Functional Interaction Between Charged Nanoparticles and Cardiac Tissue: A New Paradigm for Cardiac Arrhythmia?

Abstract

Aim: To investigate the effect of surface charge of therapeutic nanoparticles on sarcolemmal ionic homeostasis and the initiation of arrhythmias. Materials & methods: Cultured neonatal rat myocytes were exposed to 50 nm-charged polystyrene latex nanoparticles and examined using a combination of hopping probe scanning ion conductance microscopy, optical recording of action potential characteristics and patch clamp. Results: Positively charged, amine-modified polystyrene latex nanoparticles showed cytotoxic effects and induced large-scale damage to cardiomyocyte membranes leading to calcium alternans and cell death. By contrast, negatively charged, carboxyl-modified polystyrene latex nanoparticles (NegNPs) were not overtly cytotoxic but triggered formation of 50–250-nm nanopores in the membrane. Cells exposed to NegNPs revealed pro-arrhythmic events, such as delayed afterdepolarizations, reduction in conduction velocity and pathological increment of action potential duration together with an increase in ionic current throughout the membrane, carried by the nanopores. Conclusion: The utilization of charged nanoparticles is a novel concept for targeting cardiac excitability. However, this unique nanoscopic investigation reveals an altered electrophysiological substrate, which sensitized the heart cells towards arrhythmias.

Original submitted 8 March 2012; Revised submitted 12 July 2012; Published online 12 November 2012

Keywords::

• action potential
• arrhythmia
• calcium transient
• cardiac electrophysiology
• cell topography
• conduction velocity
• DADs
• electrically charged nanoparticles
• nanopores
• scanning ion conductance microscopy

Financial & competing interests disclosure

The authors are supported by the following funds: Medical Research Council UK grant no. G0700926 to TD Tetley, YE Korchev and J Gorelik; Wellcome Trust grant no. WTN090594 to J Gorelik and M Miragoli; Young Researcher Project, Italian Ministry of Health grant no. GR-2009-1530528 to M Miragoli. P Novak, AI Shevchuk, YE Korchev and MJ Lab hold shares of Ionscope Ltd, UK, a small spin-out company manufacturing scanning ion conductance microscopes. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

Isolation procedures from 1-day-old Wistar rats were in accordance with the guidelines of the UK Home Office Animal (Scientific Procedures) Act 1986. The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgements

The authors thank S Rohr for kindly providing pattern growth coverslips for the experiments and AV Rogers (EM Unit, Royal Brompton Hospital, London, UK) for proficient assistance with electron microscopy.

Additional information

Funding

The authors are supported by the following funds: Medical Research Council UK grant no. G0700926 to TD Tetley, YE Korchev and J Gorelik; Wellcome Trust grant no. WTN090594 to J Gorelik and M Miragoli; Young Researcher Project, Italian Ministry of Health grant no. GR-2009-1530528 to M Miragoli. P Novak, AI Shevchuk, YE Korchev and MJ Lab hold shares of Ionscope Ltd, UK, a small spin-out company manufacturing scanning ion conductance microscopes. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.