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Arrhythmic Effects Evaluated on Caenorhabditis elegans: The Case of Polypyrrole Nanoparticles
Sumithra Yasaswini Srinivasan1, Pilar Alvarez Illera2, Dmytro Kukhtar3
1Universitat de Autonoma de Barcelona, Institut de Ciència de Materials de Barcelona (ICMAB), 08193, Bellaterra, Barcelona, Spain.
Abstract:
Experimental studies and clinical trials of nanoparticles for treating diseases are increasing continuously. However, the reach to the market does not correlate with these efforts due to the enormous cost, several years of development, and off-target effects like cardiotoxicity. Multicellular organisms such as the Caenorhabditis elegans (C. elegans) can bridge the gap between in vitro and vertebrate testing as they can provide extensive information on systemic toxicity and specific harmful effects through facile experimentation following 3R EU directives on animal use. Since the nematodes' pharynx shares similarities with the human heart, we assessed the general and pharyngeal effects of drugs and polypyrrole nanoparticles (Ppy NPs) using C. elegans. The evaluation of FDA-approved drugs, such as Propranolol and Racepinephrine reproduced the arrhythmic behavior reported in humans and supported the use of this small animal model. Consequently, Ppy NPs were evaluated due to their research interest in cardiac arrhythmia treatments. The NPs' biocompatibility was confirmed by assessing survival, growth and development, reproduction, and transgenerational toxicity in C. elegans. Interestingly, the NPs increased the pharyngeal pumping rate of C. elegans in two slow-pumping mutant strains, JD21 and DA464. Moreover, the NPs increased the pumping rate over time, which sustained up to a day post-excretion. By measuring pharyngeal calcium levels, we found that the impact of Ppy NPs on the pumping rate could be mediated through calcium signaling. Thus, evaluating arrhythmic effects in C. elegans offers a simple system to test drugs and nanoparticles, as elucidated through Ppy NPs.
Insights
The nematode Caenorhabditis elegans (C. elegans) serves as a model for testing drug and nanoparticle toxicity. Polypyrrole nanoparticles (Ppy NPs) showed biocompatibility and improved pharyngeal pumping in C. elegans, suggesting potential for cardiac treatments.
Area of Science:
- Biomedical Engineering
- Toxicology
- Nanotechnology
Background:
- Nanoparticle drug development faces market entry challenges due to cost, development time, and cardiotoxicity.
- Caenorhabditis elegans (C. elegans) offers a model for systemic toxicity testing, aligning with animal research ethics (3Rs).
- The C. elegans pharynx shares functional similarities with the human heart, enabling cardiac-related drug and nanoparticle evaluation.
Purpose of the Study:
- To assess the utility of C. elegans as a model for evaluating drug and nanoparticle effects on cardiac function.
- To investigate the biocompatibility and pharyngeal effects of polypyrrole nanoparticles (Ppy NPs) in C. elegans.
- To explore the potential of Ppy NPs in treating cardiac arrhythmia.
Main Methods:
- Validated C. elegans model by testing FDA-approved drugs (Propranolol, Racepinephrine) for known human cardiac effects.
- Administered Ppy NPs to C. elegans and assessed survival, growth, reproduction, and transgenerational toxicity.
- Measured pharyngeal pumping rates in wild-type and mutant C. elegans strains exposed to Ppy NPs.
- Investigated the role of calcium signaling in Ppy NP-mediated pharyngeal effects.
Main Results:
- C. elegans accurately reproduced human arrhythmic responses to Propranolol and Racepinephrine.
- Ppy NPs demonstrated biocompatibility in C. elegans across multiple generations.
- Ppy NPs significantly increased pharyngeal pumping rates in specific slow-pumping C. elegans mutants.
- The observed increase in pumping rate was sustained post-excretion and linked to calcium signaling pathways.
Conclusions:
- C. elegans provides a viable and efficient model for evaluating cardiac effects of drugs and nanoparticles.
- Ppy NPs are biocompatible and exhibit a positive effect on pharyngeal function in C. elegans.
- Ppy NPs modulate pharyngeal pumping via calcium signaling, indicating potential therapeutic applications for cardiac conditions.
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