We acknowledge partial financial support from National Science Foundation (NSF) award # 005084-002, National Institute of Health (NIH) DA # 027049, and Department of Defense (DoD) Defense Microelectronics Activity (DMEA) under contract # H94003-09-2-0904.

1. Magneto-Electric Nanoparticles: Synthesis and Characterization
	<ol>
		<li>Prepare CoFe2O4 nanoparticles by hydrothermal method described previously 6.</li>	 
		<li>Dissolve 15 ml of aqueous mixture of 0.058 g of Co(NO3)2.6H20, 0.16 g of Fe(NO3)3.9H20 and 0.2 g of polyvinylpyrrolidone in 5 ml of aqueous 0.9 g sodium borohydride at 120 &deg;C for 12 hours.</li>	 
		<li>Next, prepare the precursor so...

<ol>
 <li>Varatharajan, L. &amp; Thomas, S.A. The transport of anti-HIV drugs across blood, &Auml;&igrave;CNS interfaces: summary of current knowledge and recommendations for further research. Antiviral research. 82, A99 (2009).</li>	 
 <li>Timko, B.P., Dvir, T., &amp; Kohane, D.S. Remotely triggerable drug delivery systems. Advanced Materials. 22, 4925-4943 (2010).</li>	 
 <li>Saiyed, Z.M., Gandhi, N.H., &amp; Nair, M.P.N. Magnetic nanoformulation of azidothymidine 5,&Auml;&ocirc;-triphosphate for targeted delivery across the blood,&Auml;&igrave;brain barrier. International journal of nanomedicine. 5, 157 (2010).</li>	 
 <li>Batrakova, E.V., Gendelman, H.E., &amp; Kabanov, A.V. Cell-mediated drug delivery. Expert opinion on drug delivery. 8, 415-433 (2011).</li>	 
 <li>Yue, K., et al. Magneto-Electric Nano-Particles for Non-Invasive Brain Stimulation. PloS one. 7, e44040 (2012).</li>	 
 <li>Xie, S., Ma, F., Liu, Y., &amp; Li, J. Multiferroic CoFe2O4,&Auml;&igrave;Pb (Zr0. 52Ti0. 48) O3 core-shell nanofibers and their magnetoelectric coupling. Nanoscale. 3, 3152-3158 (2011).</li>	 
 <li>Yu, M., Huang, S., Yu, K.J., &amp; Clyne, A.M. Dextran and Polymer Polyethylene Glycol (PEG) Coating Reduce Both 5 and 30 nm Iron Oxide Nanoparticle Cytotoxicity in 2D and 3D Cell Culture. International Journal of Molecular Sciences. 13, 5554-5570 (2012).</li>	 
 <li>Mu, L. &amp; Feng, S.S. PLGA/TPGS nanoparticles for controlled release of paclitaxel: effects of the emulsifier and drug loading ratio. Pharmaceutical research. 20, 1864-1872 (2003).</li>	 
 <li>Dilnawaz, F., Singh, A., Mohanty, C., &amp; Sahoo, S.K. Dual drug loaded superparamagnetic iron oxide nanoparticles for targeted cancer therapy. Biomaterials. 31, 3694-3706 (2010).</li>	 
 <li>Babic, M., et al. Poly (L-lysine)-modified iron oxide nanoparticles for stem cell labeling. Bioconjugate chemistry 19, 740-750 (2008).</li>	 
 <li>Rovers, S.A., Hoogenboom, R., Kemmere, M.F., &amp; Keurentjes, J.T.F. Repetitive on-demand drug release by magnetic heating of iron oxide containing polymeric implants. Soft Matter. 8, 1623-1627 (2012).</li>	 
 <li>Hoare, T., et al. A magnetically triggered composite membrane for on-demand drug delivery. Nano letters. 9, 3651-3657 (2009).</li>	 
 <li>Torchilin, V.P. Recent advances with liposomes as pharmaceutical carriers. Nature Reviews Drug Discovery. 4, 145-160 (2005).</li>	
</ol>

Below, we discuss the most important aspects one should bear in mind while conducting the above experiments on field-controlled delivery and on-demand release of the drug carried by MENs. These aspects mostly relate to the use of field and power sources according to the described protocols and procedures.
MENs display all the properties that are displayed by the conventional MNs. Therefore, MENs can replace MNs in any existing application, e.g., as drug nano-carriers or contrast...

