Beyond the TPP(+) “gold standard”: a new generation mitochondrial delivery vector based on extended PN frameworks

Mitochondrial targeting represents an attractive strategy for treating metabolic, degenerative and hyperproliferative diseases, since this organelle plays key roles in essential cellular functions. Triphenylphosphonium (TPP(+)) moieties – the current “gold standard” – have been widely used as mitochondrial targeting vectors for a wide range of molecular cargo. Recently, further optimisation of the TPP(+) platform drew considerable interest as a way to enhance mitochondrial therapies. However, although the modification of this system appears promising, the core structure of the TPP(+) moiety remains largely unchanged. Thus, this study explored the use of aminophosphonium (PN(+)) and phosphazenylphosphonium (PPN(+)) main group frameworks as novel mitochondrial delivery vectors. The PPN(+) moiety was found to be a highly promising platform for this purpose, owing to its unique electronic properties and high lipophilicity. This has been demonstrated by the high mitochondrial accumulation of a PPN(+)-conjugated fluorophore relative to its TPP(+)-conjugated counterpart, and has been further supported by density functional theory and molecular dynamics calculations, highlighting the PPN(+) moiety's unusual electronic properties. These results demonstrate the potential of novel phosphorus-nitrogen based frameworks as highly effective mitochondrial delivery vectors over traditional TPP(+) vectors.