Effect of inhibitors of endocytosis and NF-kB signal pathway on folate-conjugated nanoparticle endocytosis by rat Kupffer cells
Hongbo Tang,1 Hongli Chen,2 Yajing Jia,2 Xiaoyan Liu,1 Zhaohong Han,1 Aihua Wang,1 Qi Liu,1 Xinlei Li,1 Xin Feng1 1Department of Pharmacy, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 2School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang,...
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Dove Medical Press
2017
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oai:doaj.org-article:df122c21cb454775922d482917a1648b2021-12-02T05:14:21ZEffect of inhibitors of endocytosis and NF-kB signal pathway on folate-conjugated nanoparticle endocytosis by rat Kupffer cells1178-2013https://doaj.org/article/df122c21cb454775922d482917a1648b2017-09-01T00:00:00Zhttps://www.dovepress.com/effect-of-inhibitors-of-endocytosis-and-nf-kb-signal-pathway-on-folate-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Hongbo Tang,1 Hongli Chen,2 Yajing Jia,2 Xiaoyan Liu,1 Zhaohong Han,1 Aihua Wang,1 Qi Liu,1 Xinlei Li,1 Xin Feng1 1Department of Pharmacy, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 2School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China Abstract: The regular accumulation of nanoparticles in the liver makes them hepatotoxic and decreases the circulation time, thus reducing their therapeutic effect. Resolving this problem will be significant in improving bioavailability and reducing side effects. In this study, we reduced the phagocytosis of epirubicin (EPI)-loaded folic acid-conjugated pullulan acetate (FPA/EPI) nanoparticles by Kupffer cells (KCs) through internalization and nuclear factor kappa B (NF-kB) signal pathway inhibitors, thus allowing development of FPA/EPI nanoparticles as a nanodrug delivery system (NDDS) based on our previous study. FPA/EPI nanoparticles were prepared by the dialysis method. Rat KCs were preincubated with the following individual or compound inhibitors: chlorpromazine (CPZ), nystatin (NY), colchicine (Col), amiloride (AMR), and pyrrolidine dithiocarbamate (PDTC). Dose- and time-dependent cellular uptake effects of inhibitors on FPA/EPI nanoparticles were determined through fluorometry. The cytokine levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 were tested in culture supernatants by bead-based multiplex flow cytometry. The uptake study demonstrated that inhibitors had an obvious inhibitory effect (P<0.05 or P<0.01), with NY, AMR and Col all showing time-dependent inhibitory effects. PDTC + NY had the strongest inhibitory effect, with an uptake rate of 14.62%. The levels of the three proinflammatory cytokines were changed significantly by the compound inhibitors. TNF-α was significantly inhibited (P<0.05 or P<0.01), but IL-1β and IL-6 showed smaller decreases. These results suggested that clathrin- and caveolae-mediated endocytosis were the main routes via which nanoparticles entered KCs and that the NF-kB signal pathway was very important too. In summary, multiple mechanisms, including clathrin- and caveolae-mediated endocytosis, contribute to cytokine production in macrophages following exposure to folic acid-conjugated pullulan acetate nanoparticles. Thus, the endocytosis inhibition strategy has great potential for improving therapy and reducing toxicity of an NDDS in the treatment of cancer. Keywords: nanodrug delivery system, Kupffer cells, endocytosis inhibitor, folate-conjugated pullulan acetate, NF-kB signal pathwayTang HChen HJia YLiu XHan ZWang ALiu QLi XFeng XDove Medical PressarticlenanoparticlesKupffer cellendocytosis inhibitorfolate-conjugated pullulan acetateNF-kB signal pathwayMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 6937-6947 (2017) |
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nanoparticles Kupffer cell endocytosis inhibitor folate-conjugated pullulan acetate NF-kB signal pathway Medicine (General) R5-920 |
