Tumor imaging by means of proteolytic activation of cell-penetrating peptides
AUTOR(ES)
Jiang, Tao
FONTE
National Academy of Sciences
RESUMO
We have devised and tested a new strategy for selectively delivering molecules to tumor cells. Cellular association of polyarginine-based, cell-penetrating peptides (CPPs) is effectively blocked when they are fused to an inhibitory domain made up of negatively charged residues. We call these fusions activatable CPPs (ACPPs) because cleavage of the linker between the polycationic and polyanionic domains, typically by a protease, releases the CPP portion and its attached cargo to bind to and enter cells. Association with cultured cells typically increases 10-fold or more upon linker cleavage. In mice xenografted with human tumor cells secreting matrix metalloproteinases 2 and 9, ACPPs bearing a far-red-fluorescent cargo show in vivo contrast ratios of 2-3 and a 3.1-fold increase in standard uptake value for tumors relative to contralateral normal tissue or control peptides with scrambled linkers. Ex vivo slices of freshly resected human squamous cell carcinomas give similar or better contrast ratios. Because CPPs are known to import a wide variety of nonoptical contrast and therapeutic agents, ACPPs offer a general strategy toward imaging and treating disease processes associated with linker-cleaving activities such as extracellular proteases.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=539314Documentos Relacionados
- Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides
- Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics
- Novel human-derived cell-penetrating peptides for specific subcellular delivery of therapeutic biomolecules
- Arginine-Rich Peptides Destabilize the Plasma Membrane, Consistent with a Pore Formation Translocation Mechanism of Cell-Penetrating Peptides
- Synthesis, cellular uptake and HIV-1 Tat-dependent trans-activation inhibition activity of oligonucleotide analogues disulphide-conjugated to cell-penetrating peptides