title: Temperature-sensitive magnetic drug carriers for concurrent gemcitabine chemohyperthermia.
abstract: To improve the efficacy of gemcitabine (GEM) for the treatment of advanced pancreatic cancer via local hyperthermia potentiated via a multi-functional nanoplatform permitting both in vivo heating and drug delivery is the goal of this study. Here, a chemohyperthermia approach to synergistically achieve high intra-tumoral drug concentrations, while permitting concurrent hyperthermia for more effective tumor cell kill and growth inhibition, is proposed. Drug delivery and hyperthermia are achieved using a hydroxypropyl cellulose (HPC)-grafted porous magnetic drug carrier that is MRI visible to permit in vivo visualization of the biodistribution. These synthesized magnetic drug carriers produce strong T2 -weighted image contrast and permit efficient heating using low-magnetic-field intensities. The thermomechanical response of HPC permits triggered GEM release confirmed during in vitro drug release studies. During in vitro studies, pancreatic cancer cell growth is significantly inhibited (≈82% reduction) with chemohyperthermia compared to chemotherapy or hyperthermia alone. Using PANC-1 xenografts in nude mice, the delivery of injected GEM-loaded magnetic carriers (GEM-magnetic carriers) is visualized with both MRI and fluorescent imaging techniques. Chemohyperthermia with intra-tumoral injections of GEM-magnetic carriers (followed by heating) results in significant increases in apoptotic cell death compared to tumors treated with GEM-magnetic carriers injections alone. Chemohyperthermia with GEM-magnetic carriers offers the potential to significantly improve the therapeutic efficacy of GEM for the treatment of pancreatic cancer. In vivo delivery confirmation with non-invasive imaging techniques could permit patient-specific adjustments therapeutic regimens for improve longitudinal outcomes.
authors.affiliation: Department of Radiology, Northwestern University, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Yang
authors.initials: Y
authors.lastname: Guo
authors.forename: Zhuoli
authors.initials: Z
authors.lastname: Zhang
authors.forename: Daniel
authors.initials: D
authors.lastname: Procissi
authors.forename: Jodi
authors.initials: J
authors.lastname: Nicolai
authors.forename: Reed A
authors.initials: RA
authors.lastname: Omary
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Larson
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002482:Cellulose / Q000031:analogs & derivatives / Q000737:chemistry; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006979:Hyperthermia, Induced / Q000379:methods*; D058185:Magnetite Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D058185:Magnetite Nanoparticles; D003841:Deoxycytidine; D002482:Cellulose; C008079:hydroxypropylcellulose; D000093542:Gemcitabine
keywords: chemohyperthermia; drug carriers; gemcitabine; nanoparticles; pancreatic cancers