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

Abstract

The mitochondrion is an important intracellular organelle for drug targeting due to its key roles and functions in cellular proliferation and death. In the last few decades, several studies have revealed mitochondrial functions, attracting the focus of many researchers to work in this field over nuclear targeting. Mitochondrial targeting was initiated in 1995 with a triphenylphosphonium-thiobutyl conjugate as an antioxidant agent. The major driving force for mitochondrial targeting in cancer cells is the higher mitochondrial membrane potential compared with that of the cytosol, which allows some molecules to selectively target mitochondria. In this review, we discuss mitochondria-targeting ligand-conjugated anticancer agents and their in vitro and in vivo behaviors. In addition, we describe a mitochondria-targeting nanocarrier system for anticancer drug delivery. As previously reported, several agents have been known to have mitochondrial targeting potential; however, they are not sufficient for direct application for cancer therapy. Thus, many studies have focused on direct conjugation of targeting ligands to therapeutic agents to improve their efficacy. There are many variables for optimal mitochondria-targeted agent development, such as choosing a correct targeting ligand and linker. However, using the nanocarrier system could solve some issues related to solubility and selectivity. Thus, this review focuses on mitochondria-targeting drug conjugates and mitochondria-targeted nanocarrier systems for anticancer agent delivery.

Updates in Anthracycline-Mediated Cardiotoxicity

“…Conjugating DOX with mitochondria penetrating peptide ( Chamberlain et al, 2013 ) generated an adduct called as a mitochondrial-targeted DOX (MtDOX) that can recover cardiomyocytes from mitochondrial damage by activation of compensatory mitochondrial biogenesis without nuclear damage associated with cardiotoxicity ( Jean et al, 2015 ). Although MtDOX is less cytotoxic in drug-sensitive cells, it displays a strong cytotoxic effect in DOX-resistance cells ( Battogtokh et al, 2018 ). Unfortunately, the in vivo anticancer activity of these agents has not been reported yet.…”

Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells

“…Several studies have reported drug delivery systems for the transport of anticancer compounds to the mitochondria [18], highlighting the use of the lipophilic cations pyridinium [53][54][55] and TPP + [56][57][58][59]. In particular, we showed that TPP + derivatives of gallic acid and GA selectively induce cell death in BC cells [19,20] in a receptor status-independent manner [20] without toxic effects on nontumoral tissues in vivo [21].…”

“…An extensively studied strategy for mitochondrial delivery of small molecules is the incorporation of lipophilic cationic groups such as pyridinium or triphenylphosphonium (TPP + ), which allow the accumulation of lipophilic cationic-linked compounds specifically in the "negative" mitochondrial matrix based on the mitochondrial transmembrane potential (∆Ψm) [15][16][17]. Several TPP + -linked small molecules with anticancer effects, such as FDA-approved drugs, polyphenols, therapeutic peptides, and photosensitizers, have been reported [18]. We showed that TPP + -linked natural hydroxybenzoic acids induce OXPHOS inhibition and consistently decrease mitochondrial depolarization and ATP without increasing ROS production.…”

Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

“…[53] In mammalian cells,several types of mitochondrial proteins serve as targets for anticancer agents.I np arasites and fungal pathogens the mitochondrion-residing electrontransfer chain and the redox system are important targets for drug development. [53] In mammalian cells,several types of mitochondrial proteins serve as targets for anticancer agents.I np arasites and fungal pathogens the mitochondrion-residing electrontransfer chain and the redox system are important targets for drug development.…”