Ping Liang¹, Alexandra Rodzinski², Rakesh Guduru², Ali Hadjikhani², Carolyn Runowicz³, Richard Cote⁴, Norman Altman⁴, Ram Datar⁵,Sakhrat Khizroev²

¹Cellular Nanomed Inc., Weston, USA, ²Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, USA, ³Department of Obstetrics and Gynecology, Herbert Wertheim College of Medicine, Florida International University, Miami, USA, ⁴Department of Pathology, Miller School of Medicine, University of Miami, Miami, USA, ⁵John T. Macdonald Foundation Biomedical Nanotechnology Institute, University of Miami, Miami, USA

Objective:This in vivo study on nude mice bearing SKOV-3 human ovarian carcinoma xenografts aims to show that intravenously administrated 30-nm CoFe2O4@BaTiO3 coreshell magneto-electric nanoparticles (MENs) can enable field controlled high-specificity physical targeting, delivery and release of mitotic inhibitor paclitaxel (PTX) into cancer cells through nano-electroporation. Method: PTX-loaded MENs were administrated through systemic IV injection into a lateral tail vein or through localized subcutaneous injection directly into the tumor site grown on the animal's back. The tumor progression was monitored through infrared (IR) imaging with an IV administrated mAb-conjugated fluorescent agent Her2Sense 645. After a specimen was sacrificed, the cell morphology in different organs was further studied with hematoxylin and eosin stain (H&E stain). The same organ tissues are imaged for tumor presence with the antibody-conjugated fluorescent agent Her2Sense. The biodistribution of MENs in tumor sites and different organs of mice treated under different field conditions was studied through energy-dispersive spectroscopy (EDS) mode of high-resolution scanning electron microscopy (SEM). After completion of treatment, cured mice were monitored for three months before being sacrificed for further immunohistochemistry and particle biodistribution studies. Result: s show only the mice which were subjected to an hour-long magnetic field treatment immediately following each weekly injection of PTX-loaded MENs were completely cured of the tumor after approximately 3 months of weekly IV injections. It shows strong dependence of the amount of MENs in tumor site and various organs of treated and control mice on the external magnetic field. Conclusion: This study shows that MENs can enable an unprecedented high-specificity mechanism for externally controlled targeted drug delivery and release to treat cancer. Application of a local magnetic field after each injection and systemic IV injections were critical in complete eradication of the tumor.  The key discoveries are (a) the physical mechanism for MENs to target cancer cells driven by the electric-field gradient enhanced by external magnetic field, achieving higher specificity targeting than enhanced permeability and retention effect and not depending on availability of antibodies or ligands; and (b) controlled delivery of PTX inside cancer cells via targeted nano-electroporation of cancer cell membranes and on-demand release of PTX inside cancer cells under the control of external magnetic field.

Key Words: paclitaxel