Cytotoxicity of doxorubicin conjugated with C60 fullerene. Structural and in vitro studies

Kamila Butowska,Michał Rychłowski,Anna Herman-Antosiewicz,Samanta Makurat,Jacek Piosik,Magdalena Zdrowowicz,Witold Kozak,Janusz Rak,Aleksandra Hać

doi:10.1007/s11224-019-01428-4

Kamila Butowska, Michał Rychłowski + Show 7 more

Open Access

https://doi.org/10.1007/s11224-019-01428-4

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Abstract

Conjugating an anticancer drug of high biological efficacy but large cytotoxicity with a “transporting” molecule of low toxicity constitutes a valuable approach to design safe drug delivery system. In the present study, doxorubicin (DOX) a drug of large cardiotoxicity was chemically conjugated to a C60-fullerene. The synthesized molecule, a fullerene-doxorubicin conjugate (Ful-DOX), was characterized using the 1H NMR and MALDI TOF mass spectrometry. The absorption and fluorescence spectra and dynamic light scattering of the conjugate were recorded in an aqueous solution, while the impact on viability of several cancer cell lines of the free DOX and the conjugate was compared using the SRB and WST-1 assays. A low antiproliferative activity of the conjugate as compared to the free DOX is a consequence of the presence of fullerene moiety in the former, which is also responsible for the conjugate aggregation in an aqueous solution. Unlike free DOX, these aggregates cannot pass through the nuclear membrane (as demonstrated by the confocal microscopy measurements), which makes them marginally cytotoxic.

Highlights

Doxorubicin (DOX; for its chemical structure, see Fig. 1) is well known for its anticancer activity
Forming a covalent bond between DOX and fullerene should lead to the lowered cytotoxicity of the drug and its improved pharmacokinetics
Despite the mentioned above, intuitively understandable idea, there are literature reports, which demonstrate that a doxorubicin conjugate with fullerene is toxic as the free DOX

Summary

Introduction

Doxorubicin (DOX; for its chemical structure, see Fig. 1) is well known for its anticancer activity. It is commonly used in clinics against various types of cancer in adults. Topoisomerase II, which is suppressed by DOX, was identified as a cardiotoxicity mediator [10]. Oxidative stress, mediated by doxorubicin via enzymatic route employing intracellular or intramitochondrial oxidant enzymes, produces hydroxyl radicals that trigger DNA damage, protein modification, lipid peroxidation, and cell death by apoptosis or necrosis, which is considered as the main reason for DOX cardiotoxicity [2]. In the context of Struct Chem (2019) 30:2327–2338 cardiotoxicity, the literature mentions that DOX impaired Ca2+ handling [11], activated p53-dependent pathways [12], and cytochrome c mediated apoptosis via activation of caspase 9 and 3 [13]

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