醇或 CreEL-紫杉醇处理 C57BL/6 小鼠。通过液相色谱-串联质谱 (LC-MS/MS) 测量血清、肝脏、背根神经节 (DRG) 和坐骨神经 (SCN) 中的紫杉醇水平。通过免疫染色可见紫杉醇在背根神经节神经元和 SCN 中的积累。在用 nab 或 CreEL 紫杉醇治疗 4 周后，通过神经形态、行为和功能测定评估神经毒性。两个治疗组之间的体外细胞核大小和形态相似。与 CreEL-紫杉醇相比，暴露于 nab-紫杉醇的神经元的活力增加。体内紫杉醇主要在 DRG 中积累。SCN 显示较低的紫杉醇摄取。两种紫杉醇制剂主要在神经丝 200 阳性大口径神经元中积累，而在异凝集素 B4 或降钙素基因相关肽阳性小口径神经元中积累较少。感觉神经传导研究表明，白蛋白结合型紫杉醇治疗的动物在 11 天后感觉潜伏期增加，而 CreEL-紫杉醇处理的动物在 22 天后出现增加。行为测试没有显示不同组之间的显着差异。两个治疗组的皮肤去神经、轴突计数、髓鞘厚度和 F4/80 阳性细胞积累具有可比性。我们的研究结果表明，不同的药物配方会通过不同的组织摄取影响紫杉醇诱导的神经病变的严重程度。两种紫杉醇制剂的神经毒性相当。我们的研究结果表明，不同的药物配方会通过不同的组织摄取影响紫杉醇诱导的神经病变的严重程度。两种紫杉醇制剂的神经毒性相当。我们的研究结果表明，不同的药物配方会通过不同的组织摄取影响紫杉醇诱导的神经病变的严重程度。两种紫杉醇制剂的神经毒性相当。