title: Nanogel DDS enables sustained release of IL-12 for tumor immunotherapy.
abstract: For a valid cytokine immunotherapy of malignancies, a suitable delivery system that ensures slow-release of cytokines is required, because short half-life in vivo of the molecules ruins therapeutic efficacy while causing severe systemic toxic effects. We previously showed that the cholesterol-bearing pullulan (CHP)-based hydrogel nanoparticles, or nanogel, encapsulates, stabilizes and releases various molecules. Here we applied this nanogel to administration in vivo of interleukin-12 (IL-12). Recombinant murine IL-12 (rmIL-12) was successfully incorporated into CHP nanogel simply by incubated with CHP at room temperature. After subcutaneously injected into mice, the CHP/rmIL-12 complex led to a prolonged elevation in IL-12 concentration in the sera. Repetitive administrations of the CHP/rmIL-12, but not rmIL-12 alone, induced drastic growth retardation of preestablished subcutaneous fibrosarcoma without causing any serious toxic event. The present study proposes a novel therapeutic intervention technology, taking advantage of slow and sustained release of bioactive cytokines from the self-assembling biocompatible nanoparticles.
authors.affiliation: Department of Surgery, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602-8566, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Tsunao
authors.initials: T
authors.lastname: Kishida
authors.forename: Urara
authors.initials: U
authors.lastname: Hasegawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ueda
authors.forename: Jiro
authors.initials: J
authors.lastname: Imanishi
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Yamagishi
authors.forename: Kazunari
authors.initials: K
authors.lastname: Akiyoshi
authors.forename: Eigo
authors.initials: E
authors.lastname: Otsuji
authors.forename: Osam
authors.initials: O
authors.lastname: Mazda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005782:Gels / Q000737:chemistry; D005936:Glucans / Q000737:chemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007167:Immunotherapy; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D005782:Gels; D005936:Glucans; D007166:Immunosuppressive Agents; D018664:Interleukin-12; C009109:pullulan; D002784:Cholesterol