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 stra...

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Bibliographic Details
Published in:Bioconjugate chemistry 2006-05, Vol.17 (3), p.787-796
Main Authors: Goun, Elena A, Shinde, Rajesh, Dehnert, Karen W, Adams-Bond, Angie, Wender, Paul A, Contag, Christopher H, Franc, Benjamin L
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acid Transport Systems - metabolism
Cell Line, Tumor
Cells
Chromatography, High Pressure Liquid
Enzyme Activation - drug effects
Humans
Male
Medical imaging
Membrane Proteins - genetics
Membrane Proteins - metabolism
Molecular Sequence Data
Oligopeptides - pharmacology
Peptide Library
Peptides
Pharmacology
Prostate cancer
Prostate-Specific Antigen - genetics
Prostate-Specific Antigen - metabolism
Prostatic Neoplasms - metabolism
Proteases
Protein Denaturation
Serum
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Summary: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.
ISSN:1043-1802
1520-4812
DOI:10.1021/bc0503216