ISSN# 1545-4428 | Published date: 19 April, 2024
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At-A-Glance Session Detail
   
Therapeutic Evaluations in Animal Models
Oral
Preclinical
Monday, 06 May 2024
Room 325-326
13:45 -  15:45
Moderators: Durga Udayakumar & Bram Coolen
Session Number: O-66
CME Credit

13:450162.
Prolonged Central Thalamic Intermittent Theta-Burst Stimulation Rescued Memory Deficits in Alzheimer's Disease Mouse Model
Yi-Chen Lin1, Ssu-Ju Li1, Yu-Chun Lo2, Yun-Ting Liu1, Yi-Chun Lee3, Ting-Chieh Chen1, Ching-Wen Chang1, Yao-Wen Liang1, Ching-Te Chen4, Sheng-Huang Lin5,6, and You-Yin Chen1,2
1Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan, 2PhD Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, 3School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, 4Abbott Neuromodulation, Austin, TX, United States, 5Department of Neurology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, 6Department of Neurology, School of Medicine, Tzu Chi University, Hualien, Taiwan

Keywords: Alzheimer's Disease, Alzheimer's Disease, Intermittent theta-burst stimulation (iTBS)

Motivation: Addressing the global AD crisis by investigating CT-iTBS as a non-pharmacological treatment to enhance memory and cognition.

Goal(s): To explore the therapeutic efficacy and determine the optimal treatment protocol of CT-iTBS in AD while unveiling its potential underlying mechanism for enhancing memory and cognitive functions.

Approach: Utilized brain magnetic resonance imaging analysis, behavioral tests, and immunofluorescence staining for assessing the therapeutic effect of different durations of CT-iTBS treatment.

Results: Prolonged CT-iTBS significantly enhanced cognitive and memory behaviors, altered brain functional connectivity, promoted a neuroprotective effect, and reduced amyloid accumulation in AD mouse model. These findings present a promising therapeutic avenue for AD patients.

Impact: Our findings revealed a highly promising avenue for enhancing the quality of life for individuals with AD and provided insights into the potential underlying neuroprotective mechanisms of CT-iTBS in alleviating memory deficits.

13:570163.
Longitudinal study tracking physiological changes through multiparametric MRI during repeated MRgFUS-induced BBB opening
Sébastien Rigollet1,2, Thomas Ador3,4, Erik Dumont1, Chantal Pichon3,4,5, Emmanuel Barbier2,6, Anthony Delalande3,4, and Vasile Stupar2,6
1Image Guided Therapy, Pessac, France, 2Univ. Grenoble Alpes, Inserm U1216, Grenoble Institut des Neurosciences, Grenoble, France, 3Université d’Orléans, CNRS, UPR 4301, Centre de Biophysique Moléculaire, Orléans, France, 4ART ARNm, Inserm UMS55 and University of Orléans, Orléans, France, 5Institut Universitaire de Paris, Paris, France, 6Univ. Grenoble Alpes, Inserm , CHU Grenoble Alpes, CNRS, IRMaGe, Grenoble, France

Keywords: Small Animals, Focused Ultrasound, MR-guided FUS, Multiparametric MRI

Motivation: Long-term delivery of therapeutic agents via repeated MRgFUS is an innovative approach for enhancing glioblastoma treatment but underlying mechanisms are not well documented.

Goal(s): Find the best strategy for long-term drug delivery after multiple MRgFUS mediated BBB opening.

Approach: Repeated MRgFUS treatments were delivered up to 8 sessions over one month along with a multi-parametric MRI protocol follow-up to measure physiological, hemodynamic and oxygenation parameters in order to assess the safety and effectiveness of the procedure.

Results: Intensive, repeated treatments, may lead to tissue modifications that require attention and limit the frequency of ultrasound mediated drug delivery to once a week.

Impact: Long-term delivery of therapeutics through a FUS-induced permeabilized BBB redefines therapeutic strategies as it improves patient outcomes. To ensure the best translation towards clinical treatment, evaluation of hemodynamics and oxygenation modifications in the CNS is necessary to refine treatment parameters.

