CK2 targeted RNAi therapeutic delivered via malignant cell-directed tenfibgen nanocapsule: dose and molecular mechanisms of response in xenograft prostate tumors
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Khalil Ahmed1,2,3,6,*, Betsy T. Kren1,2,6,*, Md. Joynal Abedin1,2,*, Rachel I. Vogel4,6, Daniel P. Shaughnessy1,2, Lucas Nacusi7, Vicci L. Korman7, Yingming Li2, Scott M. Dehm2,3,6, Cheryl L. Zimmerman5, Gloria A. Niehans1,2, Gretchen M. Unger7, Janeen H. Trembley1,2,6
1Research Service, Minneapolis VA Health Care System, University of Minnesota, Minneapolis, MN, U.S.A
2Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, U.S.A
3Department of Urology, University of Minnesota, Minneapolis, MN, U.S.A
4Department of Obstretrics, Gynecology and Women’s Health, University of Minnesota, Minneapolis, MN, U.S.A
5Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, U.S.A
6Masonic Cancer Center, University of Minnesota, Minneapolis, MN, U.S.A
7GeneSegues Therapeutics, Minnetonka, MN, U.S.A
*These authors contributed equally to this work
Khalil Ahmed, email: [email protected]
Keywords: prostate, CK2, RNAi, nanoparticle, tumor-specific
Received: June 03, 2016 Accepted: August 15, 2016 Published: August 20, 2016
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.
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