An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation
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)-incorp...
Guardado en:
| Autores principales: | , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Dove Medical Press
2017
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/f28b04af07e345a1ab2cd4ba1255a3aa |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:f28b04af07e345a1ab2cd4ba1255a3aa |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:f28b04af07e345a1ab2cd4ba1255a3aa2021-12-02T02:10:30ZAn in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation1178-2013https://doaj.org/article/f28b04af07e345a1ab2cd4ba1255a3aa2017-02-01T00:00:00Zhttps://www.dovepress.com/an-in-vivo-mechanism-for-the-reduced-peripheral-neurotoxicity-of-nk105-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Iwao 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 permeabilityNakamura IIchimura EGoda RHayashi HMashiba HNagai DYokoyama HOnda TMasuda ADove Medical Pressarticlemicellepaclitaxelperipheral neuropathydorsal root ganglionvascular permeabilityMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 1293-1304 (2017) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
micelle paclitaxel peripheral neuropathy dorsal root ganglion vascular permeability Medicine (General) R5-920 |
| spellingShingle |
micelle paclitaxel peripheral neuropathy dorsal root ganglion vascular permeability Medicine (General) R5-920 Nakamura I Ichimura E Goda R Hayashi H Mashiba H Nagai D Yokoyama H Onda T Masuda A An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation |
| description |
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 |
| format |
article |
| author |
Nakamura I Ichimura E Goda R Hayashi H Mashiba H Nagai D Yokoyama H Onda T Masuda A |
| author_facet |
Nakamura I Ichimura E Goda R Hayashi H Mashiba H Nagai D Yokoyama H Onda T Masuda A |
| author_sort |
Nakamura I |
| title |
An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation |
| title_short |
An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation |
| title_full |
An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation |
| title_fullStr |
An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation |
| title_full_unstemmed |
An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation |
| title_sort |
in vivo mechanism for the reduced peripheral neurotoxicity of nk105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation |
| publisher |
Dove Medical Press |
| publishDate |
2017 |
| url |
https://doaj.org/article/f28b04af07e345a1ab2cd4ba1255a3aa |
| work_keys_str_mv |
AT nakamurai aninvivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT ichimurae aninvivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT godar aninvivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT hayashih aninvivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT mashibah aninvivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT nagaid aninvivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT yokoyamah aninvivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT ondat aninvivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT masudaa aninvivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT nakamurai invivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT ichimurae invivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT godar invivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT hayashih invivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT mashibah invivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT nagaid invivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT yokoyamah invivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT ondat invivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation AT masudaa invivomechanismforthereducedperipheralneurotoxicityofnk105apaclitaxelincorporatingpolymericmicellarnanoparticleformulation |
| _version_ |
1718402686968135680 |