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Int J Nanomedicine. 2019 Aug 6;14:6269-6285. doi: 10.2147/IJN.S208938. eCollection 2019.

Paclitaxel-loaded biodegradable ROS-sensitive nanoparticles for cancer therapy.

Author information

1
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
2
Institute of Macromolecular Chemistry v.v.i, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
3
Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
4
Department of Chemistry, University of Oslo, Oslo, Norway.
5
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
6
Department of Biosciences, University of Oslo, Oslo, Norway.
7
Institute of Medical Biology, Faculty of Health Sciences, The Arctic University of Norway - University of Tromsø, Tromsø, Norway.

Abstract

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.

KEYWORDS:

ROS-sensitive nanoparticles; macrophage infiltration; paclitaxel; reactive oxygen species; treatment efficacy

Conflict of interest statement

Dr Martin Hrubý reports grants from Norwegian Grants, Ministry of Education, Youth and Sports of the Czech Republic, and Czech Science Foundation, during the conduct of the study. The authors report no other conflicts of interest in this work.

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