title: CK2 targeted RNAi therapeutic delivered via malignant cell-directed tenfibgen nanocapsule: dose and molecular mechanisms of response in xenograft prostate tumors.
abstract: CK2, a protein serine/threonine kinase, promotes cell proliferation and suppresses cell death. This essential-for-survival signal demonstrates elevated expression and activity in all cancers examined, and is considered an attractive target for cancer therapy. Here, we present data on the efficacy of a tenfibgen (TBG) coated nanocapsule which delivers its cargo of siRNA (siCK2) or single stranded RNA/DNA oligomers (RNAi-CK2) simultaneously targeting CK2α and α' catalytic subunits. Intravenous administration of TBG-siCK2 or TBG-RNAi-CK2 resulted in significant xenograft tumor reduction at low doses in PC3-LN4 and 22Rv1 models of prostate cancer. Malignant cell uptake and specificity in vivo was verified by FACS analysis and immunofluorescent detection of nanocapsules and PCR detection of released oligomers. Dose response was concordant with CK2αα' RNA transcript levels and the tumors demonstrated changes in CK2 protein and in markers of proliferation and cell death. Therapeutic response corresponded to expression levels for argonaute and GW proteins, which function in oligomer processing and translational repression. No toxicity was detected in non-tumor tissues or by serum chemistry. Tumor specific delivery of anti-CK2 RNAi via the TBG nanoencapsulation technology warrants further consideration of translational potential.
authors.affiliation: Research Service, Minneapolis VA Health Care System, University of Minnesota, Minneapolis, MN, U.S.A.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, U.S.A.|Department of Urology, University of Minnesota, Minneapolis, MN, U.S.A.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, U.S.A.
authors.forename: Khalil
authors.initials: K
authors.lastname: Ahmed
authors.affiliation: Research Service, Minneapolis VA Health Care System, University of Minnesota, Minneapolis, MN, U.S.A.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, U.S.A.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, U.S.A.
authors.forename: Betsy T
authors.initials: BT
authors.lastname: Kren
authors.affiliation: Research Service, Minneapolis VA Health Care System, University of Minnesota, Minneapolis, MN, U.S.A.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, U.S.A.
authors.forename: Md Joynal
authors.initials: MJ
authors.lastname: Abedin
authors.affiliation: Department of Obstretrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN, U.S.A.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, U.S.A.
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Vogel
authors.affiliation: Research Service, Minneapolis VA Health Care System, University of Minnesota, Minneapolis, MN, U.S.A.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, U.S.A.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Shaughnessy
authors.affiliation: GeneSegues Therapeutics, Minnetonka, MN, U.S.A.
authors.forename: Lucas
authors.initials: L
authors.lastname: Nacusi
authors.affiliation: GeneSegues Therapeutics, Minnetonka, MN, U.S.A.
authors.forename: Vicci L
authors.initials: VL
authors.lastname: Korman
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, U.S.A.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, U.S.A.|Department of Urology, University of Minnesota, Minneapolis, MN, U.S.A.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, U.S.A.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dehm
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, U.S.A.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Zimmerman
authors.affiliation: Research Service, Minneapolis VA Health Care System, University of Minnesota, Minneapolis, MN, U.S.A.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, U.S.A.
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Niehans
authors.affiliation: GeneSegues Therapeutics, Minnetonka, MN, U.S.A.
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Unger
authors.affiliation: Research Service, Minneapolis VA Health Care System, University of Minnesota, Minneapolis, MN, U.S.A.|Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, U.S.A.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, U.S.A.
authors.forename: Janeen H
authors.initials: JH
authors.lastname: Trembley
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D053769:Nanocapsules / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D034622:RNA Interference; D000067492:RNAi Therapeutics; D015398:Signal Transduction; D019063:Tenascin / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D053769:Nanocapsules; D010446:Peptide Fragments; D019063:Tenascin; C000597115:tenfibgen
keywords: CK2; RNAi; nanoparticle; prostate; tumor-specific