Aptamer-mediated delivery of splice-switching oligonucleotides to the nuclei of cancer cells.
To reduce the adverse effects of cancer therapies and increase their efficacy, new delivery agents that specifically target cancer cells are needed. We and others have shown that aptamers can selectively deliver therapeutic oligonucleotides to the endosome and cytoplasm of cancer cells that express a particular cell surface receptor. Identifying a single aptamer that can internalize into many different cancer cell-types would increase the utility of aptamer-mediated delivery of therapeutic agents. We investigated the ability of the nucleolin aptamer (AS1411) to internalize into multiple cancer cell types and observed that it internalizes into a wide variety of cancer cells and migrates to the nucleus. To determine if the aptamer could be utilized to deliver therapeutic oligonucleotides to modulate events in the nucleus, we evaluated the ability of the aptamer to deliver splice-switching oligonucleotides. We observed that aptamer-splice-switching oligonucleotide chimeras can alter splicing in the nuclei of treated cells and are effective at lower doses than the splice switching oligonucleotides alone. Our results suggest that aptamers can be utilized to deliver oligonucleotides to the nucleus of a wide variety of cancer cells to modulate nuclear events such as RNA splicing.
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Jonathan W
JW
Kotula
Elizabeth D
ED
Pratico
Xin
X
Ming
Osamu
O
Nakagawa
Rudolph L
RL
Juliano
Bruce A
BA
Sullenger
D052157:Aptamers, Nucleotide; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004705:Endocytosis; D066246:ErbB Receptors / Q000235:genetics; D005434:Flow Cytometry; D006801:Humans; D009369:Neoplasms / Q000378:metabolism; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics; D034622:RNA Interference; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics; D000097796:Nucleolin
D052157:Aptamers, Nucleotide; D066246:ErbB Receptors; D009841:Oligonucleotides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin