Chemotherapy utilizing cytotoxic drugs, such as paclitaxel (PTX), is still a commonly used therapeutic approach to treat both localized and metastasized cancers. Unlike traditional regimens in which PTX is administered at the maximum tolerated dose, alternative regimens like metronomic dosing are beneficial by administering PTX more frequently and in much lower doses exploiting antiangiogenic and immunomodulatory effects. However, PTX-induced peripheral neuropathy and lack of patient compliant dosage forms of PTX are major roadblocks for the successful implementation of metronomic regimens. Because of the success of polyester nanoparticle drug delivery, we explored the potential of nanoparticle-encapsulated paclitaxel (nPTX) in alleviating peripheral neuropathy using a rat model. Rats were injected intraperitoneally with 2 mg/kg body weight of PTX or nPTX on four alternate days, and neuropathic pain and neuronal damage were characterized using behavioral assessments, histology, and immunohistochemistry. The reduction in tactile and nociceptive pressure thresholds was significantly less in nPTX-treated rats than in PTX-treated rats over a 16-day study period. Histological analysis showed that the degree of dorsal root ganglion (DRG) degeneration and reduction in motor neurons in the spinal cord was significantly lower in the nPTX group than the PTX group. Further, immunofluorescence data reveals that nPTX-treated rats had an increased density of a neuronal marker, β-tubulin-III, reduced TUNEL positive cells, and increased high molecular weight neurofilament in the spinal cord, DRG, and sciatic nerves compared with PTX-treated rats. Therefore, this work has important implications in improving risk–benefit profile of PTX, paving the way for metronomic regimens.

中文翻译：

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聚酯纳米粒子封装减轻紫杉醇诱导的周围神经病变。

利用细胞毒性药物如紫杉醇（PTX）的化学疗法仍然是治疗局部和转移性癌症的常用治疗方法。与以最大耐受剂量施用PTX的传统方案不同，替代方案（如节拍剂量）通过更频繁地施用PTX并以低得多的剂量利用抗血管生成和免疫调节作用而受益。但是，PTX引起的周围神经病变和患者缺乏顺应性的PTX剂型是成功实施节律疗法的主要障碍。由于聚酯纳米颗粒药物递送的成功，我们使用大鼠模型探索了纳米颗粒包裹的紫杉醇（nPTX）在缓解周围神经病变方面的潜力。在每隔4天给大鼠腹膜内注射2 mg / kg体重的PTX或nPTX，并通过行为评估，组织学和免疫组化来表征神经性疼痛和神经元损伤。在16天的研究期内，nPTX处理的​​大鼠的触觉和伤害感受阈值的降低明显少于PTX处理的​​大鼠。组织学分析表明，nPTX组的脊髓背根神经节（DRG）变性和运动神经元减少程度明显低于PTX组。此外，免疫荧光数据显示，经nPTX处理的​​大鼠神经元标记物β-微管蛋白III密度增加，TUNEL阳性细胞减少，而脊髓DRG中高分子量神经丝增多，和坐骨神经相比，PTX治疗的大鼠。因此，这项工作对改善PTX的风险收益特征具有重要意义，为节拍疗法铺平了道路。