Furin Targeted Drug Delivery for Treatment of Rhabdomyosarcoma in a Mouse Model
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.
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