title: An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation.
abstract: In our previous rodent studies, the paclitaxel (PTX)-incorporating polymeric micellar nanoparticle formulation NK105 had showed significantly stronger antitumor effects and reduced peripheral neurotoxicity than PTX dissolved in Cremophor®EL and ethanol (PTX/CRE). Thus, to elucidate the mechanisms underlying reduced peripheral neurotoxicity due to NK105, we performed pharmacokinetic analyses of NK105 and PTX/CRE in rats. Among neural tissues, the highest PTX concentrations were found in the dorsal root ganglion (DRG). Moreover, exposure of DRG to PTX (Cmax_PTXand AUC0-inf._PTX) in the NK105 group was almost half that in the PTX/CRE group, whereas exposure of sciatic and sural nerves was greater in the NK105 group than in the PTX/CRE group. In histopathological analyses, damage to DRG and both peripheral nerves was less in the NK105 group than in the PTX/CRE group. The consistency of these pharmacokinetic and histopathological data suggests that high levels of PTX in the DRG play an important role in the induction of peripheral neurotoxicity, and reduced distribution of PTX to the DRG of NK105-treated rats limits the ensuing peripheral neurotoxicity. In further analyses of PTX distribution to the DRG, Evans blue (Eb) was injected with BODIPY®-labeled NK105 into rats, and Eb fluorescence was observed only in the DRG. Following injection, most Eb dye bound to albumin particles of ~8 nm and had penetrated the DRG. In contrast, BODIPY®-NK105 particles of ~90 nm were not found in the DRG, suggesting differential penetration based on particle size. Because PTX also circulates as PTX-albumin particles of ~8 nm following injection of PTX/CRE, reduced peripheral neurotoxicity of NK105 may reflect exclusion from the DRG due to particle size, leading to reduced PTX levels in rat DRG (275).
authors.affiliation: Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
authors.forename: Iwao
authors.initials: I
authors.lastname: Nakamura
authors.affiliation: Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ichimura
authors.affiliation: Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Goda
authors.affiliation: Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Mashiba
authors.affiliation: Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Nagai
authors.affiliation: Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yokoyama
authors.affiliation: Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Onda
authors.affiliation: Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Masuda
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D000431:Ethanol / Q000737:chemistry; D005070:Evans Blue / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D007150:Immunohistochemistry; D007267:Injections; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D009498:Neurotoxins / Q000633:toxicity*; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011108:Polymers / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology
chemical_list: D000418:Albumins; D015415:Biomarkers; D008823:Micelles; C500671:NK105; D009498:Neurotoxins; D011108:Polymers; D000431:Ethanol; D005070:Evans Blue; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol
keywords: dorsal root ganglion; micelle; paclitaxel; peripheral neurotoxicity; vascular permeability