title: Targeted cancer theranostics using alpha-tocopheryl succinate-conjugated multifunctional dendrimer-entrapped gold nanoparticles.
abstract: Development of multifunctional theranostic nanoplatforms for targeted cancer imaging and therapy still remains a great challenge. Herein, we report the use of multifunctional dendrimer-entrapped gold nanoparticles (Au DENPs) covalently linked with α-tocopheryl succinate (α-TOS) as a platform for targeted cancer computed tomography (CT) imaging and therapy. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) conjugated with fluorescein isothiocyanate (FI), polyethylene glycol (PEG)-modified α-TOS, and PEGylated folic acid (FA) were used as templates to synthesize Au DENPs, followed by acetylation of the remaining dendrimer terminal amines. The formed multifunctional Au DENPs were characterized via different techniques. We show that the Au DENPs conjugated with approximately 9.8 α-TOS molecules per dendrimer and with an Au core size of 3.3 nm are water-dispersible, and stable under different pH and temperature conditions and in different aqueous media. The FA modification onto the Au DENPs enables efficient targeting of the particles to cancer cells overexpressing FA receptors (FAR), and effective targeted CT imaging of the cancer cells in vitro and the xenografted tumor model in vivo. Likewise, the covalent conjugation of α-TOS does not compromise its therapeutic activity, instead significantly improves its water solubility. Importantly, thanks to the role of FA-directed targeting, the formed multifunctional Au DENPs are able to exert the specific therapeutic efficacy of α-TOS to the FAR-overexpressing cancer cells in vitro and the xenografted tumor model in vivo. The developed multifunctional Au DENPs may hold a great promise to be used as a unique theranostic nanoplatform for targeted CT imaging and therapy of different types of cancer.
authors.affiliation: State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, People's Republic of China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Radiology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, People's Republic of China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Zheng
authors.affiliation: College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People's Republic of China.
authors.forename: Shihui
authors.initials: S
authors.lastname: Wen
authors.affiliation: Experiment Center, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, People's Republic of China.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Tang
authors.affiliation: College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People's Republic of China.
authors.forename: Mingwu
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Radiology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, People's Republic of China. Electronic address: guixiangzhang@sina.com.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, People's Republic of China; College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People's Republic of China. Electronic address: xshi@dhu.edu.cn.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Shi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry / Q000627:therapeutic use; D050091:Dendrimers / Q000737:chemistry / Q000627:therapeutic use*; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism; D006046:Gold / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use / Q000648:ultrastructure; D009369:Neoplasms / Q000175:diagnosis* / Q000628:therapy; D011092:Polyethylene Glycols / Q000737:chemistry / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed / Q000379:methods; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D003287:Contrast Media; D050091:Dendrimers; D014810:Vitamin E; D011092:Polyethylene Glycols; D006046:Gold; D005492:Folic Acid; C014225:tocophersolan
keywords: Alpha-tocopheryl succinate; CT imaging; Dendrimers; Gold nanoparticles; Targeted cancer therapy