title: Multiple hyperthermia-mediated release of TRAIL/SPION nanocomplex from thermosensitive polymeric hydrogels for combination cancer therapy.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) possesses strong anti-cancer potential because of its ability to specifically kill cancer cells. However, clinical use of TRAIL is impeded by its short in vivo half-life and native TRIAL-resistant cancer cell populations. To overcome these limitations, we designed a multiple magnetic hyperthermia (MHT)-mediated TRAIL release system for combination therapy using an injectable, biodegradable and thermosensitive polymeric hydrogel. In this system, positively charged TRAIL and hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) are complexed with negatively charged poly(organophosphazene) polymers via ionic and hydrophobic interactions, respectively. Transmission electron microscopy images showed a nano-sized core-shell structure of the TRAIL/SPION polymeric nanocomplex in aqueous solution that transformed into a hydrogel at body temperature. Hyperthermia can enhance the release of TRAIL from hydrogels through temperature-sensitive hydrogel dissolution. TRAIL-resistant U-87 MG cells were killed by the combination of TRAIL and multiple hyperthermia via caspase-3 and -8 active apoptosis. The hyperthermia-enhanced cytotoxicity of TRAIL was dependent on the hyperthermia cycle number and corresponding TRAIL release. Significant in vivo tumor reduction was observed by combining 2 cycles of mild MHT and TRAIL release using a single injection of TRAIL/SPION nanocomplex hydrogels without damage to main organs. Furthermore, the therapeutic outcomes can be monitored by long-term magnetic resonance imaging.
authors.affiliation: Center for Biomaterials, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Department of Biomolecular Science, University of Science and Technology (UST), Daejeon 305-350, Republic of Korea.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Zhang
authors.affiliation: Center for Biomaterials, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Department of Biomolecular Science, University of Science and Technology (UST), Daejeon 305-350, Republic of Korea. Electronic address: scsong@kist.re.kr.
authors.forename: Soo-Chang
authors.initials: SC
authors.lastname: Song
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006207:Half-Life; D064593:Heterografts; D006358:Hot Temperature; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D058185:Magnetite Nanoparticles / Q000737:chemistry*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009943:Organophosphorus Compounds / Q000737:chemistry*; D010316:Particle Size; D011108:Polymers / Q000737:chemistry*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D020100:Hydrogels; D058185:Magnetite Nanoparticles; D009943:Organophosphorus Compounds; D011108:Polymers; D053221:TNF-Related Apoptosis-Inducing Ligand; C515246:poly(organophosphazene); D053148:Caspase 3; D053181:Caspase 8
keywords: Controlled release; Multiple magnetic hyperthermia; SPION; TRAIL; Thermosensitive hydrogel