Biology subjects

Raghunand, N.

Publications and source records attributed to Raghunand, N..

3 recordsLinked to original sources

bioRxiv2024

Nanoparticles use magnetoelectricity to target and eradicate cancer cells

This study presents the first in vivo and in vitro evidence of an externally controlled, predictive, MRI-based nanotheranostic agent capable of cancer cell specific targeting and killing via irreversible electroporation (IRE) in solid tumors. The rectangular-prism-shaped magnetoelectric nanoparticle is a smart nanoparticle that produces a local electric field in response to an externally applied magnetic field. When externally activated, MENPs are preferentially attracted to the highly conductive cancer cell membranes, which occurs in cancer cells because of dysregulated ion flux across their membranes. In a pancreatic adenocarcinoma murine model, MENPs activated by external magnetic fields during magnetic resonance imaging (MRI) resulted in a mean three-fold tumor volume reduction (62.3% vs 188.7%; P < .001) from a single treatment. In a longitudinal confirmatory study, 35% of mice treated with activated MENPs achieved a durable complete response for 14 weeks after one treatment. The degree of tumor volume reduction correlated with a decrease in MRI T2* relaxation time (r = .351; P = .039) which suggests that MENPs have a potential to serve as a predictive nanotheranostic agent at time of treatment. There were no discernable toxicities associated with MENPs at any timepoint or on histopathological analysis of major organs. MENPs are a noninvasive alternative modality for the treatment of cancer. SummaryWe investigated the theranostic capabilities of magnetoelectric nanoparticles (MENPs) combined with MRI via a murine model of pancreatic adenocarcinoma. MENPs leverage the magnetoelectric effect to convert an applied magnetic field into local electric fields, which can induce irreversible electroporation of tumor cell membranes when activated by MRI. Additionally, MENPs modulate MRI relaxivity, which can be used to predict the degree of tumor ablation. Through a pilot study (n=21) and a confirmatory study (n=27), we demonstrated that, [≥]300 {micro}g of MRI-activated MENPs significantly reduced tumor volumes, averaging a three-fold decrease as compared to controls. Furthermore, there was a direct correlation between the reduction in tumor T2 relaxation times and tumor volume reduction, highlighting the predictive prognostic value of MENPs. Six of 17 mice in the confirmatory studys experimental arms achieved a durable complete response, showcasing the potential for durable treatment outcomes. Importantly, the administration of MENPs was not associated with any evident toxicities. This study presents the first in vivo evidence of an externally controlled, MRI-based, theranostic agent that effectively targets and treats solid tumors via irreversible electroporation while sparing normal tissues, offering a new and promising approach to cancer therapy.

bioengineering↗

bioRxiv2021

Bridging cell-scale simulations and radiologic images to explain short-time intratumoral oxygen fluctuations

Radiologic images provide a way to monitor tumor development and its response to therapies in a longitudinal and minimally invasive fashion. However, they operate on a macroscopic scale (average value per voxel) and are not able to capture microscopic scale (cell level) phenomena. Nevertheless, to examine the causes of frequent fast fluctuations in tissue oxygenation, the models simulating individual cells behavior are needed. Here, we provided a link between the average data value recorded for radiologic image voxels and the cellular and vascular architecture of the tissue that fills these voxels. Using hybrid agent-based modeling, we generated a set of tissue morphologies capable of reproducing tissue oxygenation levels observed in radiologic images. We applied this approach to investigate whether oxygen fluctuations can be explained by changes in vascular oxygen supply or by modulations in cellular oxygen absorption. Our studies showed that intravascular changes in oxygen supply can reproduce the observed fluctuations in tissue oxygenation in all considered regions of interest. However, large magnitude fluctuations cannot be recreated by modifications in cellular absorption of oxygen in biologically feasible manner. Additionally, we developed a procedure to identify plausible tissue morphologies for a given temporal series of average data from radiology images. In future applications this approach can be used to generate a set of tissues representative for radiology images and to simulate tumor response to various anti-cancer treatments on the tissue-scale level. Authors SummaryLow levels of oxygen, called hypoxia, are observable in many solid tumors. They are associated with more aggressive malignant cells which are resistant to chemo-, radio- and immunotherapies. Recently developed imaging techniques provide a way to measure the magnitude of frequent short-term oxygen fluctuation, however they operate on a macro-scale voxel level. To examine the causes of rapid oxygen fluctuations on the cell level, we developed a hybrid agent-based mathematical model. We tested two different mechanisms that could be responsible for these cyclic effects in tissue oxygenation: variations in vascular influx of oxygen and modulations in cellular oxygen absorption. Additionally, we developed a procedure to identify plausible tissue morphologies from data collected from radiological images. This will also provide a bridge between the micro-scale simulations with individual cells and the longitudinal medical images containing average voxel values. In the future applications, this approach can be used to generate a set of tissues representative of radiology images and to simulate tumor response to various anticancer treatments on the cell-scale level.

systems biology↗

bioRxiv2018

ENvironmental Dynamics Underlying Responsive Extreme Survivors (ENDURES) of Glioblastoma: a Multi-disciplinary Team-based, Multifactorial Analytical Approach

Although glioblastoma is a fatal primary brain cancer with a short median survival of 15 months, a small number of patients survive more than 5 years after diagnosis; they are known as extreme survivors (ES). Due to their rarity, very little is known about what differentiates these outliers from other glioblastoma patients. For the purpose of identifying unknown drivers of extreme survivorship in glioblastoma, we developed the ENDURES consortium (ENvironmental Dynamics Underlying Responsive Extreme Survivors of glioblastoma). This consortium is a multicenter collaborative network of investigators focused on the integration of multiple types of clinical data and the creation of patient-specific models of tumor growth informed by radiographic and histological parameters. Leveraging our combined resources, the goals of the ENDURES consortium are two-fold: (1) to build a curated, searchable, multilayered repository housing clinical and outcome data on a large cohort of ES patients with glioblastoma and (2) to leverage the ENDURES repository for new insights on tumor behavior and novel targets for prolonging survival for all glioblastoma patients. In this article, we review the available literature and discuss what is already known about ES. We then describe the creation of our consortium and some of our preliminary results.\n\nFundingThis review was financially supported by a grant from the James S. McDonnell Foundation\n\nConflicts of InterestThe authors have declared that no conflicts of interest exist.\n\nAuthorshipConceptualized consortium: LW, RG, KME, PC, and KRS. Built consortium: SKJ, PK, NR, JS, KME, PC, and KRS. Wrote the manuscript: SKJ, PW, SCM, PK, AP, and KME. Reviewed and edited the manuscript: LFGC, MMM, AHD, PRJ, and LSH. Contributed to writing, provided feedback, and approved of final manuscript: All authors.\n\nLink to website for ENDUREShttp://mathematicalneurooncology.org/?page_id=2125

cancer biology↗