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Unique Triphenylphosphonium Derivatives for Enhanced Mitochondrial Uptake and Photodynamic Therapy

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journal contribution
posted on 03.01.2017, 00:00 by Zhang Hu, Ying Sim, Oi Lian Kon, Wai Har Ng, António J. M. Ribeiro, Maria J. Ramos, Pedro A. Fernandes, Rakesh Ganguly, Bengang Xing, Felipe García, Edwin K. L. Yeow
In this study, unique methyl-functionalized derivatives (T*PP+) of the drug carrier triphenylphosphonium (TPP+) that exhibit significant enhancement of the accumulation of both the cation and its conjugated cargo in cell mitochondria are designed. We show that the presence of methyl group(s) at key positions within the phenyl ring results in an increase in the hydrophobicity and solvent accessible surface area of T*PP+. In particular, when the para position of the phenyl ring in T*PP+ is functionalized with a methyl group, the cation is most exposed to the surrounding environment, leading to a large decrease in water entropy and an increase in the level of van der Waals interaction with and partition into a nonpolar solvent. Therefore, stronger binding between the hydrophobic T*PP+ and mitochondrial membrane occurs. This is exemplified in a (hexachloro-fluorescein)–TPP+ conjugate system, where an ∼12 times increase in the rate of mitochondrial uptake and a 2 times increase in photodynamic therapy (PDT) efficacy against HeLa and FU97 cancer cells are achieved when TPP+ is replaced with T*PP+. Importantly, nearly all the FU97 cells treated with the (hexachloro-fluorescein)–T*PP+ conjugate are killed as compared to only half the population of cells in the case of the (hexachloro-fluorescein)–TPP+ conjugate at a similar PDT light dosage. This study thus forms a platform for the healthcare community to explore alternative TPP+ derivatives that can act as optimal drug transporters for enhanced mitochondrially targeted therapies.

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