A Cisplatin‐Selective Fluorescent Probe for Real‐Time Monitoring of Mitochondrial Platinum Accumulation in Living Cells

Abstract

Mitochondria have emerged as important targets for cisplatin in cancer therapy. Apart from cisplatin, anticancer Pt complexes based on similar scaffolds have also been developed to target mitochondria. Yet cellular processing of cisplatin or these mitochondria‐targeting Pt analogues remained unexplored, largely due to a lack of tools capable of probing these Pt drugs within an intracellular environment. We developed the first mitochondria‐targeted fluorescent probe for real‐time monitoring of Pt accumulation in mitochondria. We applied the probe to investigate mitochondria as cellular targets for Pt drug complexes and uncovered two distinct pathways whereby these Pt complexes could be delivered to mitochondria after cell entry.

Albumin-targeting of an oxaliplatin-releasing platinum(iv) prodrug results in pronounced anticancer activity due to endocytotic drug uptake in vivo

“…Interestingly, we also found indications that the compound might be metabolized (intra-and/or extracellularly) to a DACH-free platinum species. Noteworthy, there are only a few studies so far, which address the intracellular or even intratumoral drug distribution of metal-based drugs or their nanoformulations in vitro 44,45 or in vivo. 42…”

In Vitro Anticancer Activity of Nanoformulated Mono‐ and Di‐nuclear Pt Compounds

“…There is still an intense research interest in developing novel Pt‐based therapeutics for cancer treatment four decades after the approval of cisplatin [4c,5a,9] . A primary challenge is to improve patient benefit by reducing damage to normal tissues resulting in nausea and hair loss among other side effects.…”

“…Multiple therapeutic and/or diagnostic modalities have been integrated to try and achieve synergistic and spatiotemporal treatment [19] . Aside from nanomaterial assembly, carefully designed Pt‐based complexes can also be used to achieve fine‐tuning of the drug‐biomolecule interaction [4c,e,f,20] …”

“…The hyperpolarized membrane potential of mitochondria in cancer cells has been exploited in anticancer drug design by, for example, incorporating cationic functionality [4c,29] . In this regard, the use of ligand PPh 2 PhNMe 2 is preferred as the −NMe 2 function in the ligand is assumed to readily react with MeI to give the −[NMe 3 ] + cation [30] .…”

Mitochondrial Transplantation: Is It a Feasible Therapy to Prevent the Cardiorenal Side Effects of Cisplatin?

“…Cisplatin accumulates in the mitochondria of renal PTCs and forms crosslinks with mtDNA and proteins [25]. Recent evidence using a platinum selective fluorescent probe has shown that the Cytochrome c oxidase copper chaperone 17 (COX17), a mitochondrial intermembrane enzyme involved in copper transfer [61], mediated the mitochondrial internalization of cisplatin in HeLa cells [62], suggesting a mechanism by which mitotoxicity may occur [63].…”