Noninvasive ROS imaging and drug delivery monitoring in the tumor microenvironment.

Reactive oxygen species (ROS) that are overproduced in certain tumors can be considered an indicator of oxidative stress levels in the tissue. Here, we report a magnetic resonance imaging (MRI)-based probe capable of detecting ROS levels in the tumor microenvironment (TME) using ROS-responsive manganese ion (Mn2+)-chelated, biotinylated bilirubin nanoparticles (Mn@bt-BRNPs). These nanoparticles are disrupted in the presence of ROS, resulting in the release of free Mn2+, which induces T1-weighted MRI signal enhancement. Mn@BRNPs show more rapid and greater MRI signal enhancement in high ROS-producing A549 lung carcinoma cells compared with low ROS-producing DU145 prostate cancer cells. A pseudo three-compartment model devised for the ROS-reactive MRI probe enables mapping of the distribution and concentration of ROS within the tumor. Furthermore, doxorubicin-loaded, cancer-targeting ligand biotin-conjugated Dox/Mn@bt-BRNPs show considerable accumulation in A549 tumors and also effectively inhibit tumor growth without causing body weight loss, suggesting their usefulness as a new theranostic agent. Collectively, these findings suggest that Mn@bt-BRNPs could be used as an imaging probe capable of detecting ROS levels and monitoring drug delivery in the TME with potential applicability to other inflammatory diseases.

SPINNED: Simulation-based physics-informed neural network for deconvolution of dynamic susceptibility contrast MRI perfusion data.

PURPOSE: To propose the simulation-based physics-informed neural network for deconvolution of dynamic susceptibility contrast (DSC) MRI (SPINNED) as an alternative for more robust and accurate deconvolution compared to existing methods. METHODS: The SPINNED method was developed by generating synthetic tissue residue functions and arterial input functions through mathematical simulations and by using them to create synthetic DSC MRI time series. The SPINNED model was trained using these simulated data to learn the underlying physical relation (deconvolution) between the DSC-MRI time series and the arterial input functions. The accuracy and robustness of the proposed SPINNED method were assessed by comparing it with two common deconvolution methods in DSC MRI data analysis, circulant singular value decomposition, and Volterra singular value decomposition, using both simulation data and real patient data. RESULTS: The proposed SPINNED method was more accurate than the conventional methods across all SNR levels and showed better robustness against noise in both simulation and real patient data. The SPINNED method also showed much faster processing speed than the conventional methods. CONCLUSION: These results support that the proposed SPINNED method can be a good alternative to the existing methods for resolving the deconvolution problem in DSC MRI. The proposed method does not require any separate ground-truth measurement for training and offers additional benefits of quick processing time and coverage of diverse clinical scenarios. Consequently, it will contribute to more reliable, accurate, and rapid diagnoses in clinical applications compared with the previous methods including those based on supervised learning.

Longitudinal Magnetic Resonance Imaging with ROS-Responsive Bilirubin Nanoparticles Enables Monitoring of Nonalcoholic Steatohepatitis Progression to Cirrhosis.

Despite the vital importance of monitoring the progression of nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), an efficient imaging modality that is readily available at hospitals is currently lacking. Here, a new magnetic-resonance-imaging (MRI)-based imaging modality is presented that allows for efficient and longitudinal monitoring of NAFLD and NASH progression. The imaging modality uses manganese-ion (Mn2+)-chelated bilirubin nanoparticles (Mn@BRNPs) as a reactive-oxygen-species (ROS)-responsive MRI imaging probe. Longitudinal T1-weighted MR imaging of NASH model mice is performed after injecting Mn@BRNPs intravenously. The MR signal enhancement in the liver relative to muscle gradually increases up to 8 weeks of NASH progression, but decreases significantly as NASH progresses to the cirrhosis-like stage at weeks 10 and 12. A new dual input pseudo-three-compartment model is developed to provide information on NASH stage with a single MRI scan. It is also demonstrated that the ROS-responsive Mn@BRNPs can be used to monitor the efficacy of potential anti-NASH drugs with conventional MRI. The findings suggest that the ROS-responsive Mn@BRNPs have the potential to serve as an efficient MRI contrast for monitoring NASH progression and its transition to the cirrhosis-like stage.

Perfusion Maps Acquired From Dynamic Angiography MRI Using Deep Learning Approaches.

BACKGROUND: A typical stroke MRI protocol includes perfusion-weighted imaging (PWI) and MR angiography (MRA), requiring a second dose of contrast agent. A deep learning method to acquire both PWI and MRA with single dose can resolve this issue. PURPOSE: To acquire both PWI and MRA simultaneously using deep learning approaches. STUDY TYPE: Retrospective. SUBJECTS: A total of 60 patients (30-73 years old, 31 females) with ischemic symptoms due to occlusion or ≥50% stenosis (measured relative to proximal artery diameter) of the internal carotid artery, middle cerebral artery, or anterior cerebral artery. The 51/1/8 patient data were used as training/validation/test. FIELD STRENGTH/SEQUENCE: A 3 T, time-resolved angiography with stochastic trajectory (contrast-enhanced MRA) and echo planar imaging (dynamic susceptibility contrast MRI, DSC-MRI). ASSESSMENT: We investigated eight different U-Net architectures with different encoder/decoder sizes and with/without an adversarial network to generate perfusion maps from contrast-enhanced MRA. Relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), mean transit time (MTT), and time-to-max (Tmax ) were mapped from DSC-MRI and used as ground truth to train the networks and to generate the perfusion maps from the contrast-enhanced MRA input. STATISTICAL TESTS: Normalized root mean square error, structural similarity (SSIM), peak signal-to-noise ratio (pSNR), DICE, and FID scores were calculated between the perfusion maps from DSC-MRI and contrast-enhanced MRA. One-tailed t-test was performed to check the significance of the improvements between networks. P values < 0.05 were considered significant. RESULTS: The four perfusion maps were successfully extracted using the deep learning networks. U-net with multiple decoders and enhanced encoders showed the best performance (pSNR 24.7 ± 3.2 and SSIM 0.89 ± 0.08 for rCBV). DICE score in hypo-perfused area showed strong agreement between the generated perfusion maps and the ground truth (highest DICE: 0.95 ± 0.04). DATA CONCLUSION: With the proposed approach, dynamic angiography MRI may provide vessel architecture and perfusion-relevant parameters simultaneously from a single scan. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5.

Mapping cerebral perfusion from time-resolved contrast-enhanced MR angiographic data.

A common method to acquire both perfusion and angiographic information is to have separate MRI scans for each information. In this study, we propose to achieve the goal by deriving perfusion parameters, specifically cerebral blood volume (CBV) and Tmax, from time-resolved contrast-enhanced magnetic resonance angiography (CE-MRA). Both CE-MRA and DSC-MRI were performed on seven subjects with a diagnosed ischemic stroke. Concentration functions from CE-MRA were modeled using a modified gamma-variate function to appreciate the full first-pass transition of the tracer bolus. Perfusion parameters were calculated using concentration function derived from each imaging method and were compared to each other both visually and quantitatively by means of correlation studies. CBV and Tmax maps generally showed good agreement between the two methods. This study proved the concept of using time-resolved CE-MRA as both vascular imaging and tissue perfusion mapping while using a single injection of contrast agent, potentially reducing cost and improving patient safety and comfort.