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J Control Release. 2016 Jun 28;232:188-95. doi: 10.1016/j.jconrel.2016.04.027. Epub 2016 Apr 19.

Urokinase-controlled tumor penetrating peptide.

Author information

1
Sanford Burnham Prebys Medical Discovery Institute, Cancer Research Center, La Jolla, CA, USA.
2
Sanford Burnham Prebys Medical Discovery Institute, Cancer Research Center, La Jolla, CA, USA; Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY, USA.
3
Sanford Burnham Prebys Medical Discovery Institute, Cancer Research Center, La Jolla, CA, USA; Biomedical Sciences Graduate Program, Department of Pharmacology, University of California San Diego, La Jolla, USA.
4
Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
5
Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
6
Sanford Burnham Prebys Medical Discovery Institute, Cancer Research Center, La Jolla, CA, USA; Center for Nanomedicine, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA.
7
Sanford Burnham Prebys Medical Discovery Institute, Cancer Research Center, La Jolla, CA, USA; Center for Nanomedicine, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA; Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia. Electronic address: tambet.teesalu@ut.ee.

Abstract

Tumor penetrating peptides contain a cryptic (R/K)XX(R/K) CendR element that must be C-terminally exposed to trigger neuropilin-1 (NRP-1) binding, cellular internalization and malignant tissue penetration. The specific proteases that are involved in processing of tumor penetrating peptides identified using phage display are not known. Here we design de novo a tumor-penetrating peptide based on consensus cleavage motif of urokinase-type plasminogen activator (uPA). We expressed the peptide, uCendR (RPARSGR↓SAGGSVA, ↓ shows cleavage site), on phage or coated it onto silver nanoparticles and showed that it is cleaved by uPA, and that the cleavage triggers binding to recombinant NRP-1 and to NPR-1-expressing cells. Upon systemic administration to mice bearing uPA-overexpressing breast tumors, FAM-labeled uCendR peptide and uCendR-coated nanoparticles preferentially accumulated in tumor tissue. We also show that uCendR phage internalization into cultured cancer cells and its penetration in explants of murine tumors and clinical tumor explants can be potentiated by combining the uCendR peptide with tumor-homing module, CRGDC. Our work demonstrates the feasibility of designing tumor-penetrating peptides that are activated by a specific tumor protease. As upregulation of protease expression is one of the hallmarks of cancer, and numerous tumor proteases have substrate specificities compatible with proteolytic unmasking of cryptic CendR motifs, the strategy described here may provide a generic approach for designing proteolytically-actuated peptides for tumor-penetrative payload delivery.

KEYWORDS:

C-end rule; Neuropilin-1; Silver nanoparticles; Tumor targeting; Urokinase; α(v) integrins

PMID:
27106816
PMCID:
PMC5359125
DOI:
10.1016/j.jconrel.2016.04.027
[Indexed for MEDLINE]
Free PMC Article

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