Intracellular cargo delivery by an octaarginine transporter adapted to target prostate cancer cells through cell surface protease activation.
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.
Goun
Elena A
EA
Department of Chemistry, Stanford University, Stanford, California 94305, USA.
Shinde
Rajesh
R
Dehnert
Karen W
KW
Adams-Bond
Angie
A
Wender
Paul A
PA
Contag
Christopher H
CH
Franc
Benjamin L
BL
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
D026905:Amino Acid Transport Systems; D008565:Membrane Proteins; D009842:Oligopeptides; D019151:Peptide Library; C448619:octaarginine; D017430:Prostate-Specific Antigen