Synergy of Chemo- and Photodynamic Therapies with C60 Fullerene-Doxorubicin Nanocomplex

Abstract

A nanosized drug complex was explored to improve the efficiency of cancer chemotherapy, complementing it with nanodelivery and photodynamic therapy. For this, nanomolar amounts of a non-covalent nanocomplex of Doxorubicin (Dox) with carbon nanoparticle C60 fullerene (C60) were applied in 1:1 and 2:1 molar ratio, exploiting C60 both as a drug-carrier and as a photosensitizer. The fluorescence microscopy analysis of human leukemic CCRF-CEM cells, in vitro cancer model, treated with nanocomplexes showed Dox’s nuclear and C60’s extranuclear localization. It gave an opportunity to realize a double hit strategy against cancer cells based on Dox’s antiproliferative activity and C60’s photoinduced pro-oxidant activity. When cells were treated with 2:1 C60-Dox and irradiated at 405 nm the high cytotoxicity of photo-irradiated C60-Dox enabled a nanomolar concentration of Dox and C60 to efficiently kill cancer cells in vitro. The high pro-oxidant and pro-apoptotic efficiency decreased IC50 16, 9 and 7 × 103-fold, if compared with the action of Dox, non-irradiated nanocomplex, and C60’s photodynamic effect, correspondingly. Hereafter, a strong synergy of therapy arising from the combination of C60-mediated Dox delivery and C60 photoexcitation was revealed. Our data indicate that a combination of chemo- and photodynamic therapies with C60-Dox nanoformulation provides a promising synergetic approach for cancer treatment.

Synthesis, Characterization, Cellular Uptake, and In Vitro Anticancer Activity of Fullerenol-Doxorubicin Conjugates

“…The FU-DOX and FA-FU-DOX conjugates exhibited higher fluorescence intensity than free DOX, especially at 1 h incubation time, indicating a higher amount of cellular uptake than that for free DOX. It may be explained that the intracellular drug accumulation was efficiently promoted by the FU carrier at the experimental conditions ( Grebinyk et al, 2019 ). Moreover, FA-FU-DOX showed the best cellular uptake in FR-positive BEL-7402 cells but it did not exhibit significant higher accumulation than FU-DOX in FR-negative HepG2 and L02 cells ( Figure 5 ), which suggested that the attachment of FA to FU-DOX enhanced the uptake of the conjugates into FR-positive cells via an FR-mediated endocytic process.…”

“…The administration of fullerene alone before DOX administration or complexed with DOX via non-covalent bonds could diminish DOX-induced acute toxicity in the heart or liver ( Borović et al, 2014 ; Seke et al, 2016 ; Jacevic et al, 2019; Petrovic et al, 2018 ). More importantly, fullerene can act as a transporter for anticancer drugs, such as DOX ( Grebinyk et al, 2019 ; Kazemzadeh and Mozafari, 2019 ). These biological properties of fullerenes and the potential ability to carry drugs make it attractive to be applied in the drug delivery system.…”

Nanomaterials for cancer therapy: current progress and perspectives

“…Compared to fullerene and antenna nanoparticles (DA NPs), DAF NPs showed better reactive oxygen species and heat generation efficacy. In vitro and in vivo studies demonstrated that DAF NPs could effectively inhibit tumor growth through synergetic PDT and PTT [ 150 ]. As a nanocarrier, fullerene has also been used in chemical drug delivery combined with PDT or PTT [ 150 , 151 ].…”

Protective Effect of Water-Soluble C60 Fullerene Nanoparticles on the Ischemia-Reperfusion Injury of the Muscle Soleus in Rats

“…C 60 fullerene reduces lipid peroxidation by actively absorbing ROS [35]. C 60 fullerenes can penetrate the cell membrane and localize in the mitochondria [36,37], which are the source of ROS during the development of ischemic cell damage. Finally, the obtained above results are also confirmed by the previously obtained data on the effect of water-soluble C 60 fullerenes on the functions of the antioxidant systems of the body in inflammatory and pathological processes [38][39][40][41].…”