title: Dimeric cationic amphiphilic polyproline helices for mitochondrial targeting.
abstract: OBJECTIVE
  Efficient delivery of therapeutic biopolymers across cell membranes remains a daunting challenge. The development of cell-penetrating peptides (CPPs) has been useful; however, many CPPs are found trapped within endosomes, limiting their use as delivery agents. We optimize a class of CPPs, cationic amphiphilic polyproline helices (CAPHs), for direct transport into cells with mitochondrial localization through dimerization.
  
  
  METHODS
  The CAPH P11LRR used for this study has been found to enter cells by two distinct pathways: an endocytotic pathway was favored at low concentrations; internalization by direct transport was observed at higher concentrations. CAPH was dimerized to probe if direct transport within cells may be enhanced through increased association of CAPH with the membrane and through the association of individual peptides within the membrane.
  
  
  RESULTS
  The dimerization of the CAPH was found to significantly increase cellular uptake over its monomeric counterpart, with a concomitant lowering of the concentration threshold favoring direct transport. Evidence for direct transport within cells and mitochondrial localization was observed.
  
  
  CONCLUSIONS
  CAPH cellular uptake efficiency can be significantly enhanced through peptide dimerization while favoring cell entry via direct transport at low concentration with low cell toxicity.
authors.affiliation: Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA.
authors.forename: Iris M
authors.initials: IM
authors.lastname: Geisler
authors.forename: Jean
authors.initials: J
authors.lastname: Chmielewski
mesh_terms: D001692:Biological Transport; D002412:Cations / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D058990:Molecular Targeted Therapy; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011108:Polymers / Q000032:analysis / Q000737:chemistry / Q000378:metabolism
chemical_list: D002412:Cations; D057846:Cell-Penetrating Peptides; D010455:Peptides; D011108:Polymers; C011083:polyproline