title: Unique Triphenylphosphonium Derivatives for Enhanced Mitochondrial Uptake and Photodynamic Therapy.
abstract: 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.
authors.affiliation: School of Physical and Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University , 21 Nanyang Link, 637371 Singapore.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: School of Physical and Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University , 21 Nanyang Link, 637371 Singapore.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sim
authors.affiliation: Division of Medical Sciences, Laboratory of Applied Human Genetics, Humphrey Oei Institute of Cancer Research, National Cancer Centre , 169610 Singapore.
authors.forename: Oi Lian
authors.initials: OL
authors.lastname: Kon
authors.affiliation: Division of Medical Sciences, Laboratory of Applied Human Genetics, Humphrey Oei Institute of Cancer Research, National Cancer Centre , 169610 Singapore.
authors.forename: Wai Har
authors.initials: WH
authors.lastname: Ng
authors.affiliation: UCIBIO, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto , Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.
authors.forename: António J M
authors.initials: AJ
authors.lastname: Ribeiro
authors.affiliation: UCIBIO, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto , Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ramos
authors.affiliation: UCIBIO, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto , Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Fernandes
authors.affiliation: School of Physical and Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University , 21 Nanyang Link, 637371 Singapore.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Ganguly
authors.affiliation: School of Physical and Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University , 21 Nanyang Link, 637371 Singapore.
authors.forename: Bengang
authors.identifier: 0000-0002-8391-1234
authors.initials: B
authors.lastname: Xing
authors.affiliation: School of Physical and Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University , 21 Nanyang Link, 637371 Singapore.
authors.forename: Felipe
authors.identifier: 0000-0002-9605-3611
authors.initials: F
authors.lastname: García
authors.affiliation: School of Physical and Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University , 21 Nanyang Link, 637371 Singapore.
authors.forename: Edwin K L
authors.identifier: 0000-0003-0290-4882
authors.initials: EK
authors.lastname: Yeow
mesh_terms: D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D005452:Fluoresceins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054879:Halogenation; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008745:Methylation; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D004337:Drug Carriers; D005452:Fluoresceins; D009943:Organophosphorus Compounds; D017319:Photosensitizing Agents