Researchers across the globe have long been struggling to find a better way to navigate and dispense the cargo of drugs and/or disease-specific image contrast agents to the damaged tissue or at the site of action with adequately high efficiency and 3-D navigation precision 1. Personalized NanoMedicine (PNM) has recently emerged as a multi-disciplinary field that leverages nanotechnology to achieve these diagnostics and treatment milestones. However, in spite of its unprecedented potential, this field is at its very early stage of development and no viable PNM technologies exist today. The use of nanoparticles is often considered an essential enabling tool of PNM. Indeed, because of their unique size- and shape-dependent properties, nanoparticles promise superior applications in diverse areas such as Cancer relief, targeted drug delivery, immunoassays, functional MRI, MNI, and fluorescence imaging, and many others. For ideal medical treatment, every patient requires his or her own optimal combination of drugs and microenvironment that can be controlled at the sub-cellular level. Using nanoparticles to precisely define drug dosage and composition as well as to detect even minute disease-caused surrounding cellular and tissue changes can make such personalized treatment a reality.
There are many different types of nanoparticle systems used in medicine for drug delivery purposes alone. To mention a few, they rely on using thermally-responsive polymers, optically (UV, Visible-Wavelength, and IR) or acoustically activated materials, liposomes, electrochemical processes, and magnetic forces 2. The unique advantages of an external magnetic field control place magnetic nanoparticle (MN) systems in a class of their own, especially for the purposes of targeted delivery. In this case, the speed of delivery is limited by the external field sources and not just by the blood circulation. For instance, as it is related to the release across the blood-brain barrier (BBB), the magnetic delivery provides a unique way to transfer drugs sufficiently fast to avoid their engulfing by the reticuloendothelial system (RES) 3. However, all the existing delivery technologies suffer from the lack of certainty of drug release from the carrier if and when the nano-carrier reaches the target. Probably, the main stumbling block is the inability of the current nanoparticle systems to remotely control the intrinsic phenomena that define the interaction of the nanoparticles with the surrounding cells and tissues. The conventional approaches are extrinsic in their nature and often fail to adequately regulate cellular phenomena such as exocytosis of drug with intracellular vesicle, control of ionic channels, using externally controlled signals 4. In other words, the fundamental physics that underlies the nanoparticle system characteristics in the perspective of their intrinsic interaction with the surrounding cells and tissues in the aforementioned applications is barely exploited. Revealing and controlling the interaction of nanoparticles at the nanoscale, whether it is electric field-, magnetic spin- , photon-, or phonon-triggered, is vital for enabling perfect diagnostics and/or recovery/regeneration of all the medical functions.
Our recent discovery of the unprecedented capabilities of magneto-electric nanoparticles (MENs) paves a way to fill this gap through nanotechnology approaches. Previously, we have shown that due to the intrinsic quantum-mechanically defined coupling between electric dipoles and magnetic spins within each nanoparticle, MENs could be used as energy-efficient and dissipation-free field-controlled nano-vehicles for targeted delivery and on-demand release of anti-Cancer and anti-HIV drugs as well as nano-stimulators for non-invasive treatment of patients with central nervous system (CNS) disorders such as Parkinson's Disease, Alzheimer's Disease, and other dementia 5. Further, this intrinsic coupling between electric and magnetic fields within MENs provides molecular composition specificity that can enable an entirely new dimension even to the conventional diagnostic methods such as MRI, MNI, and PET-CT. In addition, the specificity allows assigning unique "passport" features to small groups of nanoparticles thus pushing the real-time health monitoring capability to a new level. Finally, because the coupling between magnetic and electric fields is achieved at the intrinsic level, ideally the described field-controlled PNM functions (delivery, drug release, CNS stimulation, diagnostics) can be accomplished with ideal (100%) efficacy and without any destructive heat dissipation (with no need to use high-power electronics as with the conventional NPs).
	Here, we present detailed fabrication protocols and characterization procedures for MENs that could be used for energy-efficient field-controlled targeted drug delivery and on-demand release with no heat dissipation and unprecedented high efficacy. As examples, we discuss HIV and Ovarian Cancer models.

