title: Intracellular cargo delivery by an octaarginine transporter adapted to target prostate cancer cells through cell surface protease activation.
abstract: Delivery of therapeutics and imaging agents to target tissues requires localization and activation strategies with molecular specificity. Cell-associated proteases can be used for these purposes in a number of pathologic conditions, and their enzymatic activities can be exploited for activation strategies. Here, molecules based on the d-arginine octamer (r8) protein-transduction domain (PTD, also referred to as molecular transporters) have been adapted for selective uptake into cells only after proteolytic cleavage of a PTD-attenuating sequence by the prostate-specific antigen (PSA), an extracellular protease associated with the surface and microenvironment of certain prostate cancer cells. Convergent syntheses of these activatable PTDs (APTDs) are described, and the most effective r8 PTD-attenuating sequence is identified. The conjugates are shown to be stable in serum, cleaved by PSA, and taken up into Jurkat (human T cells) and PC3M prostate cancer cell lines only after cleavage by PSA. These APTD peptide-based molecules may facilitate targeted delivery of therapeutics or imaging agents to PSA-expressing prostate cancers.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305, USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Goun
authors.forename: Rajesh
authors.initials: R
authors.lastname: Shinde
authors.forename: Karen W
authors.initials: KW
authors.lastname: Dehnert
authors.forename: Angie
authors.initials: A
authors.lastname: Adams-Bond
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wender
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Contag
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Franc
mesh_terms: D000595:Amino Acid Sequence; D026905:Amino Acid Transport Systems / Q000378:metabolism*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D019151:Peptide Library; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011489:Protein Denaturation; D044967:Serum
chemical_list: D026905:Amino Acid Transport Systems; D008565:Membrane Proteins; D009842:Oligopeptides; D019151:Peptide Library; C448619:octaarginine; D017430:Prostate-Specific Antigen