title: Development of a long-acting, protein-loaded, redox-active, injectable gel formed by a polyion complex for local protein therapeutics.
abstract: Although cancer immunotherapies are attracting much attention, it is difficult to develop bioactive proteins owing to the severe systemic toxicity. To overcome the issue, we designed new local protein delivery system by using a protein-loaded, redox-active, injectable gel (RIG), which is formed by a polyion complex (PIC) comprising three components, viz., cationic polyamine-poly(ethylene glycol)-polyamine triblock copolymer possessing ROS-scavenging moieties as side chains; anionic poly(acrylic acid); and a protein. The mixture formed the protein-loaded PIC flower micelles at room temperature, which immediately converted to a gel with high mechanical strength upon exposure to physiological conditions. Because the protein electrostatically interacts with the PIC gel network, RIG provided a sustained release of the protein without a significant initial burst, regardless of the types of proteins in vitro, and much longer retention of the protein at the local injection site in mice than that of the naked protein. Subcutaneous injections of IL-12@RIG in the vicinity of tumor tissue showed remarkable tumor growth inhibition in tumor-bearing mice, compared to that observed with injection of IL-12 alone, suppressing adverse events caused by IL-12-induced ROS. Our results indicate that RIG has potential as a platform technology for an injectable sustained-release carrier for proteins.
authors.affiliation: Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, 305-8573, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ishii
authors.affiliation: Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, 305-8573, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kaneko
authors.affiliation: Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, 305-8573, Japan; Master's School of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, 305-8573, Japan; Satellite Laboratory, International Center for Materials Nanoarchitectonics (WPI-MANA), National Institute for Materials Science (NIMS), University of Tsukuba, Tennoudai 1-1-1, Tsukuba, 305-8573, Japan. Electronic address: yukio@nagalabo.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nagasaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D019793:Fluorescein / Q000737:chemistry; D005782:Gels / Q000737:chemistry*; D007167:Immunotherapy; D007267:Injections; D018664:Interleukin-12 / Q000009:adverse effects / Q000627:therapeutic use; D007477:Ions; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D009589:Nitrogen Oxides / Q000737:chemistry; D010084:Oxidation-Reduction; D010316:Particle Size; D044367:Phase Transition; D011108:Polymers / Q000737:chemistry; D011506:Proteins / Q000627:therapeutic use*; D012212:Rheology; D013696:Temperature; D044366:Transition Temperature; D014783:Viscosity
chemical_list: D000970:Antineoplastic Agents; D005782:Gels; D007477:Ions; D008823:Micelles; D009589:Nitrogen Oxides; D011108:Polymers; D011506:Proteins; D018664:Interleukin-12; C039900:nitroxyl; D019793:Fluorescein
keywords: Cancer immunotherapy; Injectable hydrogel; Local protein delivery; Polyion complex flower micelle; Reactive oxygen species