Mitochondrial H2Sn-Mediated Anti-Inflammatory Theranostics

Abstract

Theranostic agent 1 ( TA1 ) was successfully developed to provide dual functions: anti-inflammatory therapy and precise diagnosis. TA1 selectively reacts with H 2 S n in the mitochondria in response to inflammatory reactions to simultaneously produce both indomethacin as a drug and ring-opened fluorescence-on Rhodol. Theranostic behavior of TA1 was proven by in vitro and in vivo imaging. TA1 reveals inflammatory site-selective drug release followed by significant therapeutic effects and is highly applicable in vivo model therapeutics for the inflammatory disease. The insistent demand for space-controllable delivery, which reduces the side effects of non-steroidal anti-inflammatory drugs (NSAIDs), has led to the development of a new theranostics-based approach for anti-inflammatory therapy. The current anti-inflammatory treatments can be improved by designing a drug delivery system responsive to the inflammatory site biomarker, hydrogen polysulfide (H 2 S n ). Here, we report a novel theranostic agent 1 ( TA1 ), consisting of three parts: H 2 S n -mediated triggering part, a two-photon fluorophore bearing mitochondria targeting unit (Rhodol-TPP), and anti-inflammatory COX inhibitor (indomethacin). In vitro experiments showed that TA1 selectively reacts with H 2 S n to concomitantly release both Rhodol-TPP and indomethacin. Confocal-microscopy imaging of inflammation-induced live cells suggested that TA1 is localized in the mitochondria where the H 2 S n is overexpressed. The TA1 reacted with H 2 S n in the endogenous and exogenous H 2 S n environments and in lipopolysaccharide treated inflammatory cells. Moreover, TA1 suppressed COX-2 level in the inflammatory-induced cells and prostaglandin E 2 (PGE 2 ) level in blood serum from inflammation-induced mouse models. In vivo experiments with inflammation-induced mouse models suggested that TA1 exhibits inflammation-site-elective drug release followed by significant therapeutic effects, showing its function as a theranostic agent, capable of both anti-inflammatory therapy and precise diagnosis. Theranostic behavior of TA1 is highly applicable in vivo model therapeutics for the inflammatory disease.