title: Targeted systemic delivery of siRNA to cervical cancer model using cyclic RGD-installed unimer polyion complex-assembled gold nanoparticles.
abstract: For systemic delivery of small interfering RNA (siRNA) to solid tumors, we developed an actively-targeted unimer polyion complex-assembled gold nanoparticle (uPIC-AuNP) by a two-step assembling process. First is the monodispersed uPIC formation from the single molecules of therapeutic siRNA and the block catiomer, cyclic RGD (cRGD) peptide-installed poly(ethylene glycol)-block-poly(l-lysine) modified with lipoic acid (LA) at the ω-end (cRGD-PEG-PLL-LA). Second is the surface decoration of a 20nm-sized AuNP with uPICs. The cRGD-installed uPIC-AuNPs (cRGD-uPIC-AuNP) provided the targetability for selective binding to the cancer and cancer-related endothelial cellular surface, while regulating their size <50nm with a quite narrow distribution. The targeting efficacy of the cRGD-uPIC-AuNP was confirmed by in vitro cellular uptake in cultured cervical cancer (HeLa) cells and in vivo tumor accumulation in a subcutaneous HeLa model after systemic administration, compared with a non-targeted control uPIC-AuNP. Due to the targetability of the ligand, the cRGD-uPIC-AuNP achieved the significantly enhanced gene silencing ability in the subcutaneous HeLa tumor. Ultimately, the systemic delivery of siRNA targeted for papilloma virus-derived E6 oncogene by cRGD-uPIC-AuNP significantly inhibited the growth of subcutaneous HeLa tumor. This research demonstrates that the bottom-up construction of nanocarriers using monodispersed building blocks can be employed as delivery platforms for RNA interference-based cancer therapy.
authors: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors: Yu
authors: Y
authors: Yi
authors: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Hyun Jin
authors: HJ
authors: Kim
authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, PR China; Innovation Center of Nanomedicine, Institute of Industry Promotion-KAWASAKI, 66-20 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan.
authors: Peng
authors: P
authors: Mi
authors: Centre for Advanced Theranostics, School of Life Sciences, Henan University, Jin Ming Avenue, Kaifeng, Henan 475004, PR China; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors: Meng
authors: M
authors: Zheng
authors: Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan.
authors: Hiroyasu
authors: H
authors: Takemoto
authors: Innovation Center of Nanomedicine, Institute of Industry Promotion-KAWASAKI, 66-20 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan.
authors: Kazuko
authors: K
authors: Toh
authors: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors: Beob Soo
authors: BS
authors: Kim
authors: Innovation Center of Nanomedicine, Institute of Industry Promotion-KAWASAKI, 66-20 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan.
authors: Kotaro
authors: K
authors: Hayashi
authors: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Mitsuru
authors: M
authors: Naito
authors: Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Yu
authors: Y
authors: Matsumoto
authors: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. Electronic address: miyata@bmw.t.u-tokyo.ac.jp.
authors: Kanjiro
authors: K
authors: Miyata
authors: Innovation Center of Nanomedicine, Institute of Industry Promotion-KAWASAKI, 66-20 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan; Policy Alternatives Research Institute, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: kataoka@pari.u-tokyo.ac.jp.
authors: Kazunori
authors: K
authors: Kataoka
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006046:Gold / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006367:HeLa Cells; D006801:Humans; D053768:Metal Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009856:Oncogene Proteins, Viral / Q000235:genetics; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D008063:Thioctic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
chemical_list: D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; C507169:cyclic arginine-glycine-aspartic acid peptide; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; D008063:Thioctic Acid; D006046:Gold
keywords: Cancer therapy; Gold nanoparticle; Unimer polyion complex; cRGD peptide; siRNA delivery