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nanoparticles Kupffer cell endocytosis inhibitor folate-conjugated pullulan acetate NF-kB signal pathway Medicine (General) R5-920 Tang H Chen H Jia Y Liu X Han Z Wang A Liu Q Li X Feng X Effect of inhibitors of endocytosis and NF-kB signal pathway on folate-conjugated nanoparticle endocytosis by rat Kupffer cells |
| description |
Hongbo Tang,1 Hongli Chen,2 Yajing Jia,2 Xiaoyan Liu,1 Zhaohong Han,1 Aihua Wang,1 Qi Liu,1 Xinlei Li,1 Xin Feng1 1Department of Pharmacy, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 2School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China Abstract: The regular accumulation of nanoparticles in the liver makes them hepatotoxic and decreases the circulation time, thus reducing their therapeutic effect. Resolving this problem will be significant in improving bioavailability and reducing side effects. In this study, we reduced the phagocytosis of epirubicin (EPI)-loaded folic acid-conjugated pullulan acetate (FPA/EPI) nanoparticles by Kupffer cells (KCs) through internalization and nuclear factor kappa B (NF-kB) signal pathway inhibitors, thus allowing development of FPA/EPI nanoparticles as a nanodrug delivery system (NDDS) based on our previous study. FPA/EPI nanoparticles were prepared by the dialysis method. Rat KCs were preincubated with the following individual or compound inhibitors: chlorpromazine (CPZ), nystatin (NY), colchicine (Col), amiloride (AMR), and pyrrolidine dithiocarbamate (PDTC). Dose- and time-dependent cellular uptake effects of inhibitors on FPA/EPI nanoparticles were determined through fluorometry. The cytokine levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 were tested in culture supernatants by bead-based multiplex flow cytometry. The uptake study demonstrated that inhibitors had an obvious inhibitory effect (P<0.05 or P<0.01), with NY, AMR and Col all showing time-dependent inhibitory effects. PDTC + NY had the strongest inhibitory effect, with an uptake rate of 14.62%. The levels of the three proinflammatory cytokines were changed significantly by the compound inhibitors. TNF-α was significantly inhibited (P<0.05 or P<0.01), but IL-1β and IL-6 showed smaller decreases. These results suggested that clathrin- and caveolae-mediated endocytosis were the main routes via which nanoparticles entered KCs and that the NF-kB signal pathway was very important too. In summary, multiple mechanisms, including clathrin- and caveolae-mediated endocytosis, contribute to cytokine production in macrophages following exposure to folic acid-conjugated pullulan acetate nanoparticles. Thus, the endocytosis inhibition strategy has great potential for improving therapy and reducing toxicity of an NDDS in the treatment of cancer. Keywords: nanodrug delivery system, Kupffer cells, endocytosis inhibitor, folate-conjugated pullulan acetate, NF-kB signal pathway |
| format |
article |
| author |
Tang H Chen H Jia Y Liu X Han Z Wang A Liu Q Li X Feng X |
| author_facet |
Tang H Chen H Jia Y Liu X Han Z Wang A Liu Q Li X Feng X |
| author_sort |
Tang H |
| title |
Effect of inhibitors of endocytosis and NF-kB signal pathway on folate-conjugated nanoparticle endocytosis by rat Kupffer cells |
| title_short |
Effect of inhibitors of endocytosis and NF-kB signal pathway on folate-conjugated nanoparticle endocytosis by rat Kupffer cells |
| title_full |
Effect of inhibitors of endocytosis and NF-kB signal pathway on folate-conjugated nanoparticle endocytosis by rat Kupffer cells |
| title_fullStr |
Effect of inhibitors of endocytosis and NF-kB signal pathway on folate-conjugated nanoparticle endocytosis by rat Kupffer cells |
| title_full_unstemmed |
Effect of inhibitors of endocytosis and NF-kB signal pathway on folate-conjugated nanoparticle endocytosis by rat Kupffer cells |
| title_sort |
effect of inhibitors of endocytosis and nf-kb signal pathway on folate-conjugated nanoparticle endocytosis by rat kupffer cells |
| publisher |
Dove Medical Press |
| publishDate |
2017 |
| url |
https://doaj.org/article/df122c21cb454775922d482917a1648b |
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