Prevention of paclitaxel-induced neuropathy by formulation approach.
Prevention of paclitaxel-induced neuropathy by formulation approach.
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DOI：
10.1016/j.jconrel.2019.04.013
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发表时间：
2019-06
期刊：
影响因子：
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通讯作者：
Xiaowei Zang;Jong Bong Lee;K. Deshpande;O. Garbuzenko;T. Minko;L. Kagan
中科院分区：
文献类型：
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作者：
Xiaowei Zang;Jong Bong Lee;K. Deshpande;O. Garbuzenko;T. Minko;L. Kagan
化疗引起的周围神经病变（CIPN）是紫杉醇的主要不良反应。几种基于脂质体的产品已被批准，并显示出优于其他药物的上级疗效和安全性。这项工作的第一个目的是评价紫杉醇（L-PTX）的脂质体制剂与标准Taxol®制剂相比对体外和体内神经毒性的影响。第二个目的是研究在动物模型中静脉内给药后制剂对紫杉醇生物分布的影响。游离紫杉醇在低于肺癌细胞（IC 50 = 59.1 μg/mL）的浓度下对神经元来源的细胞具有毒性（IC 50 = 18.4 μg/mL），L-PTX在两种细胞系中的毒性相当（IC 50 = 31.8和33.7 μg/mL）。与导致神经病变的相同剂量水平的Taxol®给药相比，在第0、2、4和6天以每剂量2 mg/kg的L-PTX给药大鼠共4次，未导致对后爪的机械或热刺激的敏感性增加。以6 mg/kg单次静脉给药后，评价了两种制剂在大鼠血浆、肝脏、肺、脑、脊髓、皮肤和肌肉中的紫杉醇生物处置。与Taxol®组相比，L-PTX组的脑、脊髓、肌肉和皮肤中紫杉醇暴露量较低。成功开发了含有紫杉醇的聚乙二醇化脂质体，并证明其在体外神经元细胞中降低神经毒性，并在体内防止周围神经病变的发展。这项概念验证研究表明，纳米颗粒制剂是减少（或预防）癌症药物引起的神经毒性的一种有前途的方法。
Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect of paclitaxel. Several liposome-based products have been approved and demonstrated superior efficacy and safety profiles for other drugs. The first objective of this work was to evaluate the effect of liposome formulation of paclitaxel (L-PTX) on neurotoxicityin-vitroandin-vivoin comparison to the standard Taxol® formulation. The second aim was to investigate the effect of formulation on paclitaxel biodistribution following intravenous administration in an animal model. Free paclitaxel was toxic to cell of neuronal origin (IC50 = 18.4 μg/mL) at a lower concentration than to lung cancer cells (IC50 = 59.1 μg/mL), and L-PTX demonstrated a comparable toxicity in both cell lines (IC50 = 31.8 and 33.7 μg/mL). Administration of L-PTX at 2 mg/kg per dose for a total of 4 doses on day 0, 2, 4, and 6 to rats did not result in increased sensitivity in response to mechanical or thermal stimulation of hind paws, in comparison to Taxol® administration at the same dose level that resulted in neuropathy. Paclitaxel biodisposition was evaluated for two formulations in plasma, liver, lung, brain, spinal cord, skin and muscle of rats after single intravenous dose at 6 mg/kg. The exposure to paclitaxel in brain, spinal cord, muscle, and skin was lower in the L-PTX group compared to Taxol® group. PEGylated liposomes containing paclitaxel were successfully developed and demonstrated reduced neurotoxicityin-vitroin neuronal cells and prevented development of peripheral neuropathyin-vivo. This proof of concept study showed that formulation in nanoparticles is a promising approach for reducing (or preventing) neurotoxicity caused by cancer drugs.