Glycyrrhetinic Acid Functionalized Graphene Oxide for Mitochondria Targeting and Cancer Treatment In Vivo

Abstract

Mitochondria-mediated apoptosis (MMA) is a preferential option for cancer therapy due to the presence of cell-suicide factors in mitochondria, however, low permeability of mitochondria is a bottleneck for targeting drug delivery. In this paper, glycyrrhetinic acid (GA), a natural product from Glycyrrhiza glabra, is found to be a novel mitochondria targeting ligand, which can improve mitochondrial permeability and enhance the drug uptake of mitochondria. GA-functionalized graphene oxide (GO) is prepared and used as an effective carrier for targeted delivery of doxorubicin into mitochondria. The detailed in vitro and in vivo mechanism study shows that GA-functionalized GO causes a decrease in mitochondrial membrane potential and activates the MMA pathway. The GA-functionalized drug delivery system demonstrates highly improved apoptosis induction ability and anticancer efficacy compared to the non-GA-functionalized nanocarrier delivery system. The GA-functionalized nanocarrier also shows low toxicity, suggesting that it can be a useful tool for drug delivery.

Sublethal exposure of small few-layer graphene promotes metabolic alterations in human skin cells

“…This mild mitochondrial damage caused by sFLG is also supported by the results on mitochondrial Ca 2+ levels, the deregulation of which could affect the whole cell bioenergetics 59 . This factor should be considered for future uses of GRMs, as one of the envisaged biomedical applications of these compounds is to deliver drugs into mitochondria 60 , 61 .…”

Cellular Signaling Pathways Activated by Functional Graphene Nanomaterials

“…Recently, particular attention has been devoted to the development of drug delivery strategies targeting subcellular organelles such as mitochondria [ 44 ]. Anticancer drugs such as Dox, a cytotoxic anthracycline antibiotic that acts mainly into the nucleus by intercalation with the double helix DNA, have also been investigated for their specific actions on mitochondria.…”

Mitochondrial-Targeting Anticancer Agent Conjugates and Nanocarrier Systems for Cancer Treatment

“…A number of nanoparticles have been studied for drug delivery, imaging, and therapeutic purposes, such as graphene oxide (GO), gold nanoparticles, silica nanoparticles, quantum dots, and carbon nanospheres, because of their biocompatibility, optimal size, large surface area, easy functionality, and specific physical properties ( Wilczewska et al, 2012 ; Mattoussi and Rotello, 2013 ). Some mitochondria-targeting nanoparticles that were recently developed include GO ( Wei et al, 2016 ; Zhang et al, 2018 ), lipid-coated carbon-quantum dots ( Zhang et al, 2017 ), carbon-silica nanoparticles ( Wang et al, 2018 ), polyoxometalates ( Zhang et al, 2015b ), and gold nanoparticles ( Haynes et al, 2016 ) to deliver the therapeutic agent to mitochondria and overcome drug resistance. NPs have been known to successfully deliver anticancer agents to mitochondria with or without a targeting ligand.…”

“… Zhang et al (2018) described glycyrrhetinic acid (GA)-attached GO with Dox as a model drug for mitochondria-targeted cancer treatment ( Figure 7A ). The authors chose GA for dual targeting to mitochondria and the cell membrane due to its ability to interact with the mitochondrial respiratory chain and binding affinity to protein kinase C (PKC) α, which is overexpressed on some cancer cells ( Salvi et al, 2003 ; Fiore et al, 2004 ; Stankovich et al, 2006 ; Wu et al, 2008 ).…”

“…(D) The apoptosis rate of HepG2 cells after treatment with DOX⋅HCl, GO@DOX, GA-GO@DOX, and the control. Images were adapted with permission from reference ( Zhang et al, 2018 ). Bars represent means ± SD ( n = 3); ∗ p < 0.05 and ∗∗ p < 0.01, compared to control; # p < 0.05, compared to DOX⋅HCl.…”