Hydrophobized triphenyl phosphonium derivatives for the preparation of mitochondriotropic liposomes: choice of hydrophobic anchor influences cytotoxicity but not mitochondriotropic effect

• Published in: Journal of liposome research Vol. 26; no. 1; pp. 21 - 27
• Main Authors: Benien, Parul, Solomon, Melani A., Nguyen, Paul, Sheehan, Erin M., Mehanna, Ahmed S., D'Souza, Gerard G. M.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02-01-2016
• Subjects: Cell Line, Tumor; Cell Membrane - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Humans; Hydrophobic and Hydrophilic Interactions; Liposomes; Liposomes - adverse effects; Liposomes - chemical synthesis; Liposomes - chemistry; Liposomes - pharmacology; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial membrane potential; Mitochondrial Membranes - drug effects; mitochondrial targeting; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Phospholipids - chemistry; Phospholipids - pharmacology; Structure-Activity Relationship; triphenylphosphonium; Liposomes; triphenylphosphonium; mitochondrial targeting; mitochondrial membrane potential
• ISSN: 0898-2104; 1532-2394
• DOI: 10.3109/08982104.2015.1022557

Context: Nanocarrier-based strategies to achieve delivery of bioactives specifically to the mitochondria are being increasingly explored due to the importance of mitochondria in critical cellular processes.
Objective: To test the ability of liposomes modified with newly synthesized triphenylphosphonium (TPP)-phospholipid conjugates and to test their use in overcoming the cytotoxicity of stearyl triphenylphosphonium (STPP)-modified liposomes when used for delivery of therapeutic molecules to the mitochondria.
Methods: TPP-phospholipid conjugates with the dioleoyl, dimyristoyl or dipalmitoyl lipid moieties were synthesized and liposomes were prepared with these conjugates in a 1 mol% ratio. The subcellular distribution of the liposomes was tested by confocal microscopy. Furthermore, the liposomes were tested for their effect on cell viability using a MTS assay, on cell membrane integrity using a lactate dehydrogenase assay and on mitochondrial membrane integrity using a modified JC-1 assay.
Results: The liposomes modified with the new TPP-phospholipid conjugates exhibited similar mitochondriotropism as STPP-liposomes but they were more biocompatible as compared to the STPP liposomes. While the STPP-liposomes had a destabilizing effect on cell and mitochondrial membranes, the liposomes modified with the TPP-phospholipid conjugates did not demonstrate any such effect on biomembranes.
Conclusions: Using phospholipid anchors in the synthesis of TPP-lipid conjugates can provide liposomes that exhibit the same mitochondrial targeting ability as STPP but with much higher biocompatibility.