ROS‐Responsive N‐Alkylaminoferrocenes for Cancer‐Cell‐Specific Targeting of Mitochondria

Abstract

Mitochondrial membrane potential is more negative in cancer cells than in normal cells, allowing cancer targeting by delocalized lipophilic cations (DLCs). However, as the difference is rather small, these drugs affect also normal cells. Now a concept of pro-DLCs is proposed based on an N-alkylaminoferrocene structure. These prodrugs are activated by the reaction with reactive oxygen species (ROS) forming ferrocenium-based DLCs. Since ROS are overproduced in cancer, the high-efficiency cancer-cell-specific targeting of mitochondria could be achieved as demonstrated by fluorescence microscopy in combination with two fluorogenic pro-DLCs in vitro and in vivo. We prepared a conjugate of another pro-DLC with a clinically approved drug carboplatin and confirmed that its accumulation in mitochondria was higher than that of the free drug. This was reflected in the substantially higher anticancer effect of the conjugate.

Cyanine dye mediated mitochondrial targeting enhances the anti-cancer activity of small-molecule cargoes

“…They represent three important classes of drugs in clinical application, and the molecular targets of these cargoes are believed to be in mitochondria. [33][34][35][36][37][38][39] KLAKLAKKLAKLAK (KLA) is a proapoptotic, antimicrobial peptide. 33,34 Ciprofloxacin (Cip) is a fluoroquinolone with antibiotic activity but can also cause damage to mitochondrial DNA, showing cytotoxicity to eukaryotic cells.…”

“…[35][36][37][38] CPT is a metal complex and a derivative of carboplatin (a widely used anti-cancer drug) that impairs mitochondrial function and leads to apoptosis. 39 The synthesis of all drug conjugates proved to be rapid and straightforward through simple coupling of the free carboxylic acid of the cyanine dyes. Although conjugates containing both Cy3 and Cy5 may enhance their mitochondrial localisation, they may have higher propensity for aggregation.…”

Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy

“…Recently, Mokhir et al introduced a concept called pro-delocalized charge (pro-DLC), which involves the activation of delocalized positive charge within the cell to generate delocalized charge (DLC) ( Figure 3D). This concept is based on the N-alkylamino ferrocene structure, in which the prodrugs are activated by the reaction with ROS within the cell to produce DLC [35]. Since ROS are overexpressed inside the cancer cells, higher cancer selectivity could be achieved.…”

A Noncovalent Fluorescence Turn‐on Strategy for Hypoxia Imaging

“…Schematic illustration of the design principles of the conventional covalent (a) and the proposed noncovalent( b) strategies for creating hypoxia-responsive systems. [18] Rho123 was employed as the reporter dye due to the strong complexation with CAC4A and the corresponding drastic fluorescence quenching ( Figure 1b). This leads to the release of the dye and the recovery of the fluorescence intensity.…”

“…[17] Rhodamine 123 (Rho123) is ac ommercial fluorescent dye and has been widely used in bioimaging owing to its high brightness and photostability. [18] Rho123 was employed as the reporter dye due to the strong complexation with CAC4A and the corresponding drastic fluorescence quenching ( Figure 1b). AJ obsp lot determined the 1:1b inding stoichiometry between CAC4A and Rho123 (Supporting Information, Figure S2).…”