Sonodynamic Cancer Therapy by Mn(I)‐tricarbonyl Complexes via Ultrasound‐triggered CO Release and ROS Generation.

A novel ferrocene conjugated Mn(I)‐tricarbonyl complex <italic>viz</italic> [Mn(Fc‐tpy)(CO)3Br] (<bold>Mn2</bold>) where, Fc‐tpy=4′‐ferrocenyl‐2,2′:6′,2′′‐terpyridine was synthesized and fully characterized along with its non‐ferrocene analog [Mn(Ph‐tpy)(CO)3Br] Ph‐tpy=4′‐phenyl‐2,2′:6′,2′′‐terpyridine (<bold>Mn1</bold>) for ultrasound (US) activated anticancer applications. The X‐ray structure of <bold>Mn2</bold> confirmed its distorted octahedral geometry. <bold>Mn1</bold> and <bold>Mn2</bold>, for the first time, showed US‐triggered release of CO and ROS generation (1O2 and ⋅OH) in an aqueous solution from any Mn(I)‐tricarbonyl complexes, indicating its potential for synergetic CO gas therapy and sonodynamic therapy. The above‐mentioned in‐solution chemistry was successfully translated into <italic>in vitro</italic> cellular models. These complexes showed unprecedented US‐triggered toxicity against T‐cell lymphoma and human breast cancer cells (IC50 for <bold>Mn2</bold><1 μM) while were minimally toxic without US or against normal spleen and human embryonic kidney cells. <bold>Mn2</bold> was ca. 12 fold more anticancer active than <bold>Mn1</bold>, indicating that the ferrocene conjugation augmented the US sensitivity. The apoptotic sonotoxicity of <bold>Mn2</bold> was due to US‐promoted mitochondrial depolarization via ROS generation and CO release. The apoptosis was triggered by caspase 3 activation. This is the first report of Mn(I)‐tricarbonyl‐based sonosensitizers for cancer SDT. Overall, this study, for the first time, establishes the effectiveness of 3d metal carbonyls in SDT. [ABSTRACT FROM AUTHOR]