Abstract B47: A novel mechanism for field-controlled high-specificity targeted anticancer drug delivery and on-demand release using magnetoelectric nanoparticles
Authors: Rodzinski Alexandra , Hadjikhani Ali , Stewart Tiffanie , Stimphil Emmanuel , Guduru Rakesh , Liang Ping , Runowicz Carolyn , Khizroev Sakhrat 
Published: May 2016

Abstract
Background: An important challenge in chemotherapy is targeted drug delivery to eradicate tumor cells while sparing normal cells. The circulatory system can deliver a drug to almost every cell in the body; however, delivering the drug specifically into the tumor cell and then releasing it on demand remains a formidable task. Nanoparticles posses unique properties to address this issue. Despite their great potential, a significant problem remains to ensure that the drug is not prematurely released in the plasma or interstitial space but is released at an appropriate rate once at the target site. Recently, we discovered a new class of “smart” multifunctional nanostructures known as magnetoelectric nanoparticles (MENs) that enables a high-efficacy “communication” between intrinsic electric fields at the intra-cellular level, which are inherent to the cellular membrane nature, and external magnetic fields, to control targeted drug delivery and release into specific tumor cells on demand. Herein, the results of a comprehensive in vitro study and an in vivo study on using MENs to treat ovarian cancer (OC) are presented.
Methods: A specific combination of d.c. and a.c.-magnetic fields is used to externally control and separate delivery and release functions, respectively. MENs in a wide diameter range, 5-1000nm, are made of coreshell CoFe2O4@BaTiO3 nanostructures. The novel approach is compared to current state-of-the-art nanotechnology deliveries including (i) active immunochemotherapeutic approaches using polymer nanoparticles conjugated with monoclonal antibodies (mAbs) and (ii) passive enhanced permeability and retention (EPR)-based approach using polymer nanoparticles without any immunoactive reagents. Mitotic inhibitor paclitaxel (PTX)–loaded MENs are administrated through systemic IV injection into a lateral tail vein or through localized subcutaneous injection directly into the tumor site. The tumor progression is monitored through infrared (IR) imaging witth mAb-conjugated fluorescent agent Her2Sense 645. Post euthanasia, the cell morphology and the tumor presence in different organs are further studied with H&E stain and Her2Sense agent, respectively. The biodistribution of the nanoparticles in the tumor sites and different organs of mice treated under different field conditions are studied through the energy-dispersive spectroscopy (EDS) mode of high-resolution scanning electron microscopy (SEM). Finally, after the completion of the treatment, the cured mice are monitored for a period of three months before being sacrificed for further immunohistochemical and particle biodistribution studies.
Results: Using MENs loaded with PTX, the in vivo study on nude mice bearing SKOV-3 human ovarian carcinoma xenografts shows that intravenously administrated MENs enable high-specificity delivery and release via application of d.c. and a.c. magnetic fields, respectively. MENs distinguish cancer cells from the normal counterparts by the difference in the membrane’s electric properties. The control mice are treated with PTX loaded on ferromagnetic and polymer nanoparticles conjugated with HER2-neu antibodies. Only the mice which are weekly treated for three months with PTX-loaded 30-nm MENs (15/200 µg) in a 100-Oe local field are completely cured, as confirmed through infrared imaging and post-euthanasia immunohistochemical analysis. A comparison between systemic IV and localized subcutaneous injections of PTX-loaded MENs show that although both delivery approaches significantly slow down the progression of the tumor, the IV administration is more efficient and, unlike the subcutaneous administration, can completely eradicate the tumor during the three-month treatment period. An important observation from this study is the strong dependence of the amount of MENs in the tumor site and all the organs of treated and control mice on the external magnetic field control. The same conclusion was drawn also from the comprehensive in vitro study, in which the detailed cell lysate content was measured using direct AFM/MFM imaging of MENs and spectrophotometry detection of the drug under the investigated field conditions.
Conclusion: In summary, the study directly shows that the drug-loaded MENs provide a novel way to deliver the drug specifically into the tumor site via application of a d.c. field and then, when at the site, the drug is released directly inside the cancer cells via application of an a.c. field.
Citation Format: Alexandra Rodzinski, Ali Hadjikhani, Tiffanie Stewart, Emmanuel Stimphil, Rakesh Guduru, Ping Liang, Carolyn Runowicz, Sakhrat Khizroev. A novel mechanism for field-controlled high-specificity targeted anticancer drug delivery and on-demand release using magnetoelectric nanoparticles. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B47.