It is well-recognized that solid tumors are genomically, anatomically, and physiologically heterogeneous. In general, more heterogeneous tumors have poorer outcomes, likely due to the increased probability of harboring therapy-resistant cells and regions. It is hypothesized that the genomic and physiologic heterogeneity are related, because physiologically distinct regions will exert variable selection pressures leading to the outgrowth of clones with variable genomic/proteomic profiles. To investigate this, methods must be in place to interrogate and define, at the microscopic scale, the cytotypes that exist within physiologically distinct subregions (“habitats”) that are present at mesoscopic scales. MRI provides a noninvasive approach to interrogate physiologically distinct local environments, due to the biophysical principles that govern MRI signal generation. Here, we interrogate different physiologic parameters, such as perfusion, cell density, and edema, using multiparametric MRI (mpMRI). Signals from six different acquisition schema were combined voxel-by-voxel into four clusters identified using a Gaussian mixture model. These were compared with histologic and IHC characterizations of sections that were coregistered using MRI-guided 3D printed tumor molds. Specifically, we identified a specific set of MRI parameters to classify viable-normoxic, viable-hypoxic, nonviable-hypoxic, and nonviable-normoxic tissue types within orthotopic 4T1 and MDA-MB-231 breast tumors. This is the first coregistered study to show that mpMRI can be used to define physiologically distinct tumor habitats within breast tumor models. Significance: This study demonstrates that noninvasive imaging metrics can be used to distinguish subregions within heterogeneous tumors with histopathologic correlation.

Purpose: Develop and test an analytic correction method to correct the signal intensity variation caused by the inhomogeneous reception profile of an eight‐channel phased array for hyperpolarized ¹³C imaging.Theory and Methods: Fiducial markers visible in anatomical images were attached to the individual coils to provide three dimensional localization of the receive hardware with respect to the image frame of reference. The coil locations and dimensions were used to numerically model the reception profile using the Biot‐Savart Law. The accuracy of the coil sensitivity estimation was validated with images derived from a homogenous ¹³C phantom. Numerical coil sensitivity estimates were used to perform intensity correction of in vivo hyperpolarized ¹³C cardiac images in pigs.Results: In comparison to the conventional sum‐of‐squares reconstruction, improved signal uniformity was observed in the corrected images.Conclusion: The analytical intensity correction scheme was shown to improve the uniformity of multichannel image reconstruction in hyperpolarized [1‐¹³C]pyruvate and ¹³C‐bicarbonate cardiac MRI. The method is independent of the pulse sequence used for ¹³C data acquisition, simple to implement and does not require additional scan time, making it an attractive technique for multichannel hyperpolarized ¹³C MRI. Magn Reson Med 75:859–865, 2016.

Spatially resolved images of hyperpolarized ¹³C substrates and their downstream products provide insight into real‐time metabolic processes occurring in vivo. Recently, hyperpolarized ¹³C pyruvate has been used to characterize in vivo cardiac metabolism in the rat and pig, but accurate and reproducible measurements remain challenging due to the limited period available for imaging as well as physiological motion. In this article, time‐resolved cardiac‐ and respiratory‐gated images of [1‐¹³C] pyruvate, [1‐¹³C] lactate, and ¹³C bicarbonate in the heart are acquired without the need for a breathhold. The robustness of these free‐breathing measurements is demonstrated using the time‐resolved data to produce a normalized metric of pyruvate dehydrogenase and lactate dehydrogenase activity in the heart. The values obtained are reproducible in a controlled metabolic state. In a 60‐min ischemia/reperfusion model, significant differences in hyperpolarized bicarbonate and lactate, normalized using the left ventricular pyruvate signal, were detected between scans performed at baseline and 45 min after reperfusion. The sequence is anticipated to improve quantitative measurements of cardiac metabolism, leading to feasible validation studies using fewer subjects, and potentially improved diagnosis, serial monitoring, and treatment of cardiac disease in patients. Magn Reson Med 69:1063–1071, 2013.

Nanoparticle drug carriers hold potential to improve current cancer therapy by delivering payload to the tumor environment and decreasing toxic side effects. Challenges in nanotechnology drug delivery include plasma instability, site-specific delivery, and relevant biomarkers. We have developed a triblock polymer comprising a hydroxamic acid functionalized center block that chelates iron to form a stabilized micelle that physically entraps chemotherapeutic drugs in the hydrophobic core. The iron-imparted stability significantly improves the integrity of the micelle and extends circulation pharmacokinetics in plasma over that of free drug. Furthermore, the paramagnetic properties of the iron-crosslinking exhibits contrast in the tumors for imaging by magnetic resonance. Three separate nanoparticle formulations demonstrate improved anti-tumor efficacy in xenograft models and decreased toxicity. We report a stabilized polymer micelle that improves the tolerability and efficacy of chemotherapeutic drugs, and holds potential for non-invasive MRI to image drug delivery and deposition in the tumor.

An essential method to investigate neuromodulation effects of an invasive neural interface (INI) is magnetic resonance imaging (MRI). Presently, MRI imaging of patients with neural implants is highly restricted in high field MRI (e.g., 3 T and higher) due to patient safety concerns. This results in lower resolution MRI images and, consequently, degrades the efficacy of MRI imaging for diagnostic purposes in these patients. Cubic silicon carbide (3C-SiC) is a biocompatible wide-band-gap semiconductor with a high thermal conductivity and magnetic susceptibility compatible with brain tissue. It also has modifiable electrical conductivity through doping level control. These properties can improve the MRI compliance of 3C-SiC INIs, specifically in high field MRI scanning. In this work, the MRI compliance of epitaxial SiC films grown on various Si wafers, used to implement a monolithic neural implant (all-SiC), was studied. Via finite element method (FEM) and Fourier-based simulations, the specific absorption rate (SAR), induced heating, and image artifacts caused by the portion of the implant within a brain tissue phantom located in a 7 T small animal MRI machine were estimated and measured. The specific goal was to compare implant materials; thus, the effect of leads outside the tissue was not considered. The results of the simulations were validated via phantom experiments in the same 7 T MRI system. The simulation and experimental results revealed that free-standing 3C-SiC films had little to no image artifacts compared to silicon and platinum reference materials inside the MRI at 7 T. In addition, FEM simulations predicted an ~30% SAR reduction for 3C-SiC compared to Pt. These initial simulations and experiments indicate an all-SiC INI may effectively reduce MRI induced heating and image artifacts in high field MRI. In order to evaluate the MRI safety of a closed-loop, fully functional all-SiC INI as per ISO/TS 10974:2018 standard, additional research and development is being conducted and will be reported at a later date.