title: Production of Cisplatin-Incorporating Hyaluronan Nanogels via Chelating Ligand-Metal Coordination.
abstract: Hyaluronan (HA) is a promising drug carrier for cancer therapy because of its CD44 targeting ability, good biocompatibility, and biodegradability. In this study, cisplatin (CDDP)-incorporating HA nanogels were fabricated through a chelating ligand-metal coordination cross-linking reaction. We conjugated chelating ligands, iminodiacetic acid or malonic acid, to HA and used them as a precursor polymer. By mixing the ligand-conjugated HA with CDDP, cross-linking occurred via coordination of the ligands with the platinum in CDDP, resulting in the spontaneous formation of CDDP-loaded HA nanogels. The nanogels showed pH-responsive release of CDDP, because the stability of the ligand-platinum complex decreases in an acidic environment. Cell viability assays for MKN45P human gastric cancer cells and Met-5A human mesothelial cells revealed that the HA nanogels selectively inhibited the growth of gastric cancer cells. In vivo experiments using a mouse model of peritoneal dissemination of gastric cancer demonstrated that HA nanogels specifically localized in peritoneal nodules after the intraperitoneal administration. Moreover, penetration assays using multicellular tumor spheroids indicated that HA nanogels had a significantly higher ability to penetrate tumors than conventional, linear HA. These results suggest that chelating-ligand conjugated HA nanogels will be useful for targeted cancer therapy.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Ohta
authors.forename: Syota
authors.initials: S
authors.lastname: Hiramoto
authors.forename: Yuki
authors.initials: Y
authors.lastname: Amano
authors.forename: Mayu
authors.initials: M
authors.lastname: Sato
authors.forename: Yukimitsu
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Institute of Industrial Science, The University of Tokyo , 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
authors.forename: Marie
authors.initials: M
authors.lastname: Shinohara
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Emoto
authors.forename: Hironori
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Hironori
authors.initials: H
authors.lastname: Ishigami
authors.affiliation: Institute of Industrial Science, The University of Tokyo , 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sakai
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
authors.forename: Taichi
authors.initials: T
authors.lastname: Ito
mesh_terms: D000818:Animals; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry*; D002945:Cisplatin / Q000737:chemistry*; D005782:Gels; D006820:Hyaluronic Acid / Q000737:chemistry*; D008024:Ligands; D008670:Metals / Q000737:chemistry*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D049329:Nanostructures
chemical_list: D002614:Chelating Agents; D005782:Gels; D008024:Ligands; D008670:Metals; D006820:Hyaluronic Acid; D002945:Cisplatin