RRC ID 62764
Author Thangavel S, Yoshitomi T, Sakharkar MK, Nagasaki Y.
Title Redox nanoparticle increases the chemotherapeutic efficiency of pioglitazone and suppresses its toxic side effects.
Journal Biomaterials
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.
Volume 99
Pages 109-23
Published 2016-8-1
DOI 10.1016/j.biomaterials.2016.05.001
PII S0142-9612(16)30162-4
PMID 27235996
MeSH Administration, Oral Animals Antineoplastic Agents / administration & dosage Antineoplastic Agents / pharmacology* Antineoplastic Agents / toxicity Apoptosis Biocompatible Materials / chemistry Cell Line, Tumor Cell Survival Drug Carriers Drug Liberation Free Radical Scavengers / chemistry Humans Hydrophobic and Hydrophilic Interactions Liver / drug effects Liver / pathology Male Mice, Inbred BALB C Mice, Nude Nanoparticles / chemistry* Nitrogen Oxides / metabolism Oxidation-Reduction Particle Size Pioglitazone Polyethylene Glycols / chemistry* Polystyrenes / chemistry* Prostatic Neoplasms Reactive Oxygen Species / metabolism Thiazolidinediones / administration & dosage Thiazolidinediones / pharmacology* Thiazolidinediones / toxicity
IF 10.317
Human and Animal Cells PC-3(RCB2145) LNCap.FGC(RCB2144)