- MeSH
- dermatologie MeSH
- kyslík MeSH
- venerologie MeSH
- volné radikály chemie metabolismus MeSH
- Publikační typ
- přehledy MeSH
Background: Reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, trigger biodegradation of polymer-based nanoparticles (NPs) bearing pinacol-type boronic ester groups. These NPs may selectively release their cargo, in this case paclitaxel (PTX), at the high levels of ROS present in the intracellular environment of inflamed tissues and most tumors. Purpose: The main objective was to determine anti-tumor efficacy of PTX-loaded ROS-sensitive NPs and to examine whether macrophage infiltration had any impact on treatment efficacy. Methods: NPs were synthesized and their characteristics in the presence of H2O2 were demonstrated. Both confocal microscopy as well as flow cytometry approaches were used to determine degradation of ROS-sensitive NPs. HeLa cells were cultured in vitro and used to establish tumor xenografts in nude mice. In vivo experiments were performed to understand toxicity, biodistribution and anti-tumor efficacy of the NPs. Moreover, we performed immunohistochemistry on tumor sections to study infiltration of M1 and M2 subsets of macrophages. Results: We demonstrated that PTX delivered in NPs containing a ROS-sensitive polymer exhibits a better anti-tumor efficacy than PTX in NPs containing ROS-non-sensitive polymer, free PTX or Abraxane® (nab-PTX). The biodistribution revealed that ROS-sensitive NPs exhibit retention in liver, spleen and lungs, suggesting a potential to target cancer metastasizing to these organs. Finally, we demonstrated a correlation between infiltrated macrophage subsets and treatment efficacy, possibly contributing to the efficient anti-tumor effects. Conclusion: Treatment with ROS-sensitive NPs containing PTX gave an improved therapeutic effect in HeLa xenografts than their counterpart, free PTX or nab-PTX. Our data revealed a correlation between macrophage infiltration and efficiency of the different antitumor treatments, as the most effective NPs resulted in the highest infiltration of the anti-tumorigenic M1 macrophages.
- MeSH
- albuminy farmakologie terapeutické užití MeSH
- HeLa buňky MeSH
- hydrodynamika MeSH
- lidé MeSH
- makrofágy účinky léků metabolismus MeSH
- myši nahé MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie MeSH
- nanočástice terapeutické užití MeSH
- paclitaxel farmakologie terapeutické užití MeSH
- paklitaxel vázaný na albumin terapeutické užití MeSH
- polymery chemie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- tkáňová distribuce účinky léků MeSH
- velikost částic MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.
- MeSH
- Evropská unie MeSH
- lidé MeSH
- mezinárodní spolupráce * MeSH
- molekulární biologie organizace a řízení trendy MeSH
- oxidace-redukce MeSH
- reaktivní formy kyslíku chemie metabolismus MeSH
- signální transdukce MeSH
- společnosti vědecké MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
We investigated hydrogen peroxide production in mitochondria with low (liver, heart, brain) and high (brown adipose tissue, BAT) content of glycerophosphate dehydrogenase (mGPDH). ROS production at state 4 due to electron backflow from mGPDH was low, but after inhibition of electron transport with antimycin A high rates of mGPDH-dependent ROS production were observed in liver, heart and brain mitochondria. When this ROS production was related to activity of mGPDH, many-fold higher ROS production was found in contrast to succinate- (39-, 28-, 3-fold) or pyruvate plus malate-dependent ROS production (32-, 96-, 5-fold). This specific rate of mGPDH-dependent ROS production was also exceedingly higher (28-, 66-, 22-fold) compared to that in BAT. mGPDH-dependent ROS production was localized to the dehydrogenase+CoQ and complex III, the latter being the highest in all mitochondria but BAT. Our results demonstrate high efficiency of mGPDH-dependent ROS production in mammalian mitochondria with a low content of mGPDH and suggest its endogenous inhibition in BAT.
- MeSH
- antimycin A farmakologie MeSH
- financování organizované MeSH
- glycerolfosfátdehydrogenasa metabolismus MeSH
- hnědá tuková tkáň metabolismus MeSH
- jaterní mitochondrie metabolismus účinky léků MeSH
- křečci praví MeSH
- krysa rodu rattus MeSH
- kyselina jantarová metabolismus MeSH
- kyselina pyrohroznová metabolismus MeSH
- mitochondrie metabolismus účinky léků MeSH
- mozek metabolismus MeSH
- peroxid vodíku metabolismus MeSH
- potkani Wistar MeSH
- reaktivní formy kyslíku metabolismus MeSH
- respirační komplex III metabolismus MeSH
- srdeční mitochondrie metabolismus účinky léků MeSH
- techniky in vitro MeSH
- transport elektronů MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
