title: Mechanism and efficacy of sub-50-nm tenfibgen nanocapsules for cancer cell-directed delivery of anti-CK2 RNAi to primary and metastatic squamous cell carcinoma.
abstract: Improved survival for patients with head and neck cancers (HNC) with recurrent and metastatic disease warrants that cancer therapy is specific, with protected delivery of the therapeutic agent to primary and metastatic cancer cells. A further objective should be that downregulation of the intracellular therapy target leads to cell death without compensation by an alternate pathway. To address these goals, we report the utilization of a sub-50-nm tenfibgen (s50-TBG) nanocapsule that delivers RNAi oligonucleotides directed against the essential survival signal protein kinase CK2 (RNAi-CK2) in a cancer cell-specific manner. We have evaluated mechanism and efficacy of using s50-TBG-RNAi-CK2 nanocapsules for therapy of primary and metastatic head and neck squamous cell carcinoma (HNSCC). s50-TBG nanocapsules enter cancer cells via the lipid raft/caveolar pathway and deliver their cargo (RNAi-CK2) preferentially to malignant but not normal tissues in mice. Our data suggest that RNAi-CK2, a unique single-stranded oligonucleotide, co-opts the argonaute 2/RNA-induced silencing complex pathway to target the CK2αα' mRNAs. s50-TBG-RNAi-CK2 inhibited cell growth corresponding with reduced CK2 expression in targeted tumor cells. Treatment of three xenograft HNSCC models showed that primary tumors and metastases responded to s50-TBG-RNAi-CK2 therapy, with tumor shrinkage and 6-month host survival that was achieved at relatively low doses of the therapeutic agent without any adverse toxic effect in normal tissues in the mice. We suggest that our nanocapsule technology and anti-CK2 targeting combine into a therapeutic modality with a potential of significant translational promise.
authors.affiliation: GeneSegues, Chaska; Departments of.
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Unger
authors.affiliation: Medicine, Masonic Cancer Center, University of Minnesota; and.
authors.forename: Betsy T
authors.initials: BT
authors.lastname: Kren
authors.affiliation: GeneSegues, Chaska; Departments of.
authors.forename: Vicci L
authors.initials: VL
authors.lastname: Korman
authors.affiliation: Otolaryngology, and.
authors.forename: Tyler G
authors.initials: TG
authors.lastname: Kimbrough
authors.affiliation: Masonic Cancer Center, University of Minnesota; and.
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Vogel
authors.affiliation: Otolaryngology, and.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Ondrey
authors.affiliation: Laboratory Medicine and Pathology; Masonic Cancer Center, University of Minnesota; and Cellular and Molecular Biochemistry Research Laboratory (151), Minneapolis VA Health Care System, Minneapolis, Minnesota.
authors.forename: Janeen H
authors.initials: JH
authors.lastname: Trembley
authors.affiliation: Otolaryngology, and Laboratory Medicine and Pathology; Masonic Cancer Center, University of Minnesota; and Cellular and Molecular Biochemistry Research Laboratory (151), Minneapolis VA Health Care System, Minneapolis, Minnesota ahmedk@umn.edu.
authors.forename: Khalil
authors.initials: K
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000556:secondary / Q000628:therapy*; D047390:Casein Kinase II / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry*; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013160:Splenic Neoplasms / Q000556:secondary / Q000628:therapy*; D019063:Tenascin / Q000737:chemistry*; D014018:Tissue Distribution; D014162:Transfection
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D053769:Nanocapsules; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D019063:Tenascin; C000597115:tenfibgen; D047390:Casein Kinase II