Abstract

BackgroundPolymer nanoparticles (PNP) are becoming increasingly important in nanomedicine and food-based applications. Size and surface characteristics are often considered to be important factors in the cellular interactions of these PNP, although systematic investigations on the role of surface properties on cellular interactions and toxicity of PNP are scarce.ResultsFluorescent, monodisperse tri-block copolymer nanoparticles with different sizes (45 and 90 nm) and surface charges (positive and negative) were synthesized, characterized and studied for uptake and cytotoxicity in NR8383 and Caco-2 cells. All types of PNP were taken up by the cells. The positive smaller PNP45 (45 nm) showed a higher cytotoxicity compared to the positive bigger PNP90 (90 nm) particles including reduction in mitochondrial membrane potential (ΔΨm), induction of reactive oxygen species (ROS) production, ATP depletion and TNF-α release. The negative PNP did not show any cytotoxic effect. Reduction in mitochondrial membrane potential (ΔΨm), uncoupling of the electron transfer chain in mitochondria and the resulting ATP depletion, induction of ROS and oxidative stress may all play a role in the possible mode of action for the cytotoxicity of these PNP. The role of receptor-mediated endocytosis in the intracellular uptake of different PNP was studied by confocal laser scanning microscopy (CLSM). Involvement of size and charge in the cellular uptake of PNP by clathrin (for positive PNP), caveolin (for negative PNP) and mannose receptors (for hydroxylated PNP) were found with smaller PNP45 showing stronger interactions with the receptors than bigger PNP90.ConclusionsThe size and surface characteristics of polymer nanoparticles (PNP; 45 and 90 nm with different surface charges) play a crucial role in cellular uptake. Specific interactions with cell membrane-bound receptors (clathrin, caveolin and mannose) leading to cellular internalization were observed to depend on size and surface properties of the different PNP. These properties of the nanoparticles also dominate their cytotoxicity, which was analyzed for many factors. The effective reduction in the mitochondrial membrane potential (ΔΨm), uncoupling of the electron transfer chain in mitochondria and resulting ATP depletion, induction of ROS and oxidative stress likely all play a role in the mechanisms behind the cytotoxicity of these PNP.

Highlights

  • Polymer nanoparticles (PNP) are becoming increasingly important in nanomedicine and food-based applications

  • From proton nuclear magnetic resonance (1 H NMR) (Additional file 1) analysis of the polymer, an estimation of the molecular weight (~9 kDa) was made, which was in agreement with the data obtained from size exclusion chromatography (SEC) (Additional file 2)

  • A size-dependent induction of intracellular reactive oxygen species (ROS) production identifies oxidative stress as a possible mechanism of cytotoxicity with subsequent release of inflammatory cytokines representing another mechanism for NP induced adverse effects

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Summary

Introduction

Polymer nanoparticles (PNP) are becoming increasingly important in nanomedicine and food-based applications. With the rapid appearance of nanotechnology-based products in the consumer market, human exposure to nanoparticles (NP) is unavoidable [1]. One of the factors is related to size Due to their small size, NP have a high surface area to mass ratio, which may play a role in the interactions of NP with biomolecules (proteins, cell wall constituents, etc.) and in mechanisms underlying their toxicity when compared to undissolved bulk material. These mechanisms can involve chemical reactions and physical adsorption processes with different biomolecules. Little is known on the mechanism of cellular uptake and intracellular distribution of different NP inside cells, and how factors like size can influence these

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