Tumor-penetrating iRGD peptide inhibits metastasis.
Tumor-specific tissue-penetrating peptides deliver drugs into extravascular tumor tissue by increasing tumor vascular permeability through interaction with neuropilin (NRP). Here, we report that a prototypic tumor-penetrating peptide iRGD (amino acid sequence: CRGDKGPDC) potently inhibits spontaneous metastasis in mice. The antimetastatic effect was mediated by the NRP-binding RXXK peptide motif (CendR motif), and not by the integrin-binding RGD motif. iRGD inhibited migration of tumor cells and caused chemorepulsion in vitro in a CendR- and NRP-1-dependent manner. The peptide induced dramatic collapse of cellular processes and partial cell detachment, resulting in the repellent activity. These effects were prominently displayed when the cells were seeded on fibronectin, suggesting a role of CendR in functional regulation of integrins. The antimetastatic activity of iRGD may provide a significant additional benefit when this peptide is used for drug delivery to tumors.
Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California. Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York. sugahara@sanfordburnham.org.
Kazuki N
KN
Sugahara
Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California. Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California Santa Barbara, Santa Barbara, California.
Gary B
GB
Braun
Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California.
Tatiana Hurtado
TH
de Mendoza
Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California.
Venkata Ramana
VR
Kotamraju
Division of Surgical Oncology and Moores Cancer Center, University of California, San Diego, La Jolla, California.
Randall P
RP
French
Division of Surgical Oncology and Moores Cancer Center, University of California, San Diego, La Jolla, California.
Andrew M
AM
Lowy
Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California. Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
Tambet
T
Teesalu
Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California. Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California Santa Barbara, Santa Barbara, California.
Erkki
E
Ruoslahti
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008297:Male; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D039942:Neuropilin-1 / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage* / Q000494:pharmacology; D009928:Organ Specificity; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D012834:Silver; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D009842:Oligopeptides; D039942:Neuropilin-1; D012834:Silver; C047981:arginyl-glycyl-aspartic acid