Redox nanoparticle increases the chemotherapeutic efficiency of pioglitazone and suppresses its toxic side effects

摘要

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 (RNPN) which is an effective scavenger of reactive oxygen species (ROS) as a drug carrier. RNPN 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 RNPN 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 RNPN due to the presence of nitroxide radicals. It is interesting to note that oral administration of encapsulated pioglitazone, and co-administration of RNPN and pioglitazone, i.e., no encapsulation of pioglitazone in RNPN also significantly contributed to suppression of the liver injury. Therefore, use of RNPN either as an adjuvant or as a carrier for drugs with severe side effects is a promising chemotherapeutic strategy. (C) 2016 Elsevier Ltd. All rights reserved.