title: Fusogenic-oligoarginine peptide-mediated silencing of the CIP2A oncogene suppresses oral cancer tumor growth in vivo.
abstract: Intracellular delivery and endosomal escape of functional small interfering RNAs (siRNAs) remain major barriers limiting the clinical translation of RNA interference (RNAi)-based therapeutics. Recently, we demonstrated that a cell-penetrating endosome-disruptive peptide we synthesized, termed 599, enhanced the intracellular delivery and bioavailability of siRNAs designed to target the CIP2A oncoprotein (siCIP2A) into oral cancer cells and consequently inhibited oral cancer cell invasiveness and anchorage-independent growth in vitro. Thus, to further assess the therapeutic potential of the 599 peptide in mediating RNAi-based therapeutics for oral cancer and its prospective applicability in clinical settings, the objective of the current study was to determine whether intratumoral dosing of the 599 peptide-siCIP2A complex could induce silencing of CIP2A and consequently impair tumor growth using a xenograft oral cancer mouse model. Our results demonstrate that the 599 peptide is able to protect siRNAs from degradation by serum and ribonucleases in vitro and upon intratumoral injection in vivo, confirming the stability of the 599 peptide-siRNA complex and its potential for therapeutic utility. Moreover, 599 peptide-mediated delivery of siCIP2A to tumor tissue induces CIP2A silencing without any associated toxicity, consequently resulting in reduction of the mitotic index and significant inhibition of tumor growth. Together, these data suggest that the 599 peptide carrier is a clinically effective mediator of RNAi-based cancer therapeutics.
authors.affiliation: Department of Oral Health Sciences and Center for Oral Health Research, Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA; Department of Bioengineering, Clemson University, Clemson, SC 29634, USA.
authors.forename: Angela A
authors.initials: AA
authors.lastname: Alexander-Bryant
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology, MUSC, Charleston, SC 29425, USA.
authors.forename: Anca
authors.initials: A
authors.lastname: Dumitriu
authors.affiliation: Department of Oral Health Sciences and Center for Oral Health Research, Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Attaway
authors.affiliation: Department of Oral Health Sciences and Center for Oral Health Research, Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Oral Health Sciences and Center for Oral Health Research, Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA; Department of Bioengineering, Clemson University, Clemson, SC 29634, USA. Electronic address: jakymiw@musc.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jakymiw
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry; D001324:Autoantigens / Q000235:genetics*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000627:therapeutic use; D020868:Gene Silencing; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D001324:Autoantigens; D057846:Cell-Penetrating Peptides; C573112:KIAA1524 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D001120:Arginine
keywords: CIP2A; Cell-penetrating peptide; Fusogenic peptide; Oral cancer; RNAi; siRNA delivery