An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation
| Autor: | Takeshi Onda, Hitomi Hayashi, Hiroko Mashiba, Iwao Nakamura, Akira Masuda, Daichi Nagai, Eiji Ichimura, Hirofumi Yokoyama, Rika Goda |
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| Rok vydání: | 2017 |
| Předmět: |
Glycerol
Polymers Chemistry Pharmaceutical Pharmaceutical Science Vascular permeability Pharmacology Rats Sprague-Dawley chemistry.chemical_compound 0302 clinical medicine Dorsal root ganglion International Journal of Nanomedicine Ganglia Spinal Drug Discovery Micelles Original Research Evans Blue General Medicine Immunohistochemistry Sciatic Nerve medicine.anatomical_structure Paclitaxel 030220 oncology & carcinogenesis Female Sciatic nerve endocrine system dorsal root ganglion Stereochemistry Neurotoxins Biophysics Bioengineering complex mixtures Injections Biomaterials 03 medical and health sciences Pharmacokinetics In vivo Albumins micelle medicine Animals vascular permeability peripheral neurotoxicity Ethanol Organic Chemistry Neurotoxicity medicine.disease nervous system chemistry Nanoparticles Biomarkers 030217 neurology & neurosurgery |
| Zdroj: | International Journal of Nanomedicine |
| ISSN: | 1178-2013 |
| Popis: | Iwao Nakamura, Eiji Ichimura, Rika Goda, Hitomi Hayashi, Hiroko Mashiba, Daichi Nagai, Hirofumi Yokoyama, Takeshi Onda, Akira Masuda Nanomedicine Group, Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan 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_PTX and 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). Keywords: micelle, paclitaxel, peripheral neurotoxicity, dorsal root ganglion, vascular permeability |
| Databáze: | OpenAIRE |
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