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Abhilash D Pandya,1 Eliézer Jäger,2 Shahla Bagheri Fam,3 Anita Höcherl,2 Alessandro Jäger,2 Vladimir Sincari,2 Bo Nyström,4 Petr Štěpánek,2 Tore Skotland,5 Kirsten Sandvig,5,6 Martin Hrubý,2 Gunhild M Mælandsmo1,71Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; 2Institute of Macromolecular Chemistry v.v.i, Academy of Sciences of the Czech Republic, Prague, Czech Republic; 3Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; 4Department of Chemistry, University of Oslo, Oslo, Norway; 5Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; 6Department of Biosciences, University of Oslo, Oslo, Norway; 7Institute of Medical Biology, Faculty of Health Sciences, The Arctic University of Norway – University of Tromsø, Tromsø, NorwayBackground: 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.Keywords: reactive oxygen species, ROS-sensitive nanoparticles, paclitaxel, treatment efficacy, macrophage infiltration