title: Redox nanoparticle increases the chemotherapeutic efficiency of pioglitazone and suppresses its toxic side effects.
abstract: Pioglitazone is a widely used anti-diabetic drug that induces cytotoxicity in cancer cells; however, its clinical use is questioned due to its associated liver toxicity caused by increased oxidative stress. We therefore employed nitroxide-radical containing nanoparticle, termed redox nanoparticle (RNP(N)) which is an effective scavenger of reactive oxygen species (ROS) as a drug carrier. RNP(N) encapsulation increased pioglitazone solubility, thus increasing cellular uptake of encapsulated pioglitazone which reduced the dose required to induce toxicity in prostate cancer cell lines. Investigation of in vitro molecular mechanism of pioglitazone revealed that both apoptosis and cell cycle arrest were involved in tumor cell death. In addition, intravenously administered pioglitazone-loaded RNP(N) produced significant tumor volume reduction in vivo due to enhanced permeation and retention effect. Most importantly, oxidative damage caused by pioglitazone in the liver was significantly suppressed by pioglitazone-loaded RNP(N) due to the presence of nitroxide radicals. It is interesting to note that oral administration of encapsulated pioglitazone, and co-administration of RNP(N) and pioglitazone, i.e., no encapsulation of pioglitazone in RNP(N) also significantly contributed to suppression of the liver injury. Therefore, use of RNP(N) either as an adjuvant or as a carrier for drugs with severe side effects is a promising chemotherapeutic strategy.
authors.affiliation: Department of Materials Sciences, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8573, Japan.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Thangavel
authors.affiliation: Department of Materials Sciences, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8573, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yoshitomi
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Tennodai 1-1-1, Ibaraki 305-8572, Japan.
authors.forename: Meena Kishore
authors.initials: MK
authors.lastname: Sakharkar
authors.affiliation: Department of Materials Sciences, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8573, Japan; Master's School of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 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, Ibaraki 305-8573, Japan. Electronic address: yukio@nagalabo.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nagasaki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis; D001672:Biocompatible Materials / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival; D004337:Drug Carriers; D065546:Drug Liberation; D016166:Free Radical Scavengers / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D009589:Nitrogen Oxides / Q000378:metabolism; D010084:Oxidation-Reduction; D010316:Particle Size; D000077205:Pioglitazone; D011092:Polyethylene Glycols / Q000737:chemistry*; D011137:Polystyrenes / Q000737:chemistry*; D011471:Prostatic Neoplasms; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D004337:Drug Carriers; D016166:Free Radical Scavengers; D009589:Nitrogen Oxides; D011137:Polystyrenes; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D011092:Polyethylene Glycols; C039900:nitroxyl; D000077205:Pioglitazone
keywords: Drug delivery system; Pioglitazone; Prostate cancer; Reactive oxygen species (ROS); Redox nanoparticle