Gadolinium-loaded liposome safety: in vitro study in human liver cells and macrophages

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F19%3AN0000282" target="_blank" >RIV/00027162:_____/19:N0000282 - isvavai.cz</a>

Výsledek na webu

<a href="http://www.setcor.org/userfiles/files/2019/NanotechFrance2019/NanotechFrance2019-and-Joint-Conferences-Book-of-Abstracts.pdf" target="_blank" >http://www.setcor.org/userfiles/files/2019/NanotechFrance2019/NanotechFrance2019-and-Joint-Conferences-Book-of-Abstracts.pdf</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Gadolinium-loaded liposome safety: in vitro study in human liver cells and macrophages

Popis výsledku v původním jazyce

NANOTECH FRANCE 2019, 26 Jun - 28 Jun 2019, Paris, France – lecture. Gadolinium-based contrast agents (GBCA) are extensively used for magnetic resonance imaging. Gadolinium is chelated in relatively stable complexes, and thus believed to be nontoxic. However, recently, GBCA have been shown to induce side effects, such as nephrotoxicity, neurotoxicity and hepatotoxicity. Liposomes are studied as potential carriers of both magnetic resonance contrast agents, including gadolinium, and drug molecules, such as trombolytic agents. Therefore, liposomes can serve as diagnostic as well as theranostic agents for imaging and treatement of various pathological states and ilnesses including stroke. They also exhibit favourable platform for a new generation of targeted diagnostic and theranostic systems. As compared to low molecular gadolinium complexes, the biodistribution of gadolinium chelates formulated into liposomes can significantly differ after their administration to the patients. Therefore, a more intesive study of potencial toxiciological effects of gadolinium formulations on different organs and cell types including liver cells and immune cells seems to be necessary. In this study, liposomes containing PE-DTPA gadolinium chelator were tested for its potencial toxicological effects. The cytotoxicity of gadolinium-loaded nanoliposomes (Gd-L) was tested by neutral red uptake in human liver cancer Hep G2 cells, liver progenitor (non-differentiated) HepaRG cells and HepaRG cells differentiated into two cell populations, hepatocyte-like and biliary epithelial cells, which is a liver model closest to primary hepatocytes and well established model for drug-induced human hepatotoxicity studies. The concentration of gadolinium ranged between 1 μM and 100 μM, and we found no cytotoxicity up to 72 h. Next, we used complex system of general biomarkers of toxicity, including induction of early response genes, heat shock, ER stress, oxidative stress, and DNA damage responses and modulation of xenobioticmetabolizing enzymes. Differentiated HepaRG cells were exposed to Gd-L (total lipid concentration 25 ug/ml) for 24 h and changes in mRNA expression were measured by RT-PCR. Finally, pro-inflammatory effects of Gd-L were studied. The amount of eicosanoids released from HepaRG, exposed to Gd-L, into the cultivation medium was determined by LC/MSMS. Activation of inflammasome was detected using activated THP1 (model human macrophages). We did not detect any changes in any tested parameters, which indicates that Gd-L were not toxcic to liver HepaRG cells, also, that they not induce inflammasome activation. In conclusion, we established a complex system highly suitable for in vitro identification of major possible toxic responses with possible implications in evaluation of nanosafety.

Název v anglickém jazyce

Gadolinium-loaded liposome safety: in vitro study in human liver cells and macrophages

Popis výsledku anglicky

NANOTECH FRANCE 2019, 26 Jun - 28 Jun 2019, Paris, France – lecture. Gadolinium-based contrast agents (GBCA) are extensively used for magnetic resonance imaging. Gadolinium is chelated in relatively stable complexes, and thus believed to be nontoxic. However, recently, GBCA have been shown to induce side effects, such as nephrotoxicity, neurotoxicity and hepatotoxicity. Liposomes are studied as potential carriers of both magnetic resonance contrast agents, including gadolinium, and drug molecules, such as trombolytic agents. Therefore, liposomes can serve as diagnostic as well as theranostic agents for imaging and treatement of various pathological states and ilnesses including stroke. They also exhibit favourable platform for a new generation of targeted diagnostic and theranostic systems. As compared to low molecular gadolinium complexes, the biodistribution of gadolinium chelates formulated into liposomes can significantly differ after their administration to the patients. Therefore, a more intesive study of potencial toxiciological effects of gadolinium formulations on different organs and cell types including liver cells and immune cells seems to be necessary. In this study, liposomes containing PE-DTPA gadolinium chelator were tested for its potencial toxicological effects. The cytotoxicity of gadolinium-loaded nanoliposomes (Gd-L) was tested by neutral red uptake in human liver cancer Hep G2 cells, liver progenitor (non-differentiated) HepaRG cells and HepaRG cells differentiated into two cell populations, hepatocyte-like and biliary epithelial cells, which is a liver model closest to primary hepatocytes and well established model for drug-induced human hepatotoxicity studies. The concentration of gadolinium ranged between 1 μM and 100 μM, and we found no cytotoxicity up to 72 h. Next, we used complex system of general biomarkers of toxicity, including induction of early response genes, heat shock, ER stress, oxidative stress, and DNA damage responses and modulation of xenobioticmetabolizing enzymes. Differentiated HepaRG cells were exposed to Gd-L (total lipid concentration 25 ug/ml) for 24 h and changes in mRNA expression were measured by RT-PCR. Finally, pro-inflammatory effects of Gd-L were studied. The amount of eicosanoids released from HepaRG, exposed to Gd-L, into the cultivation medium was determined by LC/MSMS. Activation of inflammasome was detected using activated THP1 (model human macrophages). We did not detect any changes in any tested parameters, which indicates that Gd-L were not toxcic to liver HepaRG cells, also, that they not induce inflammasome activation. In conclusion, we established a complex system highly suitable for in vitro identification of major possible toxic responses with possible implications in evaluation of nanosafety.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30108 - Toxicology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů