Rakesh Guduru

Targeted and controlled anticancer drug delivery and release with magnetoelectric nanoparticles.

It is a challenge to eradicate tumor cells while sparing normal cells. We used magnetoelectric nanoparticles (MENs) to control drug delivery and release. The physics is due to electric-field interactions (i) between MENs and a drug and (ii) between drug-loaded MENs and cells. MENs distinguish cancer cells from normal cells through the membrane’s electric properties; cancer cells have a significantly smaller threshold field to induce electroporation. In vitro and in vivo studies (nude mice with SKOV-3 xenografts) showed that (i) drug (paclitaxel (PTX)) could be attached to MENs (30-nm CoFe2O4@BaTiO3 nanostructures) through surface functionalization to avoid its premature release, (ii) drug-loaded MENs could be delivered into cancer cells via application of a d.c. field (~100 Oe), and (iii) the drug could be released off MENs on demand via application of an a.c. field (~50 Oe, 100 Hz). The cell lysate content was measured with scanning probe microscopy and spectrophotometry. MENs and control ferromagnetic and polymer nanoparticles conjugated with HER2-neu antibodies, all loaded with PTX were weekly administrated intravenously. Only the mice treated with PTX-loaded MENs (15/200 μg) in a field for three months were completely cured, as confirmed through infrared imaging and post-euthanasia histology studies via energy-dispersive spectroscopy and immunohistochemistry.

Magneto-Electric Nano-Particles for Non-Invasive Brain Stimulation

This paper for the first time discusses a computational study of using magneto-electric (ME) nanoparticles to artificially stimulate the neural activity deep in the brain. The new technology provides a unique way to couple electric signals in the neural network to the magnetic dipoles in the nanoparticles with the purpose to enable a non-invasive approach. Simulations of the effect of ME nanoparticles for non-invasively stimulating the brain of a patient with Parkinsons Disease to bring the pulsed sequences of the electric field to the levels comparable to those of healthy people show that the optimized values for the concentration of the 20-nm nanoparticles (with the magneto-electric (ME) coefficient of 100 V cm−1 Oe−1 in the aqueous solution) is 3×106 particles/cc, and the frequency of the externally applied 300-Oe magnetic field is 80 Hz.

Magnetoelectric ‘spin’ on stimulating the brain

AIM The in vivo study on imprinting control region mice aims to show that magnetoelectric nanoparticles may directly couple the intrinsic neural activity-induced electric fields with external magnetic fields. METHODS Approximately 10 µg of CoFe2O4-BaTiO3 30-nm nanoparticles have been intravenously administrated through a tail vein and forced to cross the blood-brain barrier via a d.c. field gradient of 3000 Oe/cm. A surgically attached two-channel electroencephalography headmount has directly measured the modulation of intrinsic electric waveforms by an external a.c. 100-Oe magnetic field in a frequency range of 0-20 Hz. RESULTS The modulated signal has reached the strength comparable to that due the regular neural activity. CONCLUSION The study opens a pathway to use multifunctional nanoparticles to control intrinsic fields deep in the brain.

Assessment of the Resistance to Uranium (VI) Exposure by Arthrobacter sp. Isolated from Hanford Site Soil

Production of nuclear fuel has resulted in hazardous waste streams that have contaminated the soil and groundwater. Arthrobacter strains, G975, G968, and G954 were used in the prescreening tests to evaluate their tolerance to UO2 2+ and investigate bacteria-U(VI) interactions under oxidizing pH-neutral conditions. Experiments have shown G975 is the fastest growing and the most uranium tolerant strain that removed about 90% of uranium from growth media. Atomic Force Microscopy images exhibited an irregular surface structure, which perhaps provided a larger surface area for uranium precipitation. The data indicate that aerobic heterotrophic bacteria may offer a solution to sequestering uranium in oxic conditions, which prevail in the vadose zone.

Physics considerations in targeted anticancer drug delivery by magnetoelectric nanoparticles

In regard to cancer therapy, magnetoelectric nanoparticles (MENs) have proven to be in a class of its own when compared to any other nanoparticle type. Like conventional magnetic nanoparticles, they can be used for externally controlled drug delivery via application of a magnetic field gradient and image-guided delivery. However, unlike conventional nanoparticles, due to the presence of a non-zero magnetoelectric effect, MENs provide a unique mix of important properties to address key challenges in modern cancer therapy: (i) a targeting mechanism driven by a physical force rather than antibody matching, (ii) a high-specificity delivery to enhance the cellular uptake of therapeutic drugs across the cancer cell membranes only, while sparing normal cells, (iii) an externally controlled mechanism to release drugs on demand, and (iv) a capability for image guided precision medicine. These properties separate MEN-based targeted delivery from traditional biotechnology approaches and lay a foundation for the comp...

Multiferroic coreshell magnetoelectric nanoparticles as NMR sensitive nanoprobes for cancer cell detection

Magnetoelectric (ME) nanoparticles (MENs) intrinsically couple magnetic and electric fields. Using them as nuclear magnetic resonance (NMR) sensitive nanoprobes adds another dimension for NMR detection of biological cells based on the cell type and corresponding particle association with the cell. Based on ME property, for the first time we show that MENs can distinguish different cancer cells among themselves as well as from their normal counterparts. The core-shell nanoparticles are 30 nm in size and were not superparamagnetic. Due to presence of the ME effect, these nanoparticles can significantly enhance the electric field configuration on the cell membrane which serves as a signature characteristic depending on the cancer cell type and progression stage. This was clearly observed by a significant change in the NMR absorption spectra of cells incubated with MENs. In contrast, conventional cobalt ferrite magnetic nanoparticles (MNPs) did not show any change in the NMR absorption spectra. We conclude that different membrane properties of cells which result in distinct MEN organization and the minimization of electrical energy due to particle binding to the cells contribute to the NMR signal. The nanoprobe based NMR spectroscopy has the potential to enable rapid screening of cancers and impact next-generation cancer diagnostic exams.

Biodistribution and clearance of magnetoelectric nanoparticles for nanomedical applications using energy dispersive spectroscopy

AIM The biodistribution and clearance of magnetoelectric nanoparticles (MENs) in a mouse model was studied through electron energy dispersive spectroscopy. MATERIALS & METHODS This approach allows for detection of nanoparticles (NPs) in tissues with the spatial resolution of scanning electron microscopy, does not require any tissue-sensitive staining and is not limited to MENs. RESULTS The size-dependent biodistribution of intravenously administrated MENs was measured in vital organs such as the kidneys, liver, spleen, lungs and brain at four different postinjection times including 1 day, 1 week, 4 and 8 weeks, respectively. CONCLUSION The smallest NPs, 10-nm MENs, were cleared relatively rapidly and uniformly across the organs, while the clearance of the larger NPs, 100- and 600-nm MENs, was highly nonlinear with time and nonuniform across the organs.

Abstract B47: A novel mechanism for field-controlled high-specificity targeted anticancer drug delivery and on-demand release using magnetoelectric nanoparticles

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 HE 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B47.

Magnetoelectric nanoparticles for delivery of antitumor peptides into glioblastoma cells by magnetic fields

AIM We studied externally controlled anticancer effects of binding tumor growth inhibiting synthetic peptides to magnetoelectric nanoparticles (MENs) on treatment of glioblastomas. METHODS Hydrothermally synthesized 30-nm MENs had the core-shell composition of CoFe2O4@BaTiO3. Molecules of growth hormone-releasing hormone antagonist of the MIA class (MIA690) were chemically bound to MENs. In vitro experiments utilized human glioblastoma cells (U-87MG) and human brain microvascular endothelial cells. RESULTS The studies demonstrated externally controlled high-efficacy binding of MIA690 to MENs, targeted specificity to glioblastoma cells and on-demand release of the peptide by application of d.c. and a.c. magnetic fields, respectively. CONCLUSION The results support the use of MENs as an effective drug delivery carrier for growth hormone-releasing hormone antagonists in the treatment of human glioblastomas.

Mapping the Brain’s electric fields with Magnetoelectric nanoparticles

BackgroundNeurodegenerative diseases are devastating diagnoses. Examining local electric fields in response to neural activity in real time could shed light on understanding the origins of these diseases. To date, there has not been found a way to directly map these fields without interfering with the electric circuitry of the brain. This theoretical study is focused on a nanotechnology concept to overcome the challenge of brain electric field mapping in real time. The paper shows that coupling the magnetoelectric effect of multiferroic nanoparticles, known as magnetoelectric nanoparticles (MENs), with the ultra-fast and high-sensitivity imaging capability of the recently emerged magnetic particle imaging (MPI) can enable wirelessly conducted electric-field mapping with specifications to meet the requirements for monitoring neural activity in real time.MethodsThe MPI signal is numerically simulated on a realistic human brain template obtained from BrainWeb, while brain segmentation was performed with BrainSuite software. The finite element mesh is generated with Computer Geometry Algorithm Library. The effect of MENs is modeled through local point magnetization changes according to the magnetoelectric effect.ResultsIt is shown that, unlike traditional magnetic nanoparticles, MENs, when coupled with MPI, provide information containing electric field’s spatial and temporal patterns due to local neural activity with signal sensitivities adequate for detection of minute changes at the sub-cellular level corresponding to early stage disease processes.ConclusionsLike no other nanoparticles known to date, MENs coupled with MPI can be used for mapping electric field activity of the brain at the sub-neuronal level in real time. The potential applications span from prevention and treatment of neurodegenerative diseases to paving the way to fundamental understanding and reverse engineering the brain.