Quaternary ammonium‐based mitochondria targeting anticancer agents with high water solubility

Abstract

Triphenylphosphonium derivatives induce mitochondrial dysfunction by inhibiting the respiratory chain, membrane depolarization, and generation of reactive oxygen species. However, the clinical application has been limited due to low aqueous solubility. In this regard, a series of novel mitochondria targeting agents were designed by introducing quaternary ammonium that increases aqueous solubility. Among them, diquaternary ammonium containing triphenylphosphonium molecules specifically inhibited mitochondrial respiratory chain, disrupted mitochondrial proteostasis, and intra-mitochondrial protein in cancer cells, resulting in apoptosis induction. Overall, the high water-soluble mitochondria targeting agents would be a potential anticancer drug.

Enzyme-instructed morphology transformation of mitochondria-targeting peptide for the selective eradication of osteosarcoma

“…The self-assembly of this agent within the mitochondria leads to cell death via mitochondrial disruption and the consequent release of apoptotic bodies. [14][15][16][17][18][19] Promising in vitro and in vivo results have been demonstrated for this approach. 20,21 However, the small molecules can be rapidly cleared from the body, and the positive charge demanded by mitochondriontargeting molecules such as triphenylphosphonium (TPP) 22 induces undesirable nonspecific interactions with negatively charged biomolecules and serum proteins, decreasing the tumor healing efficiency.…”

Spatiotemporal Self-Assembly of Peptide Amphiphiles by Carbonic Anhydrase IX-Targeting Induces Cancer-Lysosomal Membrane Disruption

“…For example, cathepsins, which are lysosomal peptidases, are present in the form of inactive proenzymes at physiological pH. However, they undergo conformational change for generating catalytic activity in response to low pH at the lysosome. − Owing to the nature of being activated in an appropriate environment, biomacromolecules are less active and do not affect surrounding cellular processes in an aberrant subcellular location. − Inspired by the process of nature, many artificial systems, which are activated in the desired environment, are being developed to regulate cellular processes while minimizing the impact on surrounding cells. − For this strategy, it is essential to spatiotemporally localize the artificial system into the desired location. In recent years, enzyme-instructed self-assembly strategies have been developed to achieve precise spatiotemporal control of nanostructures inside cells.…”