title: Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model.
abstract: RNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction, which exacerbates carrier toxicity. We address this issue by reporting modular degradable dendrimers that achieve the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. More than 1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. A lead dendrimer, 5A2-SC8, provided a broad therapeutic window: identified as potent [EC50 < 0.02 mg/kg siRNA against FVII (siFVII)] in dose-response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors (>75 mg/kg dendrimer repeated dosing). Delivery of let-7 g microRNA (miRNA) mimic inhibited tumor growth and dramatically extended survival. Efficacy stemmed from a combination of a small RNA with the dendrimer's own negligible toxicity, therefore illuminating an underappreciated complication in treating cancer with RNA-based drugs.
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Kejin
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Children's Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Liem H
authors.initials: LH
authors.lastname: Nguyen
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Jason B
authors.initials: JB
authors.lastname: Miller
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Petra
authors.initials: P
authors.lastname: Kos
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Hu
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Children's Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Jing
authors.initials: J
authors.lastname: Hao
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Minnig
authors.affiliation: Children's Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Hao
authors.identifier: http://orcid.org/0000-0002-8417-9698
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390; daniel.siegwart@utsouthwestern.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Siegwart
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050091:Dendrimers / Q000737:chemistry* / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004952:Esters / Q000737:chemistry; D005110:Extracellular Space / Q000737:chemistry; D005453:Fluorescence; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000737:chemistry; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008954:Models, Biological; D008970:Molecular Weight; D053758:Nanoparticles / Q000737:chemistry; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; D004952:Esters; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C542687:mirnlet7 microRNA, mouse
keywords: cancer; dendrimers; miRNA