Department of Pharmaceutical Sciences, College of Pharmacy , Texas A&M University , Reynolds Medical Building, TAMU Mail Stop 1114 , College Station , Texas 77843 , United States.
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine , The University of Texas MD Anderson Cancer Center , Houston , Texas 77030 , United States.
ACS Chem Neurosci. 2019 Mar 20;10(3):1801-1812. doi: 10.1021/acschemneuro.8b00703. Epub 2019 Jan 17.
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.
利用细胞毒性药物（如紫杉醇（PTX））进行化疗仍然是治疗局部和转移性癌症的常用治疗方法。与传统方案中给予最大耐受剂量的 PTX 不同，通过更频繁和更低剂量给予 PTX 的节拍式方案更具优势，可发挥抗血管生成和免疫调节作用。然而，PTX 诱导的周围神经病变和缺乏 PTX 的患者顺应性剂型是节拍式方案成功实施的主要障碍。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。大鼠在四个交替日经腹腔注射 2 毫克/千克体重的 PTX 或 nPTX，并通过行为评估、组织学和免疫组织化学来表征神经病变和神经元损伤。在 16 天的研究期间，nPTX 治疗组大鼠的触觉和痛觉压力阈值降低明显低于 PTX 治疗组大鼠。组织学分析显示，nPTX 组大鼠的背根神经节（DRG）退化和脊髓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，与 PTX 治疗组大鼠相比，nPTX 治疗组大鼠脊髓、DRG 和坐骨神经中的神经元标志物 β-微管蛋白-III 密度增加，TUNEL 阳性细胞减少，高分子量神经丝增加。因此，这项工作对于改善 PTX 的风险效益比具有重要意义，为节拍式方案铺平了道路。
