ABSTRACT
Reactive oxygen species (ROS) are implicated in many disease such as inflammation, arteriosclerosis, cancer. Therefore, a water-soluble cationic metalloporphyrins with SOD activity are studied widely as antioxidant drugs. Further, liposomes are applied to drug delivery system (DDS) as drug carriers and investigated for example disposition and stability. We designed PEG modified liposomes for avoiding reticuloendothelial system (RES) and embedded cationic metalloporphyrins for DDS, evaluated antioxidant and anticancer property. Preservation of these particle size measured DLS in an in vitro system, in order to simulate in vivo conditions of flow. Result of this measurement, we found Pluronic F-68/ liposomes have a long circulation property, and avoid fusion with plasma protein. SOD activity was determined by the stopped-flow analysis and cytochrome c assay, which allowed the evaluation of k(cat) and IC(50) for the reaction with a superoxide anion radical (.O(2)(-)). Anti cancer property was measured by cell viability test. We found that F-68/ liposomes were the most effective catalyst as antioxidant and anticancer. These results revealed that porphyrin-embedded PEG-liposomes had the property of long circulation in blood and that this compound was effective as a SOD model compound with a drug carrier capacity.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Antioxidants/pharmacology , Metalloporphyrins/pharmacology , Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Antioxidants/chemistry , Antioxidants/therapeutic use , Arteriosclerosis/drug therapy , Arteriosclerosis/metabolism , Catalysis , Cell Line, Tumor , Cell Survival/drug effects , Cytochromes c/chemistry , Drug Screening Assays, Antitumor , Humans , Liposomes , Metalloporphyrins/chemistry , Metalloporphyrins/therapeutic use , Neoplasms/metabolism , Particle Size , Poloxamer , Superoxide Dismutase/chemistry , Superoxides/chemistry , Superoxides/metabolismABSTRACT
A novel design of anticancer drug delivery system, based on an electrostatic binding of negatively charged liposomes and cationic metalloporphyrins under physiological conditions, is reported. A lack of cytotoxicity of the iron(III) porphyrin-loaded liposomes and an efficient generation of a toxic hydroxyl radical (OH*) from a superoxide anion radical (O2-*) through the iron(III)-catalyzed dismutation and the Fenton-like reaction allow for a targeted necrosis of tumor cells where the concentration of O2-* is locally increased as a result of the reduced activity of superoxide dismutase and catalase in these cells.
