evaluations-oxygenation-vascular-perfusion-pre-clinical-models-cancer

Evaluations of Oxygenation and Vascular Perfusion in Pre-Clinical Models of Cancer and Wound Healing Using OS-DCE OAI

Oxygen-sensitive optoacoustic imaging (OS OAI) and dynamic contrast&#8211;enhanced optoacoustic imaging (DCE OAI) provide complementary, noninvasive ...

University of Wisconsin

Electron Paramagnetic Resonance Imaging (EPRI) can image the partial pressure of oxygen (pO) within in vivo tumor models. We sought to develop Oxygen Enhanced (OE) EPRI that measures tumor pO with breathing gases of 21% O (pO) and 100% O (pO), and the differences in pO between breathing gases (ΔpO). We applied OE EPRI to study the early change in tumor pathophysiology in response to radiotherapy in two tumor models of pancreatic cancer.

Evaluations of an Early Change in Tumor Pathophysiology in Response to Radiotherapy with Oxygen Enhanced Electron Paramagnetic Resonance Imaging (OE EPRI).

Preclinical models of cutaneous wound healing can be useful for improving clinical wound care. Oxygen Enhanced Photoacoustic imaging (OE PAI) can measure oxygenation, and Dynamic Contrast Enhanced (DCE) PAI can measure vascular perfusion. We investigated how a combined OE-DCE PAI protocol can measure vascular oxygenation and perfusion to a cutaneous healing model.

Evaluations of a Cutaneous Wound Healing Model Using Oxygen Enhanced - Dynamic Contrast Enhanced Photoacoustic Imaging (OE-DCE PAI).

A swelling probe for nitric oxide.

Solid crystalline spin probes, such as lithium phthalocyanine (LiPc) and lithium octa-n-butoxynaphthalocyanine (LiNc-BuO), allow repeated oxygen measurement using electron paramagnetic resonance (EPR). Due to their short relaxation times, their use for pulse EPR oxygen imaging is limited. In this study, we developed and tested a new class of solid composite spin probes that modified the relaxation rates R and R of LiPc or LiNc-BuO probes, which allowed pO measurements in the full dynamic (0-760 torr) range.

Composite spin probes with adjustable oxygen sensitivity for pulse electron paramagnetic resonance imaging.

Tumor acidosis causes resistance to immune checkpoint blockade (ICB). We hypothesized that a "pH-sensitizer" can increase tumor extracellular pH (pHe) and improve tumor control following ICB. We also hypothesized that pHe measured with acidoCEST MRI can predict improved tumor control with ICB.

Potentiation of immune checkpoint blockade with a pH-sensitizer as monitored in two pre-clinical tumor models with acidoCEST MRI.

Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRTs). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved antimalarial drug, atovaquone (AVO). We then establish the utility of oxygen-enhanced-multispectral optoacoustic tomography, a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment that results in complete elimination of tumors in all tested mice when combined with 10-gray radiotherapy, a dose several times lower than the current clinic standard. Last, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual patient cohort. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.

Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.

Hypoxia in the tumor microenvironment hinders antitumor immunity. Increasing tumor oxygenation may promote T cell infiltration and tumor control by immune checkpoint blockade (ICB). We found that a radiosensitizer, myo-inositol trispyrophosphate (ITPP), caused oxygen unloading from hemoglobin in CT26 and 4T1 tumors as indicated by photoacoustic imaging (PAI). This change in hypoxia detected by PAI was correlated with strong positive correlations with CD8+ and CD4+ FoxP3- effector T cell (Teff), and negative correlations with monocyte frequencies, indicating that ITPP promoted more immunogenic tumor microenvironments in both models. Combination ITPP and ICB improved tumor control and survival in both models. Therefore, imaging ITPP-modulated tumor hypoxia with PAI was related to ICB treatment response in these studies. Future combination immunotherapy regimens may benefit from monitoring hypoxia using molecular imaging with PAI.

Potentiation of immune checkpoint blockade with an ITPP radiosensitizer studied with oxygen saturation measurements from photoacoustic imaging.

Accurate spatiotemporal image reconstruction methods are needed for a wide range of biomedical research areas but face challenges due to data incompleteness and computational burden. Data incompleteness arises from the undersampling often required to increase frame rates, while computational burden emerges due to the memory footprint of high-resolution images with three spatial dimensions and extended time horizons. Neural fields (NFs), an emerging class of neural networks that act as continuous representations of spatiotemporal objects, have previously been introduced to solve these dynamic imaging problems by reframing image reconstruction as a problem of estimating network parameters. Neural fields can address the twin challenges of data incompleteness and computational burden by exploiting underlying redundancies in these spatiotemporal objects. This work proposes ProxNF, a novel neural field training approach for spatiotemporal image reconstruction leveraging proximal splitting methods to separate computations involving the imaging operator from updates of the network parameters. Specifically, ProxNF evaluates the (subsampled) gradient of the data-fidelity term in the image domain and uses a fully supervised learning approach to update the neural field parameters. This method is demonstrated in two numerical phantom studies and an in-vivo application to tumor perfusion imaging in small animal models using dynamic contrast-enhanced photoacoustic computed tomography (DCE PACT).

ProxNF: Neural Field Proximal Training for High-Resolution 4D Dynamic Image Reconstruction.

The clinical utility of conventional DCE-MRI methods is limited by the use of conventional qualitative dynamic T-weighted images, resulting in poor reproducibility. This study presents the initial implementation of a new DCE-magnetic resonance fingerprinting (DCE-MRF) methodology to provide reproducible, quantitative assessments of tumor vascular perfusion.

Dynamic contrast enhanced-magnetic resonance fingerprinting (DCE-MRF): A new quantitative MRI method to reliably assess tumor vascular perfusion.

The FLASH effect occurs when radiation given at ultra-high dose rates spares healthy tissue while achieving isoeffective tumor control relative to conventional (CONV) dose rate irradiation. Limited data has implicated oxygen in the FLASH effect. This study investigated the effect of tissue oxygen tension (pO) on gastrointestinal (GI) FLASH sparing in mice.

Investigating the oxygen dependence of FLASH-RT using electron paramagnetic resonance imaging.

Dynamic contrast-enhanced MRI (DCE-MRI) can assess tumor perfusion using pharmacokinetic models. However, poor DCE-MRI reproducibility from reliance on conventional T-weighted MRI has limited clinical translation. We evaluated whether Dynamic Contrast Enhanced-Magnetic Resonance Fingerprinting (DCE-MRF), which directly generates quantitative T relaxation time constant maps, provides improved precision and statistical power for detecting treatment-induced vascular changes compared to conventional DCE-MRI.

Dynamic Contrast Enhanced-Magnetic Resonance Fingerprinting (DCE-MRF) Improves Detection of Induced Vascular Perfusion Reduction in a Mouse Breast Cancer Model.

Article	Year
Evaluations of an Early Change in Tumor Pathophysiology in Response to Radiotherapy with Oxygen Enhanced Electron Paramagnetic Resonance Imaging (OE EPRI). Molecular imaging and biology\| PubMed ID: 38869818	2024
Evaluations of a Cutaneous Wound Healing Model Using Oxygen Enhanced - Dynamic Contrast Enhanced Photoacoustic Imaging (OE-DCE PAI). Molecular imaging and biology\| PubMed ID: 39532769	2024
A swelling probe for nitric oxide. Nature materials\| PubMed ID: 39753857	2025
Composite spin probes with adjustable oxygen sensitivity for pulse electron paramagnetic resonance imaging. Magnetic resonance in medicine\| PubMed ID: 39831522	2025
Potentiation of immune checkpoint blockade with a pH-sensitizer as monitored in two pre-clinical tumor models with acidoCEST MRI. British journal of cancer\| PubMed ID: 39994445	2025
Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy. Science advances\| PubMed ID: 40408469	2025
Potentiation of immune checkpoint blockade with an ITPP radiosensitizer studied with oxygen saturation measurements from photoacoustic imaging. Scientific reports\| PubMed ID: 40594309	2025
ProxNF: Neural Field Proximal Training for High-Resolution 4D Dynamic Image Reconstruction. IEEE transactions on computational imaging\| PubMed ID: 40726753	2024
Dynamic contrast enhanced-magnetic resonance fingerprinting (DCE-MRF): A new quantitative MRI method to reliably assess tumor vascular perfusion. Magnetic resonance in medicine\| PubMed ID: 40808280	2025
Investigating the oxygen dependence of FLASH-RT using electron paramagnetic resonance imaging. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology\| PubMed ID: 41389858	2026
Dynamic Contrast Enhanced-Magnetic Resonance Fingerprinting (DCE-MRF) Improves Detection of Induced Vascular Perfusion Reduction in a Mouse Breast Cancer Model. Magnetic resonance in medicine\| PubMed ID: 41621439	2026

Mark D. Pagel

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