Mitochondria-Specific Aggregation-Induced Emission Luminogens for Selective Photodynamic Killing of Fungi and Efficacious Treatment of Keratitis

Abstract

The development of effective antifungal agents remains a big challenge in view of the close evolutionary relationship between mammalian cells and fungi. Moreover, rapid mutations of fungal receptors at the molecular level result in the emergence of drug resistance. Here, with low tendency to develop drug-resistance, the subcellular organelle mitochondrion is exploited as an alternative target for efficient fungal killing by photodynamic therapy (PDT) of mitochondrial-targeting luminogens with aggregation-induced emission characteristics (AIEgens). With cationic isoquinolinium (IQ) moiety and proper hydrophobicity, three AIEgens, namely, IQ-TPE-2O, IQ-Cm, and IQ-TPA, can preferentially accumulate at the mitochondria of fungi over the mammalian cells. Upon white light irradiation, these AIEgens efficiently generate reactive 1 O 2 , which causes irreversible damage to fungal mitochondria and further triggers the fungal death. Among them, IQ-TPA shows the highest PDT efficiency against fungi and negligible toxicity to mammalian cells, achieving the selective and highly efficient killing of fungi. Furthermore, we tested the clinical utility of this PDT strategy by treating fungal keratitis on a fungus-infected rabbit model. It was demonstrated that IQ-TPA presents obviously better therapeutic effects as compared with the clinically used rose bengal, suggesting the success of this PDT strategy and its great potential for clinical treatment of fungal infections.

Recent Perspectives in the Management of Fungal Keratitis

“…The close evolutionary relationship between the mammalian cells and the fungus has always been a matter of concern with many side effects occurring due to similarity in structure. An innovative recent study [170] utilised mitochondrial-targeting luminogens with aggregation-induced emission characteristics (AIE gens) as photosensitizers in place of rose Bengal and riboflavin, which will selectively target the fungal mitochondria, the organelle which has the least potential to develop drug resistance. This comparative study [170] done in a rabbit model compared these AIE gens, namely IQTPE-2O, IQ-Cm and IQ-TPA-assisted PDT with rose Bengal PDT and found it to be less toxic and more efficacious.…”

A cell membrane-targeting AIE photosensitizer as a necroptosis inducer for boosting cancer theranostics

“…Hence, exploring distinctive AIEgen derived photosensitizers with cell membrane-specic anchoring capability would be signicantly important. [37][38][39][40] Additionally, the nucleus with large amounts of DNA is regarded as the "brain" of the cell, and hence a nucleustargeting photosensitizer could trigger a more effective outcome than that in the cytoplasm. 14 And the level of DNA damage during or aer treatment has a tremendous impact on the treatment outcome.…”

“…Hence, exploring distinctive AIEgen derived photosensitizers with cell membrane-specific anchoring capability would be significantly important. 37–40…”

Vision Defense: Efficient Antibacterial AIEgens Induced Early Immune Response for Bacterial Endophthalmitis

“…[ 21,31,32 ] Recently, Peng and Zhou et al reported that positive charged AIEgens could treat keratitis, which exhibited excellent photodynamic antibacterial ability and biosafety of ocular applications. [ 33,34 ] According to the previous studies, proper design of cationic AIEgens could specifically discriminate and kill bacteria by PDT over normal cells.…”