International Journal of Nanomedicine (Jan 2020)
In vitro Ultrasonic Potentiation of 2-Phenylethynesulfonamide/Magnetic Fluid Hyperthermia Combination Treatments for Ovarian Cancer
Abstract
Fernando Mérida, 1 Carlos Rinaldi, 2, 3 Eduardo J Juan, 4 Madeline Torres-Lugo 1 1Department of Chemical Engineering, University of Puerto Rico-Mayagüez, Mayagüez, Puerto Rico; 2Department of Chemical Engineering, University of Florida, Gainesville, FL, USA; 3J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA; 4Department of Electrical and Computer Engineering, University of Puerto Rico-Mayagüez, Mayagüez, Puerto RicoCorrespondence: Madeline Torres-Lugo Road 108 Km. 1.0 Bo. Miradero. P.O. Box 9046, Mayagüez 00681-9046, Puerto RicoTel +1787 832 4040 Ext. 2585Email [email protected]: Magnetic Fluid Hyperthermia (MFH) is a promising adjuvant for chemotherapy, potentiating the action of anticancer agents. However, drug delivery to cancer cells must be optimized to improve the overall therapeutic effect of drug/MFH combination treatments.Purpose: The aim of this work was to demonstrate the potentiation of 2-phenylethynesulfonamide (PES) at various combination treatments with MFH, using low-intensity ultrasound as an intracellular delivery enhancer.Methods: The effect of ultrasound (US), MFH, and PES was first evaluated individually and then as combination treatments. Definity® microbubbles and polyethylene glycol (PEG)-coated iron oxide nanoparticles were used to induce cell sonoporation and MFH, respectively. Assessment of cell membrane permeabilization was evaluated via fluorescence microscopy, iron uptake by cells was quantified by UV-Vis spectroscopy, and cell viability was determined using automatic cell counting.Results: Notable reductions in cancer cell viability were observed when ultrasound was incorporated. For example, the treatment US+PES reduced cell viability by 37% compared to the non-toxic effect of the drug. Similarly, the treatment US+MFH using mild hyperthermia (41°C), reduced cell viability by an additional 18% when compared to the effect of MH alone. Significant improvements were observed for the combination of US+PES+MFH with cell viability reduced by an additional 26% compared to the PES+MFH group. The improved cytotoxicity was attributed to enhanced drug/nanoparticle intracellular delivery, with iron uptake values nearly twice those achieved without ultrasound. Various treatment schedules were examined, and all of them showed substantial cell death, indicating that the time elapsed between sonoporation and magnetic field exposure was not significant.Conclusion: Superior cancer cell-killing patterns took place when ultrasound was incorporated thus demonstrating the in vitro ultrasonic potentiation of PES and mild MFH. This work demonstrated that ultrasound is a promising non-invasive enhancer of PES/MFH combination treatments, aiming to establish a sono-thermo-chemotherapy in the treatment of ovarian cancer.Keywords: MFH, ultrasound, sonoporation, microbubble, PES, membrane permeabilization, enhanced cytotoxicity
