Beyond the TPP+ "gold standard": a new generation mitochondrial delivery vector based on extended PN frameworks

• Main Authors: Ong, How Chee, Coimbra, João T. S., Ramos, Maria J., Xing, Bengang, Fernandes, Pedro A., García, Felipe
• Other Authors: School of Physical and Mathematical Sciences
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Chemistry; Triphenylphosphonium; Lipophilicity
• Online Access: https://hdl.handle.net/10356/169778
• Institution: Nanyang Technological University

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.