Chemical Exchange Saturation Transfer MRI Research Articles

Assessment of Hypoxia in Breast Cancer: Emerging Functional MR Imaging and Spectroscopy Techniques and Clinical Applications.

Breast cancer is one of the most prevalent forms of cancer affecting women worldwide. Hypoxia, a condition characterized by insufficient oxygen supply in tumor tissues, is closely associated with tumor aggressiveness, resistance to therapy, and poor clinical outcomes. Accurate assessment of tumor hypoxia can guide treatment decisions, predict therapy response, and contribute to the development of targeted therapeutic interventions. Over the years, functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) techniques have emerged as promising noninvasive imaging options for evaluating hypoxia in cancer. Such techniques include blood oxygen level-dependent (BOLD) MRI, oxygen-enhanced MRI (OE) MRI, chemical exchange saturation transfer (CEST) MRI, and proton MRS (1H-MRS). These may help overcome the limitations of the routinely used dynamic contrast-enhanced (DCE) MRI and diffusion-weighted imaging (DWI) techniques, contributing to better diagnosis and understanding of the biological features of breast cancer. This review aims to provide a comprehensive overview of the emerging functional MRI and MRS techniques for assessing hypoxia in breast cancer, along with their evolving clinical applications. The integration of these techniques in clinical practice holds promising implications for breast cancer management. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 1.

Activatable near-infrared fluorescence and chemical exchange saturation transfer MRI multimodal imaging probe for tumor detection in vitro and in vivo

Multimodal imaging has emerged as a powerful tool in biomedical research and clinical diagnostics. Ideally, it combines multiple imaging techniques to provide complementary anatomical and molecular information in living subjects. Particularly desirable are multimodal imaging probes capable of providing differential diagnostic signals upon interaction with specific molecular targets. Hydrogen peroxide (H2O2) is a key target in this regard, since it is typically overexpressed in cancer cells. In this study, we present a small-molecule probe that not only selectively detects endogenous H2O2 through multimodal imaging, with a significant H2O2-triggered 15-fold fluorescence enhancement but also turns “on” a chemical exchange saturation transfer (CEST) magnetic resonance (MR) response with 60-fold signal enhancement at pH 7.4. Excellent selectivity against various other biologically relevant species is seen. Using this probe, we observed 3.4–4.5-fold and 2.8–5.8-fold higher H2O2 levels in cancerous cell lines and tumor tissues compared to normal cell lines and tissues, respectively. Time-dependent in vivo fluorescence and CEST imaging in a HeLa (Henrietta Lacks) tumor xenograft mouse model revealed probe-dependent tumor detection by fluorescence and CEST MRI contrast in the tumor area. These observations are attributed to the relatively high endogenous H2O2 levels produced during mitosis. This newly developed probe holds promise for advancing our understanding of H2O2-related biology and for cancer detection both in vitro and in vivo.

Molecular Profiling to Understand Treatment Resistance and Response in Glioblastoma

INTRODUCTION: Patients with glioblastoma experience a wide variation in response to standard treatment, with nearly 30% experiencing tumour progression during treatment, and nearly 6% surviving more than 5 years. To date, there are few non-invasive clinical biomarkers to predict response to firstline treatment. Chemical exchange saturation transfer (CEST) MRI may have the potential to fill this gap. CEST MRI is sensitive to treatment-induced changes and changes in tumor metabolism1. Our team has obtained CEST data for patients before, during and after standard chemoradiation treatment, and found that CEST provides markers of early response and can identify early, standard and late progressors before treatment initiation.2 METHODS: Patients (n = 104) with primary, IDH wild-type glioblastoma were imaged with CEST-MRI at multiple time points throughout standard chemoradiation treatment. DNA and RNA were co-extracted from matched normal and tumour pairs and processed for whole genome sequencing and gene expression analysis using Nanostring. Clinical variables such as age, extent of resection, sex, ECOG status and MGMT promoter methylated were also collected. A survival analysis was conducted using the Kaplan-Meier method with log-rank tests. Univariate and multi-variate hazard ratios for clinical variables were calculated by fitting Cox Proportional Hazards Models. RESULTS: Early progressors reported a median progression-free survival (PFS) of 142 days compared to 296.5 in standard and 832 days in late progressors (p < 0.0001). Early progressors also harbored distinct and statistically significant differences in gene expression and genomic alterations, namely in DNA damage repair, glucose transport and arginine metabolism pathways. A gene signature was prognostic of PFS and overall survival in a Cox proportional hazards model. CONCLUSIONS: This data may serve as a radiogenomic biomarker to assess treatment response within early phases of treatment and allow for a personalized treatment plan.

Induced saturation transfer recovery steady states (iSTRESS) for proton exchange rate mapping with CEST MRI, a preliminary study

Proton exchange underpins essential mechanisms in diverse MR imaging contrasts. Omega plots have proven effective in mapping proton exchange rates (kex) in live human brains, enabling the differentiation of MS lesion activities and characterization of ischemic stroke. However, Omega plots require extended saturation durations (typically 5 to 10 s), resulting in high specific absorption rates (SAR) that can hinder clinical feasibility. In this study, we introduce a novel kex mapping approach, named induced Saturation Transfer Recovery Steady-States (iSTRESS). iSTRESS integrates an excitation flip angle pulse prior to chemical exchange saturation transfer (CEST) saturation, effectively aligning the magnetization with its steady-state value. This innovation reduces saturation times and mitigates SAR concerns. The formula for iSTRESS-based kex quantification was derived theoretically, involving two measurements with distinct excitation flip angles and saturation B1 values. Bloch-McConnell simulations confirmed that iSTRESS-based kex values closely matched input values (R2 > 0.99). An iSTRESS MRI sequence was implemented on a 9.4 T preclinical MRI, imaging protein phantoms with pH values ranging from 6.2 to 7.4 (n = 4). Z-spectra were acquired using excitation flip angles of 30° and 60°, followed by CEST saturation at powers of 30 and 120 Hz respectively, with a total saturation time of <1 s, resulting in two iSTRESS states for kex mapping. kex maps derived from the phantom study exhibited a linear correlation (R2 > 0.99) with Omega plot results. The developed iSTRESS method allows for kex quantification with significantly reduced saturation times, effectively minimizing SAR concerns.

Deep-learning-based super-resolution for accelerating chemical exchange saturation transfer MRI.

Chemical exchange saturation transfer (CEST) MRI is a molecular imaging tool that provides physiological information about tissues, making it an invaluable tool for disease diagnosis and guided treatment. Its clinical application requires the acquisition of high-resolution images capable of accurately identifying subtle regional changes in vivo, while simultaneously maintaining a high level of spectral resolution. However, the acquisition of such high-resolution images is time consuming, presenting a challenge for practical implementation in clinical settings. Among several techniques that have been explored to reduce the acquisition time in MRI, deep-learning-based super-resolution (DLSR) is a promising approach to address this problem due to its adaptability to any acquisition sequence and hardware. However, its translation to CEST MRI has been hindered by the lack of the large CEST datasets required for network development. Thus, we aim to develop a DLSR method, named DLSR-CEST, to reduce the acquisition time for CEST MRI by reconstructing high-resolution images from fast low-resolution acquisitions. This is achieved by first pretraining the DLSR-CEST on human brain T1w and T2w images to initialize the weights of the network and then training the network on very small human and mouse brain CEST datasetsto fine-tune the weights. Using the trained DLSR-CEST network, the reconstructed CEST source images exhibited improved spatial resolution in both peak signal-to-noise ratio and structural similarity index measure metrics at all downsampling factors (2-8). Moreover, amide CEST and relayed nuclear Overhauser effect maps extrapolated from the DLSR-CEST source images exhibited high spatial resolution and low normalized root mean square error, indicating a negligible loss in Z-spectrum information. Therefore, our DLSR-CEST demonstrated a robust reconstruction of high-resolution CEST source images from fast low-resolution acquisitions, thereby improving the spatial resolution and preserving most Z-spectrum information.

L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy.

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Using chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) to measure the tumor extracellular pH (pHe), we confirmed that L-DOS47 raises the tumor pHe from 4 h to 96 h post injection in acidic tumors (average increase of 0.13 units). Additional studies showed that combining L-DOS47 with anti-PD1 significantly increases the efficacy of the anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

Investigation of metabolite correlates of CEST in the human brain at 7 T.

Metabolite-weighted chemical exchange saturation transfer MRI can be used to indirectly image metabolites such as creatine and glutamate. This study aims to further explore the contrast of CEST at 2 ppm in the human brain at 7T and investigate the metabolite correlates of CEST at 2 ppm via correlations with magnetic resonance spectroscopy (MRS). Simulations were performed to establish the optimal acquisition parameters, such as total saturation time (tsat) and B1 root mean squared (B1rms) for CEST at 2 ppm in the human brain. Parameters were validated via in vitro phantom studies at 7T using concentrations, pH and temperature comparable to what is found in the human brain. Finally, 10 healthy volunteers were scanned at 7T for comparison with MRS. Our results show that the optimal parameters to acquire CEST at 2 ppm images are: B1rms = 2.14 μT & tsat = 1500 ms, respectively. Comparison with MRS showed no significant correlation between CEST at 2 ppm and total Creatine measured by MRS (R = 0.19; p-value = 0.273). However, a significant correlation was found between CEST at 2 ppm and Glu (R = 0.39; p-value = 0.033), indicating the broad Glutamate-weighted CEST as the main measurable contributor to CEST at 2 ppm. We identified and confirmed optimal CEST at 2 ppm sequence parameters and validated CEST at 2 ppm measurements in a controlled in vitro environment. Our findings suggest that glutamate is a substantial contributor to the CEST at 2 ppm contrast observed in the human brain, whereas the creatine contribution to CEST at 2 ppm in the brain did not show a measurable contribution.

PH Mapping of Gliomas Using Quantitative Chemical Exchange Saturation Transfer MRI: Quasi-Steady-State, Spillover-, and MT-Corrected Omega Plot Analysis.

Quantitative in-situ pH mapping of gliomas is important for therapeutic interventions, given its significant association with tumor progression, invasion, and metastasis. Although chemical exchange saturation transfer (CEST) offers a noninvasive way for pH imaging based on the pH-dependent exchange rate (ksw ), the reliable quantification of ksw in glioma remains constrained due to technical challenges. To quantify the pH of gliomas by measuring the proton exchange rate through optimized omega plot analysis. Prospective. Creatine and murine brain lysates phantoms, six rats with glioma xenograft model, and three patients with World Health Organization grade 2-4 gliomas. 11.7 T, 7.0 T, CEST imaging, T2 -weighted (T2 W) imaging, and T1 -mapping. Omega plot analysis, quasi-steady-state (QUASS) analysis, multi-pool Lorentzian fitting, amine and amide concentration-independent detection, pH enhanced method with the combination of amide and guanidyl (pHenh ), and magnetization transfer ratio (MTR) were utilized for pH metric quantification. The clinical outcomes were determined through radiologic follow-up and histopathological analysis. Mann-Whitney U test was performed to compare glioma with normal tissue, and Pearson's correlation analysis was used to assess the relationship between ksw and other parameters. In vitro experiments reveal that the determined ksw at 2 ppm increases exponentially with pH (creatine phantoms: ksw = 106 + 0.147 × 10(pH-4.198) ; lysates: ksw = 185.1 + 0.101 × 10(pH-3.914) ). Omega plot analysis exhibits a linear correlation between 1/MTRRex and 1/ω1 2 in the glioma xenografts (R2 > 0.98) and glioma patients (R2 > 0.99). The exchange rate in the rat glioma decreases compared to the contralateral normal tissue (349.46 ± 30.40 s-1 vs. 403.54 ± 51.01 s-1 , P = 0.025), while keeping independence from changes in concentration (r = 0.5037, P = 0.095). Similar pattern was observed in human data. Utilizing QUASS-based, spillover-, and MT-corrected omega plot analysis for the measurement of exchange rates, offers a feasible method for quantifying pH within glioma. NA TECHNICAL EFFICACY: Stage 1.

Preclinical Application of CEST MRI to Detect Early and Regional Tumor Response to Local Brain Tumor Treatment.

Treating glioblastoma and monitoring treatment response non-invasively remain challenging. Here, we developed a robust approach using a drug-loaded liposomal hydrogel that is mechanically compatible with the brain, and, simultaneously, we successfully monitored early tumor response using Chemical Exchange Saturation Transfer (CEST) MRI. This CEST-detectable liposomal hydrogel was optimized based on a sustainable drug release and a soft hydrogel for the brain tumor, which is unfavorable for tumor cell proliferation. After injecting the hydrogel next to the tumor, three distinctive CEST contrasts enabled the monitoring of tumor response and drug release longitudinally at 3T. As a result, a continuous tumor volume decrease was observed in the treatment group along with a significant decrease in CEST contrasts relating to the tumor response at 3.5 ppm (Amide Proton Transfer; APT) and at -3.5 ppm (relayed Nuclear Overhauser Effect; rNOE) when compared to the control group (p < 0.05). Interestingly, the molecular change at 3.5 ppm on day 3 (p < 0.05) was found to be prior to the significant decrease in tumor volume on day 5. An APT signal also showed a strong correlation with the number of proliferating cells in the tumors. This demonstrated that APT detected a distinctive decrease in mobile proteins and peptides in tumors before the change in tumor morphology. Moreover, the APT signal showed a regional response to the treatment, associated with proliferating and apoptotic cells, which allowed an in-depth evaluation and prediction of the tumor treatment response. This newly developed liposomal hydrogel allows image-guided brain tumor treatment to address clinical needs using CEST MRI.

COMET: Cross-space Optimization-based Mutual learning network for super-resolution of CEST-MRI.

Chemical Exchange Saturation Transfer Magn-etic Resonance Imaging (CEST-MRI) is a promising approach for detecting tissue metabolic changes. However, due to the constraints of scan time and contrast-noise-ratio, CEST-MRI always exhibits low spatial resolution, hindering the clinical applications especially for detection of small lesions. Many super-resolution (SR) methods have shown good performance in medical images. However, when applied to CEST-MRI, these methods have two shortcomings that may limit their performance. Firstly, CEST-MRI has an additional frequency dimension, but the information along this dimension is not fully utilized. The second is that these SR methods mainly focus on improving the quality of the CEST-weighted images, while the accuracy of the quantitative maps is the most concerned aspect for CEST-MRI. To address these shortcomings, we propose a Cross-space Optimization-based Mutual learning nETwork (COMET) for SR of CEST-MRI. COMET incorporates novel spatio-frequency extraction modules and a mutual learning module to leverage and combine information from both spatial and frequency spaces, thereby enhancing the SR performance. Furthermore, we propose a novel CEST-based normalization loss to address the normalization-induced distribution problem and preserve the sharpness of quantitative maps, enabling more accurate CEST-MRI quantification. COMET is evaluated on an ischemia rat brain dataset and a human brain dataset. The results demonstrate COMET achieves 8-fold SR, providing accurate quantitative maps. Moreover, COMET outperforms all other state-of-the-art SR methods. Additionally, COMET exhibits its potential in prospective study.

Spatiotemporal Dynamics of Neuroinflammation Relate to Behavioral Recovery in Rats with Spinal Cord Injury.

The degree and dynamic progression of neuroinflammation after traumatic spinal cord injuries (SCI) are crucial determinants of the severity of injury and potential for recovery. We used Positron Emission Tomography (PET) to monitor neuroinflammation longitudinally, correlating it with Chemical Exchange Saturation Transfer (CEST) Magnetic Resonance Imaging (MRI) and behavior in contusion-injured rats. These studies help validate CEST metrics and confirm how imaging may be used to evaluate the efficacy of therapies and understand their mechanisms of action. 12 SCI and 4 sham surgery rats were subjected to CEST MRI and PET-Translocator Protein (TSPO) scans for 8weeks following injury. Z-spectra from the SCI were analyzed using a 5-Lorentzian pool model for fitting. Weekly motor and somatosensory behavior were correlated with imaging metrics, which were validated through post-mortem histological and immuo-staining using ionized calcium-binding adaptor protein-1 (iba-1, microglia) and glial fibrillary acidic protein (GFAP, astrocytes). PET-TSPO showed widespread inflammation and post-mortem histology confirmed the presence of activated microglia. Changes in CEST and nuclear Overhauser Effect (NOE) peaks at 3.5ppm and -1.6ppm respectively were largest within the first week after injury and more pronounced in rostral versus caudal segments. These temporal indices of neuroinflammation corresponded to the recovery of locomotor behaviors and somatic sensation in rats with moderate contusion injury. The results confirm that CEST MRI metrics are sensitive indices of states of neuroinflammation within injured spinal cords. The detection of dynamic spatiotemporal features of neuroinflammation progression underscores the importance of considering their timings and locations for neuroprotective and anti-inflammatory therapies. The availability of noninvasive MRI indices of neuroinflammation may facilitate clinical trials aimed at treatments that promote recovery after SCI.

Corrections for Rabi oscillations in cardiac chemical exchange saturation transfer MRI under the influence of very short preparation pulses.

Very short chemical exchange saturation transfer (CEST) pulses are beneficial in cardiac continuous wave (cw) CEST MRI, especially in small animals because of their rapid heartbeat; however, they result in signal modulations caused by Rabi oscillations. Therefore, we implemented two different filter techniques, DOwnsampling by SEparation of CEST spectrum into two parts (DOSE) and time domain (TD)-based filtering, to correct for these signal corruptions, allowing a reliable quantification of glucose-weighted CEST (glucoCEST) MRI contrast. In our study, cw CEST measurements were performed on a 9.4-T small animal BioSpec system using CEST pulses in the range of 10 to 200 ms. Experimental dependencies of Rabi oscillations on key MRI parameters were validated by Bloch-McConnell (BM) simulations. Filter efficiency was explored in a glucose concentration series as well as in the myocardium of healthy mice (n = 8), and glucoCEST contrast was subsequently quantified. The experimental results showed that the impact of Rabi oscillations on CEST spectra increased with decreasing CEST pulse length, optimized B0 homogeneity, and shorter T2 relaxation time, in accordance with results from BM simulations. Both investigated filter techniques reduced these signal modulations significantly, with DOSE filtering preserving the amplitude and TD filtering the spectral information of CEST data more accurately. Upon filter application, a significant decrease in glucoCEST contrast in the myocardium of healthy mice was observed after glucose infusion (pTD = 0.0079, pDOSE = 0.0044). To conclude, this study offers comprehensive experimental insights into Rabi oscillations within CEST MRI data along with methodological considerations that could be further advanced into a robust and precise cardiac cw CEST protocol by integrating DOSE and TD filtering into the standard CEST analysis pipeline.

Metabolic brain imaging with glucosamine CEST MRI: in vivo characterization and first insights

The utility of chemical exchange saturation transfer (CEST) MRI for monitoring the uptake of glucosamine (GlcN), a safe dietary supplement, has been previously demonstrated in detecting breast cancer in both murine and human subjects. Here, we studied and characterized the detectability of GlcN uptake and metabolism in the brain. Following intravenous GlcN administration in mice, CEST brain signals calculated by magnetization transfer ratio asymmetry (MTRasym) analysis, were significantly elevated, mainly in the cortex, hippocampus, and thalamus. The in vivo contrast remained stable during 40 min of examination, which can be attributed to GlcN uptake and its metabolic products accumulation as confirmed using 13C NMR spectroscopic studies of brain extracts. A Lorentzian multi-pool fitting analysis revealed an increase in the hydroxyl, amide, and relayed nuclear Overhauser effect (rNOE) signal components after GlcN treatment. With its ability to cross the blood-brain barrier (BBB), the GlcN CEST technique has the potential to serve as a metabolic biomarker for the diagnosis and monitoring various brain disorders.

Improved postprocessing of dynamic glucose-enhanced CEST MRI for imaging brain metastases at 3 T

BackgroundDynamic glucose-enhanced (DGE) chemical exchange saturation transfer (CEST) has the potential to characterize glucose metabolism in brain metastases. Since the effect size of DGE CEST is small at 3 T (< 1%), measurements of signal-to-noise ratios are challenging. To improve DGE detection, we developed an acquisition pipeline and extended image analysis for DGE CEST on a hybrid 3-T positron emission tomography/magnetic resonance imaging system.MethodsThis cross-sectional study was conducted after local ethical approval. Static Z-spectra (from -100 to 100 ppm) were acquired to compare the use of 1.2 versus 2 ppm to calculate static glucose-enhanced (glucoCEST) maps in 10 healthy volunteers before and after glucose infusion. Dynamic CEST images were acquired during glucose infusion. Image analysis was optimized using motion correction, dynamic B0 correction, and principal component analysis (PCA) to improve the detection of DGE CEST in the sagittal sinus, cerebrospinal fluid, and grey and white matter. The developed DGE CEST pipeline was applied to four patients diagnosed with brain metastases.ResultsGlucoCEST was strongest in healthy tissues at 2 ppm. Correcting for motion, B0, and use of PCA locally improved DGE maps. A larger contrast between healthy tissues and enhancing regions in brain metastases was found when dynamic B0 correction and PCA denoising were applied.ConclusionWe demonstrated the feasibility of DGE CEST with our developed acquisition and analysis pipeline at 3 T in patients with brain metastases. This work enables a direct comparison of DGE CEST to 18F-fluoro-deoxy-D-glucose positron emission tomography of glucose metabolism in patients with brain metastases.Relevance statementContrast between brain metastasis and healthy brain tissue in DGE CEST MR images is improved by including principle component analysis and dynamic magnetic field correction during postprocessing. This approach enables the detection of increased DGE CEST signal in brain metastasis, if present.Key points• Despite the low signal-to-noise ratio, dynamic glucose-enhanced CEST MRI is feasible at 3 T.• Principal component analyses and dynamic magnetic field correction improve DGE CEST MRI.• DGE CEST MRI does not consequently show changes in brain metastases compared to healthy brain tissue.• Increased DGE CEST MRI in brain metastases, if present, shows overlap with contrast enhancement on T1-weighted images.Graphical

Abstract B125: Neutralizing acidosis with L-DOS47 urease immunoconjugate enhances responses to anti-PD1 checkpoint blockade in a preclinical orthotopic model of pancreatic adenocarcinoma

Abstract Background: Acidosis in the tumor microenvironment is an important immunosuppressive mechanism that leads to tumor growth. We have shown that neutralization of tumor pH using sodium bicarbonate improves responses to immune checkpoint blockade (ICB) in pre-clinical models, but phase I/IIa clinical trials failed due to poor patient compliance. Thus, we aimed to test clinically translatable agents to neutralize tumor acidity and improve cancer outcomes in response to ICB. We tested L-DOS47, a targeted urease immunoconjugate designed to directly neutralize tumor acidity that has been well-tolerated in phase I/IIa trials. The nanobody component of L-DOS47 binds carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6), a cell surface protein highly expressed in gastrointestinal and lung cancers; the urease moiety cleaves endogenous urea into two NH4+ and one CO2 thereby raising local pH. Materials and Methods: Immunohistochemistry screening for CEACAM6 expression and L-DOS47 binding was performed on tumor microarrays from pancreatic ductal adenocarcinoma (PDAC) cases (n=10 plus 2 normal tumor adjacent cases). We established a preclinical in vivo PDAC model by orthotopically inoculating human CEACAM6-expressing KPC961 into immunocompetent mice. Pharmacodynamic studies were performed using chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) to measure tumor extracellular pH (pHe) at baseline (pre-L-DOS47) and at various time points post-L-DOS47 (4, 18, 24, 48, 72 and 96 hours). Mean tumor pHe and histograms of pHe distributions were compared among groups. Additional biological replicates were conducted to assess therapeutic efficacy. For these experiments, mice were randomized, after measurable tumors are established, into groups with equal tumor volume averages to initiate twice-weekly therapies with 300 µg anti-PD1 or 90 µg/kg L-DOS47 monotherapies, 300 µg anti-PD1 + 90 µg/kg L-DOS47 compared to a control group receiving no therapy. Tumor volumes were measured weekly by ultrasound imaging up to 4 weeks. Results: Immunohistochemistry screening of patient tumor microarrays confirmed high CEACAM6 expression and L-DOS47 binding to PDAC tissues. CEST-MRI results showed that L-DOS47 increased tumor pHe from 4h to 96h post-injection; however, pHe increases were only evident in tumors with baseline pHe ≤ 6.60. Efficacy studies in the PDAC model showed that the combination of anti-PD1 + L-DOS47 significantly reduced tumor growth when compared with control, L-DOS47 and anti-PD1 groups at week 3 (p&amp;lt;.0001; &amp;lt;.0001 and 0.0368, respectively) and week 4 (p&amp;lt;.0001; &amp;lt;.0001 and 0.0142, respectively). Conclusion: These studies provide strong evidence that L-DOS47, by neutralizing acidic tumor pH, significantly improves responses to anti-PD1 immunotherapy. Citation Format: Bruna V Jardim-Perassi, Pietro Irrera, Dominique Abrahams, Christopher J Whelan, Matthew S Beatty, Samantha R Byrne, Andrew A Odeja, Dario L Longo, Young Ou, Kim Gaspar, Martin Koebel, Shari A Pilon-Thomas, Christof Boehler, Gabrielle M Siegers, Robert J Gillies, Arig A Ibrahim-Hashim. Neutralizing acidosis with L-DOS47 urease immunoconjugate enhances responses to anti-PD1 checkpoint blockade in a preclinical orthotopic model of pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B125.

Novel Nanoprobe with Combined Ultrasonography/Chemical Exchange Saturation Transfer Magnetic Resonance Imaging for Precise Diagnosis of Tumors.

Given that cancer mortality is usually due to a late diagnosis, early detection is crucial to improve the patient's results and prevent cancer-related death. Imaging technology based on novel nanomaterials has attracted much attention for early-stage cancer diagnosis. In this study, a new block copolymer, poly(ethylene glycol)-poly(l-lactide) diblock copolymer (PEG-PLLA), was synthesized by the ring-opening polymerization method and thoroughly characterized using Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance spectroscopy (H-NMR), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). The obtained PEG-PLLA was used to prepare nanoparticles encapsulated with perfluoropentane and salicylic acid by the emulsion-solvent evaporation method, resulting in a new dual-mode nano-image probe (PEG-PLLA@SA·PFP). The zeta potential and mean diameter of the obtained nanoparticles were measured using dynamic light scattering (DLS) with a Malvern Zetersizer Nano. The in vitro biocompatibility of the PEG-PLLA nanoparticles was evaluated with cell migration, hemolysis, and cytotoxicity assays. Ultrasonic imaging was performed using an ultrasonic imaging apparatus, and chemical exchange saturation transfer (CEST) MRI was conducted on a 7.0 T animal scanner. The results of IR and NMR confirmed that the PEG-PLLA was successfully synthesized. The particle size and negative charge of the nanoparticles were 223.8 ± 2.5 nm and -39.6 ± 1.9 mV, respectively. The polydispersity of the diameter was 0.153 ± 0.020. These nanoparticles possessed good stability at 4 °C for about one month. The results of cytotoxicity, cell migration, and hemolysis assays showed that the carrier material was biocompatible. Finally, PEG-PLLA nanoparticles were able to significantly enhance the imaging effect of tumors by the irradiation of ultrasound and saturation by a radiofrequency pulse, respectively. In conclusion, these nanoparticles exhibit promising dual-mode capabilities for US/CEST MR imaging.

Dynamic and rapid deep synthesis of chemical exchange saturation transfer and semisolid magnetization transfer MRI signals

Model-driven analysis of biophysical phenomena is gaining increased attention and utility for medical imaging applications. In magnetic resonance imaging (MRI), the availability of well-established models for describing the relations between the nuclear magnetization, tissue properties, and the externally applied magnetic fields has enabled the prediction of image contrast and served as a powerful tool for designing the imaging protocols that are now routinely used in the clinic. Recently, various advanced imaging techniques have relied on these models for image reconstruction, quantitative tissue parameter extraction, and automatic optimization of acquisition protocols. In molecular MRI, however, the increased complexity of the imaging scenario, where the signals from various chemical compounds and multiple proton pools must be accounted for, results in exceedingly long model simulation times, severely hindering the progress of this approach and its dissemination for various clinical applications. Here, we show that a deep-learning-based system can capture the nonlinear relations embedded in the molecular MRI Bloch–McConnell model, enabling a rapid and accurate generation of biologically realistic synthetic data. The applicability of this simulated data for in-silico, in-vitro, and in-vivo imaging applications is then demonstrated for chemical exchange saturation transfer (CEST) and semisolid macromolecule magnetization transfer (MT) analysis and quantification. The proposed approach yielded 63–99% acceleration in data synthesis time while retaining excellent agreement with the ground truth (Pearson’s r > 0.99, p < 0.0001, normalized root mean square error < 3%).

Glycerol-weighted chemical exchange saturation transfer nanoprobes allow 19F/1H dual-modality magnetic resonance imaging-guided cancer radiotherapy

Recently, radiotherapy (RT) has entered a new realm of precision cancer therapy with the introduction of magnetic resonance (MR) imaging guided radiotherapy systems into the clinic. Nonetheless, identifying an optimized radiotherapy time window (ORTW) is still critical for the best therapeutic efficacy of RT. Here we describe pH and O2 dual-sensitive, perfluorooctylbromide (PFOB)-based and glycerol-weighted chemical exchange saturation transfer (CEST) nano-molecular imaging probes (Gly-PFOBs) with dual fluorine and hydrogen proton based CEST MR imaging properties (19F/1H-CEST). Oxygenated Gly-PFOBs ameliorate tumor hypoxia and improve O2-dependent radiotherapy. Moreover, the pH and O2 dual-sensitive properties of Gly-PFOBs could be quantitatively, spatially, and temporally monitored by 19F/1H-CEST imaging to optimize ORTW. In this study, we describe the CEST signal characteristics exhibited by the glycerol components of Gly-PFOBs. The pH and O2 dual-sensitive Gly-PFOBs with19F/1H-CEST MR dual-modality imaging properties, with superior therapeutic efficacy and biosafety, are employed for sensitive imaging-guided lung cancer RT, illustrating the potential of multi-functional imaging to noninvasively monitor and enhance RT-integrated effectiveness.

Natalizumab Treatment for Relapsing Multiple Sclerosis Stabilises Normal-Appearing White Matter Microstructure: A One-Year Prospective Ultra-High-Field Quantitative Imaging Study.

(1) Background: Natalizumab dramatically reduces relapses and MRI inflammatory activity (new lesions and enhancing lesions) in multiple sclerosis (MS). Chemical exchange saturation transfer (CEST) MRI can explore brain tissue in vivo with high resolution and sensitivity. We investigated if natalizumab can prevent microstructural tissue damage progression measured with MRI at ultra-high field (7 Tesla) over the first year of treatment. (2) Methods: In this one-year prospective longitudinal study, patients with active relapsing-remitting MS were assessed clinically and scanned at ultra-high-field MRI at the time of their first natalizumab infusion, at 6 and 12 months, with quantitative imaging aimed to detect microstructural changes in the normal-appearing white matter (NAWM), including sequences sensitive to magnetisation transfer (MT) effects from amide proton transfer (MTRAPT) and the nuclear Overhauser effect (MTRNOE). (3) Results: 12 patients were recruited, and 10 patients completed the study. The difference in the T1 relaxation times at month 6 and month 12 of natalizumab treatment was not significant, suggesting the lack of accumulation of tissue damage, while improvements were seen in MTR (MTRAPT and MTRNOE measures) at month 12, suggesting a tissue repair effect. This paralleled the expected lack of clinical and radiological worsening of conventional MRI measures of disease activity (new lesions or gadolinium-enhancing lesions). (4) Conclusion: Natalizumab prevents microstructural brain damage and has effects suggesting an improved white matter microstructure measured at ultra-high field during the first year of treatment.

Quantitative Assessment of Peripheral Oxidative Metabolism With a New Dynamic 1H MRI Technique: A Pilot Study in People With and Without Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is linked to impaired mitochondrial function. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is a gadolinium-contrast-free 1H method to assess mitochondrial function by measuring low-concentration metabolites. A CEST MRI-based technique may serve as a non-invasive proxy for assessing mitochondrial health. A 1H CEST MRI technique may detect significant differences in in vivo skeletal muscle phosphocreatine (SMPCr) kinetics between healthy volunteers and T2DM patients undergoing standardized isometric exercise. Cross-sectional study. Seven subjects without T2DM (T2DM-) and seven age, sex, and BMI-matched subjects with T2DM (T2DM+). Single-shot rapid acquisition with refocusing echoes (RARE) and single-shot gradient-echo sequences, 3 T. Subjects underwent a rest-exercise-recovery imaging protocol to dynamically acquire SMPCr maps in calf musculature. Medial gastrocnemius (MG) and soleus SMPCr concentrations were plotted over time, and SMPCr recovery time, , was determined. Mitochondrial function index was calculated as the ratio of resting SMPCr to . Participants underwent a second exercise protocol for imaging of skeletal muscle blood flow (SMBF), and its association with SMPCr was assessed. Unpaired t-tests and Pearson correlation coefficient. A P value <0.05 was considered statistically significant. SMPCr concentrations in MG and soleus displayed expected declines during exercise and returns to baseline during recovery. was significantly longer in the T2DM+ cohort (MG 83.5 ± 25.8 vs. 54.0 ± 21.1, soleus 90.5 ± 18.9 vs. 51.2 ± 14.5). The mitochondrial function index in the soleus was significantly lower in the T2DM+ cohort (0.33 ± 0.08 vs. 0.66 ± 0.19). SMBF was moderately correlated with the SMPCr in T2DM-; this correlation was not significant in T2DM+ (r = -0.23, P = 0.269). The CEST MRI method is feasible for quantifying SMPCr in peripheral muscle tissue. T2DM+ individuals had significantly lower oxidative capacities than T2DM- individuals. In T2DM, skeletal muscle metabolism appeared to be decoupled from perfusion. 1 TECHNICAL EFFICACY: Stage 1.