Impact of drug formulations on kinetics and toxicity in a preclinical model of paclitaxel-induced neuropathy
| Autor: | Ilja Bobylev, Abhijeet R. Joshi, Martin H. J. Wiesen, Ines Klein, Virginia Albert, Carsten Müller, Helmar C. Lehmann |
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| Rok vydání: | 2021 |
| Předmět: |
Paclitaxel
Drug Compounding Pharmacology 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine In vivo Tandem Mass Spectrometry Ganglia Spinal medicine Animals Viability assay Axon Chemistry General Neuroscience Neurotoxicity Peripheral Nervous System Diseases medicine.disease Antineoplastic Agents Phytogenic Mice Inbred C57BL Kinetics medicine.anatomical_structure Peripheral neuropathy nervous system 030220 oncology & carcinogenesis Peripheral nervous system Neurotoxicity Syndromes Neurology (clinical) 030217 neurology & neurosurgery Sensory nerve Chromatography Liquid |
| Zdroj: | Journal of the peripheral nervous system : JPNSREFERENCES. 26(2) |
| ISSN: | 1529-8027 |
| Popis: | Background and aims 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. Methods 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. Results 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. Interpretation 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. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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