title: Targeting and Regulating of an Oncogene via Nanovector Delivery of MicroRNA using Patient-Derived Xenografts.
abstract: In precision cancer nanomedicine, the key is to identify the oncogenes that are responsible for tumorigenesis, based on which these genetic drivers can be each specifically regulated by a nanovector-directed, oncogene-targeted microRNA (miRNA) for tumor suppression. Fibroblast Growth Factor Receptor 3 (FGFR3) is such an oncogene. The molecular tumor-subtype harboring FGFR3 genomic alteration has been identified via genomic sequencing and referred to as the FGFR3-driven tumors. This genomics-based tumor classification provides further rationale for the development of the FGFR3-targeted miRNA replacement therapy in treating patients with FGFR3 gene abnormity. However, successful miRNA therapy has been hampered by lacking of an efficient delivery vehicle. In this study, a nanovector is developed for microRNA-100 (miR-100) -mediated FGFR3 regulation. The nanovector is composed of the mesoporous magnetic clusters that are conjugated with ternary polymers for efficient miRNAin-vivodelivery. The miRNA-loading capacity of the nanovector is found to be high due to the polycation polymer functionalized mesoporous structure, showing excellent tumor cell transfection and pH-sensitive miRNA release. Delivery of miR-100 to cancer cells effectively down-regulates the expression of FGFR3, inhibits cell proliferation, and induces cell apoptosisin vitro. Patient-derived xenografts (PDXs) are used to evaluate the efficacy of miRNA delivery in the FGFR3-driven tumors. Notably, sharp contrasts are observed between the FGFR3-driven tumors and those without FGFR3 genomic alteration. Only the FGFR3-driven PDXs are significantly inhibited via miR-100 delivery while the non-FGFR3-driven PDXs are not affected, showing promise of precision cancer nanomedicine.
authors.affiliation: Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China;; Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Sun
authors.affiliation: The Institute for Translational Nanomedicine, Shanghai East Hospital, the Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, P. R. China.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China;; Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: The Institute for Translational Nanomedicine, Shanghai East Hospital, the Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, P. R. China;; School of Materials Science and Engineering, Tongji University, Shanghai 200092, P. R. China.
authors.forename: Zicheng
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China;; Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Han
authors.affiliation: The Institute for Translational Nanomedicine, Shanghai East Hospital, the Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, P. R. China;; School of Materials Science and Engineering, Tongji University, Shanghai 200092, P. R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China;; Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Tao
authors.affiliation: The Institute for Translational Nanomedicine, Shanghai East Hospital, the Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, P. R. China;; School of Materials Science and Engineering, Tongji University, Shanghai 200092, P. R. China.
authors.forename: Zi
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China;; Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China.
authors.forename: Chaoji
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China;; Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China.
authors.forename: Duo
authors.initials: D
authors.lastname: Hong
authors.affiliation: Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China;; Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: The Institute for Translational Nanomedicine, Shanghai East Hospital, the Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, P. R. China;; The Materials Science and Engineering Program, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH 45221, USA.
authors.forename: Donglu
authors.initials: D
authors.lastname: Shi
authors.affiliation: Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China;; Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001688:Biological Products / Q000378:metabolism / Q000493:pharmacokinetics; D002277:Carcinoma / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage; D064593:Heterografts; D006801:Humans; D006863:Hydrogen-Ion Concentration; D058185:Magnetite Nanoparticles / Q000008:administration & dosage; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D058990:Molecular Targeted Therapy / Q000379:methods*; D009857:Oncogenes; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000068936:Theranostic Nanomedicine / Q000379:methods*
chemical_list: D001688:Biological Products; D004337:Drug Carriers; C544266:MIRN100 microRNA, human; D058185:Magnetite Nanoparticles; D035683:MicroRNAs; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: Patient-Derived Xenografts; mesoporous nanovector; microRNA; oncogene; precision medicine.