Abstract
Abstract Most cancer therapy is nonspecific, aimed at all dividing cells, resulting in untoward side effects. Our study demonstrates the effectiveness of magnetoelectric nanoparticles (MENs), which have been developed to address the critical issue of normal cell off-targeting in cancer treatment, in both in-vitro and in-vivo studies, as well as characterizes their biodistribution and clearance. Exploiting the difference in electric properties between normal and cancer cell membranes, MENs are able to enter cancerous cells carrying a therapeutic payload and release the payload intracellularly with the application of an external magnetic field, while not affecting normal cells. SKOV-3 human ovarian carcinoma cells were used as a model to showcase the unique cancer targeting capabilities of these CoFe2O4@BaTiO3 nanostructures coated with the mitotic inhibitor Paclitaxel (PTX). The MENs-PTX bond was characterized in the lysate of treated cells using spectroscopic analysis and scanning probe microscopy. SKOV-3 xenografted athymic nude mice were treated via subcutaneous or IV injection on a weekly basis with a MEN, conventional ferromagnetic nanoparticle (MN), or polymer nanoparticle (PLGA) formulation. Biodistribution and clearance of MENs is one of the most important open questions addressed in this study. Our approach is to investigate the key parameters that affect the therapeutic index, i.e. the maximum tolerated dose, blood circulation half-life and biodistribution due organ accumulation. The approach is to study factors such as the size and shape of MENs, chemical composition, targeting ligand functionalization, MENs’ biodegradability, and microenvironment and other biological barriers. Besides using conventional fluorescent markers, a novel nanoparticle distribution approach based on energy-dispersion spectroscopy (EDS) is exploited. In-vitro studies on the cell lysate of MENs treated SKOV-3 cells determined reliable entry into the cells by MENs with the application of a small magnetic field (∼100 Oe) and reliable payload release with the application of an a.c. magnetic field (∼50 Oe, 100 Hz). In-vivo studies demonstrated that the MENs-PTX formulation in combination with an externally applied magnetic field reduces tumor growth rate when injected subcutaneously, and fully cures the cancer when delivered via IV-injection. The MENs formulation was more successful in treating the tumor than both MN and PLGA formulations. EDS confirmed the presence of MENs in tumor tissues. MENs provide a novel mechanism by which cancer cells are targeted (using the difference in the cancer electric cell membrane properties compared to normal cells) and a drug payload is released (externally triggered with the application of an a.c. magnetic field) reliably. The underlying physics of the electric field interactions involved in the MENs drug delivery system was demonstrated here using ovarian cancer, but can be applied to virtually any cancer. Citation Format: Alexandra Rodzinski, Rakesh Guduru, Emmanuel Stimphil, Tiffanie Stewart, Ping Liang, Carolyn Runowicz, Sakhrat Khizroev. Targeted, controlled anticancer drug delivery and release with magnetoelectric nanoparticles. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2204.
