title: Hydrophobized triphenyl phosphonium derivatives for the preparation of mitochondriotropic liposomes: choice of hydrophobic anchor influences cytotoxicity but not mitochondriotropic effect.
abstract: BACKGROUND
  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.
authors: a Department of Pharmaceutical Sciences , Massachusetts College of Pharmacy and Health Sciences , Boston , MA , USA.
authors: Parul
authors: P
authors: Benien
authors: a Department of Pharmaceutical Sciences , Massachusetts College of Pharmacy and Health Sciences , Boston , MA , USA.
authors: Melani A
authors: MA
authors: Solomon
authors: a Department of Pharmaceutical Sciences , Massachusetts College of Pharmacy and Health Sciences , Boston , MA , USA.
authors: Paul
authors: P
authors: Nguyen
authors: a Department of Pharmaceutical Sciences , Massachusetts College of Pharmacy and Health Sciences , Boston , MA , USA.
authors: Erin M
authors: EM
authors: Sheehan
authors: a Department of Pharmaceutical Sciences , Massachusetts College of Pharmacy and Health Sciences , Boston , MA , USA.
authors: Ahmed S
authors: AS
authors: Mehanna
authors: a Department of Pharmaceutical Sciences , Massachusetts College of Pharmacy and Health Sciences , Boston , MA , USA.
authors: Gerard G M
authors: GG
authors: D'Souza
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008081:Liposomes / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D010743:Phospholipids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D008081:Liposomes; D009942:Organometallic Compounds; D010743:Phospholipids
keywords: Liposomes; mitochondrial membrane potential; mitochondrial targeting; triphenylphosphonium