| Amphiphilic block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), arranged in a tri-block structure PEO-PPO-PEO, Pluronics or "poloxamers", raised a considerable interest in drug delivery field. Previous studies demonstrated that Pluronics sensitize MDR cancer cells resulting in increased cytotoxic activity of Dox, paclitaxel, and other drugs by 2-3 orders of magnitude. It also prevents the development of MDR in vitro and in vivo. Additionally, promising results of clinical studies of Dox/Pluronic formulation reinforced the need to ascertain a thorough understanding of Pluronic effects in tumors. First, we evaluated the interaction of Pluronic with Pgp in MDR cancer cells and with model membranes. Pluronic was shown to co-localize both with Pgp as well as with lipid raft marker CTB. The close interaction with Pgp and Pluronic seems to induce conformational change in the Pgp structure, locking it in upward open state where it can't bind the substrate. Pluronic interaction with model membranes caused significant changes in membrane structure and phase transition, what could strongly influence the function of Pgp. Second, we have shown that Pluronic selectively inhibits the metabolism in MDR cells. It translocates into mitochondria and inhibits complex I and complex IV activities, what results in ATP depletion and inhibition of oxygen consumption. It also increased ROS production and cytochrome c release, which would promote the apoptosis and cell death induced by the drug. The selectivity of Pluronic towards MDR phenotype is important for safety because the toxicity of the Dox/copolymer formulation with respect to non-MDR cells does not increase. Finally, Dox/Pluronic formulation decreased the tumorigenicity of cancer cells and tumor aggressiveness. It effectively depleted the tumorigenic cell subpopulations and decreases the TIC frequency in vivo. In vitro pretreatment with Dox/Pluronic significantly depleted the cells' colony forming potential compared to drug alone. Our results together with previous reports suggest that due to the unique properties Pluronic copolymers have great potential for development of new drugs and formulations for cancer therapy. |
