RGD liposome-protamine-siRNA (LPR) nanoparticles targeting PAX3-FOXO1 for alveolar rhabdomyosarcoma therapy.
Alveolar rhabdomyosarcoma (ARMS) are aggressive soft tissue tumors harboring specific fusion transcripts, notably PAX3-FOXO1 (P3F). Current therapy concepts result in unsatisfactory survival rates making the search for innovative approaches necessary: targeting PAX3-FOXO1 could be a promising strategy. In this study, we developed integrin receptor-targeted Lipid-Protamine-siRNA (LPR) nanoparticles using the RGD peptide and validated target specificity as well as their post-silencing effects. We demonstrate that RGD-LPRs are specific to ARMS in vitro and in vivo. Loaded with siRNA directed against the breakpoint of P3F, these particles efficiently down regulated the fusion transcript and inhibited cell proliferation, but did not induce substantial apoptosis. In a xenograft ARMS model, LPR nanoparticles targeting P3F showed statistically significant tumor growth delay as well as inhibition of tumor initiation when injected in parallel with the tumor cells. These findings suggest that RGD-LPR targeting P3F are promising to be highly effective in the setting of minimal residual disease for ARMS.
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Venkatesh
V
Rengaswamy
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology and Biopharmacy and Freiburger, Materialforschungszentrum (FMF), University of Freiburg, Germany.
Doris
D
Zimmer
Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology and Biopharmacy and Freiburger, Materialforschungszentrum (FMF), University of Freiburg, Germany.
Regine
R
Süss
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany. Electronic address: jochen.roessler@uniklinik-freinburg.de.
Jochen
J
Rössler
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008081:Liposomes; D016513:Mice, SCID; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use; D009842:Oligopeptides / Q000008:administration & dosage* / Q000627:therapeutic use; D000072041:PAX3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D011479:Protamines / Q000008:administration & dosage* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use; D018232:Rhabdomyosarcoma, Alveolar / Q000188:drug therapy* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects
D000071161:Forkhead Box Protein O1; D008081:Liposomes; D009842:Oligopeptides; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D011479:Protamines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C047981:arginyl-glycyl-aspartic acid
Alveolar rhabdomyosarcoma; Integrin targeting; Lipid-protamine-siRNA nanoparticles; PAX3-FOXO1; siRNA delivery