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

Abstract

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.

• Liposomes
• mitochondrial membrane potential
• mitochondrial targeting
• triphenylphosphonium

Acknowledgements

The authors thank Prof. Vladimir P. Torchilin at Northeastern University, Boston, MA for generous access to the flow cytometer.

Declaration of interest

This work was supported by departmental funds and a summer undergraduate research grant from MCPHS to EMS. The authors report no declarations of interest.