Universität zu Köln

Klein, Ines, Wiesen, Martin H. J., Albert, Virginia, Bobylev, Ilja, Joshi, Abhijeet R., Mueller, Carsten and Lehmann, Helmar C. (2021). Impact of drug formulations on kinetics and toxicity in a preclinical model of paclitaxel-induced neuropathy. J. Peripher. Nerv. Syst., 26 (2). S. 216 - 227. HOBOKEN: WILEY. ISSN 1529-8027

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Klein, Ines UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiesen, Martin H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Albert, Virginia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bobylev, Ilja UNSPECIFIED UNSPECIFIED UNSPECIFIED Joshi, Abhijeet R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehmann, Helmar C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-567959
DOI:	10.1111/jns.12440
Journal or Publication Title:	J. Peripher. Nerv. Syst.
Volume:	26
Number:	2
Page Range:	S. 216 - 227
Date:	2021
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1529-8027
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/56795