<table border="1">
		<tbody>
		 <tr>
			<td></td>
			<td></td>
			<td></td>
			<td>Reagent </td>
		 </tr>
		 <tr>
			<td>Co(NO3)2.6H20</td>
			<td>Sigma-Aldrich</td>
			<td>203106-10G </td>
			<td></td>
		 </tr>
		 <tr>
			<td>Fe(NO3)3.9H20 </td>
			<td>Sigma-Aldrich</td>
			<td>254223-10G </td>
			<td></td>
		 </tr>
		 <tr>
			<td>Polyvinylpyrrolidone</td>
			<td>Sigma-Aldrich</td>
			<td>PVP40-100G </td>
			<td></td>
		 </tr>
		 <tr>
			<td>Titanium isopropoxide</td>
			<td>Sigma-Aldrich</td>
			<td>7560-500ML </td>
			<td></td>
		 </tr>
		 <tr>
			<td>BaCO3 </td>
			<td>Sigma-Aldrich</td>
			<td>237108-500G </td>
			<td></td>
		 </tr>
		 <tr>
			<td>Citric acid </td>
			<td>Sigma-Aldrich</td>
			<td>251275-500G </td>
			<td></td>
		 </tr>
		 <tr>
			<td>Ethanol</td>
			<td>Sigma-Aldrich</td>
			<td>459844-1L </td>
			<td></td>
		 </tr>
		 <tr>
			<td>GMO</td>
			<td>Pfaltz &amp;Bauer</td>
			<td>25496-72-4</td>
			<td></td>
		 </tr>
		 <tr>
			<td>PBS Buffer</td>
			<td>Gibco</td>
			<td>10010-023</td>
			<td></td>
		 </tr>
		 <tr>
			<td>AZTTP drug</td>
			<td>e-enzyme</td>
			<td>AT-013-0170 </td>
			<td></td>
		 </tr>
		 <tr>
			<td>Paclitaxel Drug</td>
			<td>Invitrogen</td>
			<td>P3456 </td>
			<td></td>
		 </tr>
		 <tr>
			<td>TE buffer</td>
			<td>Fluka</td>
			<td>93302-500ml</td>
			<td></td>
		 </tr>
		 <tr>
			<td>Sodium borohydride</td>
			<td>Sigma-Aldrich</td>
			<td>71321-25G </td>
			<td></td>
		 </tr>
		 <tr>
			<td></td>
			<td></td>
			<td></td>
			<td>Equipment </td>
		 </tr>
		 <tr>
			<td>Spectrophotometer</td>
			<td>Varian</td>
			<td>Cary-100</td>
			<td></td>
		 </tr>
		 <tr>
			<td>FTIR</td>
			<td>Jasco </td>
			<td >4100 </td>
			<td></td>
		 </tr>
		 <tr>
			<td>AFM</td>
			<td>Veeco Metrology</td>
			<td>Nanoscope-IIIa</td>
			<td></td>
		 </tr>
		 <tr>
			<td>Helmholtz coils</td>
			<td>Home Made</td>
			<td></td>
			<td></td>
		 </tr>
		 <tr>
			<td>AC Generator</td>
			<td>Agilent</td>
			<td>33220a</td>
			<td></td>
		 </tr>
		 <tr>
			<td>DC Power supply</td>
			<td>BK-Precision</td>
			<td>1660A</td>
			<td></td>
		 </tr>
		</tbody>
 </table>

external magnetic field control of intrinsic electric fields in magneto-electric nanoparticles for enabling patient- and disease-specific nanomedicine

The use of nanoparticles is often considered as an enabling force of personalized nanomedicine (PNM). Using nanoparticles to precisely navigate a drug through the patient's body and control its dosage and composition as well as to detect even minute disease-caused changes in the surrounding cellular microenvironment can make personalized treatment a reality. However, the fundamental physics that underlies the nanoparticles' characteristics in the perspective of the intrinsic interaction with the patient's body in the aforementioned applications is poorly exploited. Our recent discovery of the unprecedented capabilities of magneto-electric nanoparticles (MENs) helps fill this gap. MENs could be used as energy-efficient and dissipation-free field-controlled nano-vehicles for targeted delivery and on-demand release of anti-Cancer and anti-HIV drugs as well as nano-stimulators for field-controlled non-invasive treatment of patients with central nervous system (CNS) disorders. Further, the intrinsic coupling between electric and magnetic forces within MENs enables molecular specificity that provides an entirely new dimension even to conventional state-of-the-art diagnostic methods such as MRI, magnetic nanoparticle imaging (MNI), and PET-CT.
Here, we present detailed fabrication protocols and characterization procedures to study and develop MENs that could be used for targeted drug delivery and on-demand release with no heat dissipation. To demonstrate the new application, we use scanning probe microscopy approaches to directly trace the kinetics of a magneto-electric action used to release AZT 5'-triphosphate (AZTTP), an anti-HIV drug, from 30-nm CoFe2O4-BaTiO3 MENs by applying a DC and low-frequency (below 1000 Hz) AC field. Finally, we present a study to employ MENs for an on-demand targeted treatment of Ovarian Epithelial Cancer with Paclitaxel (Taxol), a popular mitotic inhibitor.

Qualitative results
FTIR analysis
FTIR analysis of the drug binding and release process was confirmed by performing the measurements at three key stages, 1) before loading the drug on MENs, 2) when the drugs are attached to the MENs surface, 3) after releasing the drugs by remote 44 Oe AC magnetic field strength and 100-Hz frequency. The FTIR results for AZTTP-MENs are shown in Figure 3. These results indicate 30% weaker absorbance of bou...

We describe the fabrication and characterization protocols used in our studies of magneto-electrical nanoparticles (MENs) for enabling Personalized Nanomedicine (PNM) from the perspective of fundamental physics and nanoengineering. This approach exploits quantum-mechanical coupling between electric and magnetic fields within MENs. Anti-Cancer and anti-HIV drugs were released on demand.

External Magnetic Field Control of Intrinsic Electric Fields in Magneto-Electric Nanoparticles for Enabling Patient- and Disease-Specific Nanomedicine

The use of nanoparticles is often considered as  an enabling force of personalized nanomedicine (PNM). Using nanoparticles to precisely navigate a  drug ...

External Magnetic Field Control of Intrinsic Electric Fields in Magneto-Electric Nanoparticles for Enabling Patient- and Disease-Specific Nanomedicine

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