Abstract
Aim:
Carbonaceous dots (CDs), which have been used for diagnosis, drug delivery and gene delivery, are accumulated in heart at high concentrations. To improve their biocompatibility, polyethylene glycol-modified CDs (PEG-CDs) were prepared. In this study we compared the cardiac toxicity of CDs and PEG-CDs in mouse and zebrafish models.
Methods:
Mice were intravenously treated with CDs (size: 4.9 nm, 5 mg·kg−1·d−1) or PEG-CDs (size: 8.3 nm, 5 mg·kg−1·d−1) for 21 d. Their blood biochemistry indices, ECG, and histological examination were examined for evaluation of cardiac toxicity. CDs or PEG-CDs was added in incubator of cmlc2 transgenic Zebrafish embryos at 6 hpf, and the shape and size of embryos' hearts were observed at 48 hpf using a fluorescent microscope. Furthermore, whole-mount in situ hybridization was used to examine the expression of early cardiac marker gene (clml2) at 48 hpf.
Results:
Administration of CDs or PEG-CDs in mice caused mild, but statistically insignificant reduction in serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels detected at 7 d, which were returned to the respective control levels at 21 d. Neither CDs nor PEG-CDs caused significant changes in the morphology of heart cells. Administration of CDs, but not PEG-CDs, in mice caused marked increase of heart rate. Both CDs and PEG-CDs did not affect other ECG parameters. In the zebrafish embryos, addition of CDs (20 μg/mL) caused heart development delay, whereas addition of CDs (80 μg/mL) led to heart malformation. In contrast, PEG-CDs caused considerably small changes in heart development, which was consistent with the results from the in situ hybridization experiments.
Conclusion:
CDs causes greater cardiac toxicity, especially regarding heart development. Polyethylene glycol modification can attenuate the cardiac toxicity of CDs.
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Acknowledgements
The work was supported by grants from the National Natural Science Foundation of China (81402866 and 81301974) and the Sichuan University Starting Foundation for Young Teachers (2014SCU11044).
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Chen, Jt., Sun, Hq., Wang, Wl. et al. Polyethylene glycol modification decreases the cardiac toxicity of carbonaceous dots in mouse and zebrafish models. Acta Pharmacol Sin 36, 1349–1355 (2015). https://doi.org/10.1038/aps.2015.100
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DOI: https://doi.org/10.1038/aps.2015.100