Ribozyme-Spherical Nucleic Acids.
Ribozymes are highly structured RNA sequences that can be tailored to recognize and cleave specific stretches of mRNA. Their current therapeutic efficacy remains low due to their large size and structural instability compared to shorter therapeutically relevant RNA such as small interfering RNA (siRNA) and microRNA (miRNA). Herein, a synthetic strategy that makes use of the spherical nucleic acid (SNA) architecture to stabilize ribozymes and transfect them into live cells is reported. The properties of this novel ribozyme-SNA are characterized in the context of the targeted knockdown of O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein involved in chemotherapeutic resistance of solid tumors, foremost glioblastoma multiforme (GBM). Data showing the direct cleavage of full-length MGMT mRNA, knockdown of MGMT protein, and increased sensitization of GBM cells to therapy-mediated apoptosis, independent of transfection agents, provide compelling evidence for the promising properties of this new chemical architecture.
Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.|International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States.
Jessica L
JL
Rouge
Interdisciplinary Biological Sciences Graduate Program, Evanston, Illinois 60208, United States.|International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States.|The Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, United States.
Timothy L
TL
Sita
Interdisciplinary Biological Sciences Graduate Program, Evanston, Illinois 60208, United States.|International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States.
Liangliang
L
Hao
International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States.|The Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, United States.|Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Chicago, Illinois 60611, United States.
Fotini M
FM
Kouri
Interdisciplinary Biological Sciences Graduate Program, Evanston, Illinois 60208, United States.|International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States.
William E
WE
Briley
International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States.|The Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, United States.|Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Chicago, Illinois 60611, United States.
Alexander H
AH
Stegh
Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.|International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States.
Chad A
CA
Mirkin
D001692:Biological Transport; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000172:deficiency / Q000235:genetics; D004789:Enzyme Activation; D020868:Gene Silencing; D006801:Humans; D016337:RNA, Catalytic / Q000737:chemistry* / Q000235:genetics*; D014162:Transfection
D016337:RNA, Catalytic; D015254:DNA Modification Methylases; D020169:Caspases