title: Intracellular delivery and passive tumor targeting of a self-assembled nanogel containing carborane clusters for boron neutron capture therapy.
abstract: Boron neutron capture therapy, based on the release of thermal neutron irradiation from boron, is a targeted radiation therapy for cancer. Targeted and sufficient accumulation of boron in tumor cells to achieve cytotoxic efficacy and reduce off-target effects remains a challenge. Carborane has been investigated for use as a delivery agent in boron neutron capture therapy because of its high boron content and chemical stability; however, it is cytotoxic, making safe delivery difficult. The aim of this study was to investigate the potential of carborane-bearing pullulan nanogels to safely and effectively deliver boron to tumor cells in vitro and in vivo and, consequently, assess their potential as a boron neutron capture therapeutic. Murine fibrosarcoma cells (CMS5a) were used for in vitro investigations of nanogel cytotoxicity, cell uptake. A mouse fibrosarcoma xenograft model was used to investigate the bio-distribution of nanogels after intravenous administration. The nanogels produced no apparent cytotoxicity and underwent cell uptake in CMS5a cells after a 24 h incubation at up to 2000 μg/mL and 400 μg/mL, respectively. The internalized nanogels were localized around the nuclear membrane. The nanogels were administered intravenously to mice bearing fibrosarcoma xenografts. Nanogel tumor localization likely occurred through the enhanced permeation and retention effect. The nanogels successfully reduced the cytotoxicity of carborane, were internalized into tumor cells, acted as a dual-delivery therapeutic and accumulated in tumors in vivo. Consequently, they demonstrate significant potential as a boron neutron capture therapeutic.
authors.affiliation: Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan; JST-ERATO, Japan Science and Technology Agency (JST), The Exploratory Research for Advanced Technology (ERATO), Bio-nanotransporter Project, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
authors.forename: Riku
authors.initials: R
authors.lastname: Kawasaki
authors.affiliation: Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan; JST-ERATO, Japan Science and Technology Agency (JST), The Exploratory Research for Advanced Technology (ERATO), Bio-nanotransporter Project, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan. Electronic address: akiyoshi@bio.polym.kyoto-u.ac.jp.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Akiyoshi
mesh_terms: D000818:Animals; D001895:Boron / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D005354:Fibrosarcoma / Q000188:drug therapy / Q000532:radiotherapy; D005936:Glucans / Q000737:chemistry; D008807:Mice, Inbred BALB C; D000080385:Nanogels; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D005936:Glucans; D000080385:Nanogels; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; C009109:pullulan; D011094:Polyethyleneimine; D001895:Boron
keywords: Boron neutron capture therapy; Carborane; Drug delivery system; Polysaccharides; Self-assembled nanogel