title: Furin targeted drug delivery for treatment of rhabdomyosarcoma in a mouse model.
abstract: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Improvement of treatment efficacy and decreased side effects through tumor-targeted drug delivery would be desirable. By panning with a phage-displayed cyclic random peptide library we selected a peptide with strong affinity for RMS in vitro and in vivo. The peptide minimal binding motif Arg-X-(Arg/Lys)(Arg/Lys) identified by alanine-scan, suggested the target receptor to be a proprotein convertase (PC). Expression profiling of all PCs in RMS biopsies and cell lines revealed consistent high expression levels for the membrane-bound furin and PC7. Direct binding of RMS-P3 peptide to furin was demonstrated by affinity chromatography and supported by activity and colocalization studies. Treatment of RMS in mice with doxorubicin coupled to the targeting peptide resulted in a two-fold increase in therapeutic efficacy compared to doxorubicin treatment alone. Our findings indicate surface-furin binding as novel mechanism for therapeutic cell penetration which needs to be further investigated. Furthermore, this work demonstrates that specific targeting of membrane-bound furin in tumors is possible for and suggests that RMS and other tumors might benefit from proprotein convertases targeted drug delivery.
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Katarina
authors.initials: K
authors.lastname: Hajdin
authors.forename: Valentina
authors.initials: V
authors.lastname: D'Alessandro
authors.forename: Felix K
authors.initials: FK
authors.lastname: Niggli
authors.forename: Beat W
authors.initials: BW
authors.lastname: Schäfer
authors.forename: Michele
authors.initials: M
authors.lastname: Bernasconi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D045683:Furin / Q000378:metabolism*; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D015203:Reproducibility of Results; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D019151:Peptide Library; D010455:Peptides; D011956:Receptors, Cell Surface; D004317:Doxorubicin; D045683:Furin; D016650:Fluorescein-5-isothiocyanate
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