14:090164.
Sustained Tumour Response to Repeated STING Activation Assessed by Diffusion Weighted MRI
Upasana Roy1, Carol Box1, Malin Pedersen1, Jessica K. R. Boult1, Antonio Rullan1, Michael Schmohl2, Mario Amend2, Sebastian Carotta3, Anne Vogt3, Kevin J. Harrington1, and Simon P. Robinson1
1Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom, 2Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany, 3Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

Keywords: Biology, Models, Methods, Cancer, Biomarker

Motivation: Cancer immunotherapy with cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) agonists aims to generate an immune response by T cell priming, activation and infiltration into the tumour microenvironment leading to cell death.

Goal(s): The clinical development of STING agonists would benefit from imaging biomarkers that inform on intratumoural pharmacodynamics and potentially anti-tumour response.

Approach: Longitudinal diffusion-weighted MRI in a thyroid xenograft model indicated sustained increase in ADC as an imaging biomarker of tumour microenvironment changes following treatment with a STING agonist.

Results: The potential use of MRI as an indicator of early STING pathway related pharmacodynamic effects in situ is demonstrated.

Impact: Increased ADC is a sensitive, clinically-translatable imaging biomarker of tumour response to a STING agonist.

14:210165.
Hyperpolarized 129Xe MRI of the Irradiated Lung using a Chemical Shift Imaging – Chemical Shift Saturation Recovery (CSI-CSSR) Technique
Luis Loza1, Kai Ruppert1, Yohn Taylor2, Jiawei Chen1, Faraz Amzajerdian1, Mostafa Ismail1, Hooman Hamedani1, Harrilla Profka1, Ian Duncan1, and Rahim Rizi1
1University of Pennsylvania, Philadelphia, PA, United States, 2University College London, London, United Kingdom

Keywords: Small Animals, Hyperpolarized MR (Gas), RILI, radiation, CSSR

Motivation: Chemical shift saturation recovery (CSSR) measurements are incredibly useful for quantifying pulmonary gas exchange and uptake; because CSSR is a spectroscopic technique, however, such measures are only global in nature. 

Goal(s): Our goal was to develop an imaging-based technique for spatially-resolving CSSR measurements.

Approach: We demonstrated our technique’s utility in a rodent model of radiation-induced lung injury.

Results: Images of hyperpolarized-129Xe dissolved in the pulmonary membrane (Mem) and red blood cells (RBC) showed higher Mem signal and reduced RBC signal in radiated vs non-radiated lungs. Septal wall thickness (SWT) measurements derived on a quadrant level also revealed elevated SWT in the irradiated region.

Impact: We demonstrated a new imaging technique for regionally quantifying radiation-induced alterations in pulmonary gas exchange and uptake. This study lays the groundwork for future investigations aimed at improving radiotherapy strategies, mitigating radiotoxicity, and treating radiation-associated illness. 

14:330166.
Multi-Modal Protein-Engineered Theranostic Fibers: Drug encapsulation, Imaging, and enhanced 19F MRS
Dustin Britton1, Jakub Legocki1,2, Orlando Aristizabal3, Orin Mishkit3, Chengliang Liu1, Sihan Jia1, Paul Douglas Renfrew4, Richard Bonneau4,5,6, Jin Kim Montclare1,3,7,8, and Youssef Z Wadghiri3
1Department of Chemical and Biomolecular Engineering, NYU Tandon, Brooklyn, NY, United States, 2New York University, Brooklyn, NY, United States, 3Department of Radiology, NYU Grossman School of Medicine, New York, NY, United States, 4Flatiron Institute - Simons Foundation, New York City, NY, United States, 5Computer Science Department, NYU Courant, New York City, NY, United States, 6Center for Genomics and Systems Biology, NYU, New York, NY, United States, 7Chemistry, NYU, New York, NY, United States, 8Department of Biomaterials, NYU College of Dentistry, New York, NY, United States

Keywords: Probes & Targets, Multimodal, theranostic, temperature probe, fluorine

Motivation: Theranostic materials allows for simultaneous therapeutic and diagnostic disease intervention.

Goal(s): We aimed to engineer a protein-based theranostic with multiple imaging modalities.

Approach: Using noncannonical amino acid incorporation of trifluoroleucine (TFL), we synthesize fluorinated coiled-coil, Q2TFL, imageable by 1H MRI and high-frequency ultrasound, and sensitive to 19F MRS.

