title: Delivery of Therapeutics Targeting the mRNA-Binding Protein HuR Using 3DNA Nanocarriers Suppresses Ovarian Tumor Growth.
abstract: Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumor-targeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined siRNAs against HuR with FA-3DNA and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumor-bearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo-targeted delivery of a cancer therapeutic and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer.
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania. Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Yu-Hung
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
authors.forename: Weidan
authors.initials: W
authors.lastname: Peng
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
authors.forename: Narumi
authors.initials: N
authors.lastname: Furuuchi
authors.affiliation: Genisphere, LLC, Hatfield, Pennsylvania.
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Gerhart
authors.affiliation: Genisphere, LLC, Hatfield, Pennsylvania.
authors.forename: Kelly
authors.initials: K
authors.lastname: Rhodes
authors.affiliation: Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Neelanjan
authors.initials: N
authors.lastname: Mukherjee
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Masaya
authors.initials: M
authors.lastname: Jimbo
authors.affiliation: NanoString Technologies, Seattle, Washington.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Gonye
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
authors.affiliation: Genisphere, LLC, Hatfield, Pennsylvania.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Getts
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. sawickij@mlhs.org.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Sawicki
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods; D000067780:ELAV-Like Protein 1 / Q000008:administration & dosage* / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics; D053758:Nanoparticles / Q000008:administration & dosage*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D034622:RNA Interference / Q000187:drug effects; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000008:administration & dosage* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014018:Tissue Distribution / Q000235:genetics
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins