title: Real-time in vivo molecular detection of primary tumors and metastases with ratiometric activatable cell-penetrating peptides.
abstract: Management of metastatic disease is integral to cancer treatment. Evaluation of metastases often requires surgical removal of all anatomically susceptible lymph nodes for ex vivo pathologic examination. We report a family of novel ratiometric activatable cell-penetrating peptides, which contain Cy5 as far red fluorescent donor and Cy7 as near-infrared fluorescent acceptor. Cy5 is quenched in favor of Cy7 re-emission until the intervening linker is cut by tumor-associated matrix metalloproteinases-2 and 9 (MMP2,9) or elastases. Such cleavage increases the Cy5:Cy7 emission ratio 40-fold and triggers tissue retention of the Cy5-containing fragment. This ratiometric increase provides an accelerated and quantifiable metric to identify primary tumors and metastases to liver and lymph nodes with increased sensitivity and specificity. This technique represents a significant advance over existing nonratiometric protease sensors and sentinel lymph node detection methods, which give no information about cancer invasion.
authors.affiliation: Department of Pharmacology, Division of Head and Neck Surgery, Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Elamprakash N
authors.initials: EN
authors.lastname: Savariar
authors.forename: Csilla N
authors.initials: CN
authors.lastname: Felsen
authors.forename: Nadia
authors.initials: N
authors.lastname: Nashi
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Ellies
authors.forename: Paul
authors.initials: P
authors.lastname: Steinbach
authors.forename: Roger Y
authors.initials: RY
authors.lastname: Tsien
authors.forename: Quyen T
authors.initials: QT
authors.lastname: Nguyen
mesh_terms: D000818:Animals; D002232:Carbocyanines; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides; D003199:Computer Systems; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000556:secondary*; D008207:Lymphatic Metastasis / Q000175:diagnosis* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D012680:Sensitivity and Specificity; D014183:Transplantation, Heterologous
chemical_list: D002232:Carbocyanines; D057846:Cell-Penetrating Peptides; C085321:cyanine dye 5; C501744:indotricarbocyanine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9