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Mitochondria-targeting probes that allow us to induce and report mitochondrial dysfunction have become promising theranostic agents for cancer; however, the lack of selectivity toward tumor cells over normal tissue cells has impeded the treatment outcome. Herein, we develop 10 fluorescent dehydroberberine derivatives ( B1-B10 ) capable of lighting up mitochondria and exerting moderate cytotoxicity against tumor cells. To enable the selectivity toward tumor cells over normal tissue cells, we introduced a lipophilic anion tetraphenylborate (TPB - ) into the most potent compound B3 + Cl - to drive molecular self-assembly into monodisperse organic nanoassemblies ( B3NPs ) in aqueous solution, which efficiently enhance the delivery of B3 + into HeLa cells assisted by an electrostatic interaction-driven anion-exchange process. Fluorescence imaging reveals that B3 + can initially accumulate in the mitochondria after entering HeLa cells, followed by inducing mitochondrial dysfunction and then migrating into the nucleus. Strong B3 + fluorescence translocating from mitochondria to nucleus can be monitored in real-time, allowing for self-reporting of mitochondrial dysfunction in HeLa cells. Moreover, we demonstrate that B3NPs exert significantly higher cytotoxicity against seven different tumor cells (e.g., U87MG, HeLa, MDA-MB-468, MDA-MB-435, MDA-MB-231, MCF-7, and HCT116 cells) compared to human normal tissue cells (e.g., HUVEC, HEK293). This work highlights the utility of the self-assembly approach to improve the cytotoxicity and selectivity of mitochondria-targeting agents against tumor cells.

Selective imaging and inducing mitochondrial dysfunction in tumor cells using mitochondria-targeting probes has become as a promising approach for cancer diagnosis and therapy. Here, we report the design of a fluorescent berberine analog, dehydroberberine (DH-BBR), as a new mitochondria-targeting probe capable of self-assembling into monodisperse organic nanoparticles (DTNPs) upon integration with a lipophilic counter anion, allowing for enhanced fluorescence imaging and treatment of tumors in living mice. X-ray crystallography revealed that the self-assembly process was attributed to a synergy of different molecular interactions, including π-π stacking, O⋅⋅⋅π interaction and electrostatic interaction between DH-BBR and counter anions. We demonstrated that DTNPs could efficiently enter tumor tissue following intravenous injection and enhance mitochondrial delivery of DH-BBR via an electrostatic interaction driven anion exchange process. Selective accumulation in the mitochondria capable of emitting strong fluorescence and causing mitochondrial dysfunction was achieved, enabling efficient inhibition of tumor growth in living mice. This study demonstrates promise for applying lipophilic anions to control molecular self-assembly and tune antitumor activity of mitochondria-targeting probes, which can facilitate to improve cancer treatment in vivo., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Abstract: Selective imaging and inducing mitochondrial dysfunction in tumor cells using mitochondria‐targeting probes has become as a promising approach for cancer diagnosis and therapy. Here, we report the design of a fluorescent berberine analog, dehydroberberine (DH‐BBR), as a new mitochondria‐targeting probe capable of self‐assembling into monodisperse organic nanoparticles (DTNPs) upon integration with a lipophilic counter anion, allowing for enhanced fluorescence imaging and treatment of tumors in living mice. X‐ray crystallography revealed that the self‐assembly process was attributed to a synergy of different molecular interactions, including π–π stacking, O⋅⋅⋅π interaction and electrostatic interaction between DH‐BBR and counter anions. We demonstrated that DTNPs could efficiently enter tumor tissue following intravenous injection and enhance mitochondrial delivery of DH‐BBR via an electrostatic interaction driven anion exchange process. Selective accumulation in the mitochondria capable of emitting strong fluorescence and causing mitochondrial dysfunction was achieved, enabling efficient inhibition of tumor growth in living mice. This study demonstrates promise for applying lipophilic anions to control molecular self‐assembly and tune antitumor activity of mitochondria‐targeting probes, which can facilitate to improve cancer treatment in vivo. [ABSTRACT FROM AUTHOR]

Mitochondria-targeting theranostic probes that enable the simultaneously reporting of and triggering of mitochondrial dysfunctions in cancer cells are highly attractive for cancer diagnosis and therapy. Three fluorescent mitochondria-targeting theranostic probes have been developed by linking a mitochondrial dye, coumarin-3-carboximide, with a widely used traditional Chinese medicine, artemisinin, to kill cancer cells. Fluorescence images showed that the designed coumarin-artemisinin conjugates localized mainly in mitochondria, leading to enhanced anticancer activities over artemisinin. High cytotoxicity against cancer cells correlated with the strong ability to accumulate in mitochondria, which could efficiently increase the intracellular reactive oxygen species level and induce cell apoptosis. This study highlights the potential of using mitochondria-targeting fluorophores to selectively trigger and directly visualize subcellular drug delivery in living cells. [ABSTRACT FROM AUTHOR]