Results: Q2TFL demonstrates reduced signal contrast in 1H MRI, echogenic signals under high-frequency ultrasound, and enhances sensitivity in linear ratiometric 19F MRS. This allows for thermoresponsiveness and potential protein conformation analysis. Q2TFL serves as a promising platform for versatile and effective theranostic agents, bringing together therapeutic and diagnostic modalities in a compact and efficient manner.

Impact: Q2TFL, a fluorinated protein fiber, enables drug delivery and offers unique multimodal imaging. It acts as a temperature probe and protein structure monitor, paving the way for innovative theranostic biomaterials.

14:450167.
An MRI-visible mesenchymal stem cell therapy reinvigorates T lymphocytes in glioblastoma
Jianing Li1, Ruichen Yang1, Junwei Chen1, Qin Wen1, Kan Deng2, Jiaji Mao1, and Jun Shen1
1Department of Radiology, Sun Yat-Sen University, Sun Yat-Sen Memorial Hospital, Guangzhou, China, 2Philips Healthcare, Guangzhou, China

Keywords: Probes & Targets, MR-Guided Interventions, Glioblastoma, Mesenchymal stem cells

Motivation: Immunotherapy resistance in glioblastoma (GBM) has been linked to a paucity of tumor-infiltrating T lymphocytes and concurrent T-cell dysfunction.

Goal(s): This research aims to determine whether MRI-visible mesenchymal stem cells (MSCs) could be employed for GBM immunotherapy.

Approach: CXCL10-Nrf2-FTH-MSCs with enhanced T lymphocyte recruitment (Cxcl10 gene), oxidative stress tolerance (Nrf2 gene), and MRI visibility (Fth gene) were genetically engineered. With the guidance of FTH-MRI, these MSCs were injected into the tumor periphery of orthotopic GL261 GBMs in mice.

Results: In vivo MRI monitoring and histology examinations demonstrated that CXCL10-Nrf2-FTH-MSCs can significantly limit GBM growth by reviving T lymphocytes within the tumor.

Impact: FTH-MRI is a practical method for guiding intracranial stem cell transplantation. MRI-guided peritumoral implantation of CXCL10-Nrf2-FTH-MSCs provides a novel immunotherapeutic approach based on tumoricidal stem cells for the treatment of GBM.

14:570168.
Metabolic detection of BTK inhibition in mantle cell lymphoma models
Kavindra Nath1, Pradeep Gupta1, Stepan Orlovskiy1, Neil Sen2, Shengchun Wang2, Jyoti Tomar1, David Nelson1, Fernando Arias-Mendoza1,3, Jerry Glickson1, and Mariusz Wasik2
1University of Pennsylvania, Philadelphia, PA, United States, 2Fox Chase Cancer Center, Philadelphia, PA, United States, 3Advanced Imaging Research, Inc., Cleveland, OH, United States

Keywords: Biology, Models, Methods, Cancer, BTK inhibition, mantle cell lymphoma models, early metabolic biomarker of response, 1H MRS with slice selective double frequency Hadamard Selective Multiple Quantum Coherence transfer pulse sequence, STEAM pulse sequence

Motivation: The current approaches to assess Bruton’s kinase inhibitor (BTK) therapeutic effects in cancer are not ideal. 

Goal(s): Employing metabolic imaging, we evaluated the mode of action of ibrutinib (IBR), a BTK inhibitor, in mantle cell lymphoma (MCL) cells and xenografts.

Approach: Our approach using 1H MRS demonstrated that, in sensitive MCL models, IBR significantly impacted critical metabolic pathways, including glycolysis, glutaminolysis, and phospholipid metabolism, but had far less of an impact on IBR-poorly responsive cells.

Results: Changes in 1H MRS detectable lactate, alanine, and choline concentrations on various MCL models emerged as promising biomarkers of response or resistance to IBR.

Impact: Decreased intra-tumoral concentrations of lactate, alanine, and choline measured by 1H MRS during treatment can potentially become early and sensitive biomarkers of BTK inhibition in MCL and, likely, other lymphoma treatments.

15:090169.
Multifunctional Nanocomposite for Enhanced Diagnosis and Therapeutic Intervention in Breast Cancer via T1-T2 dual-enhanced and NIR II imaging
Xiuhong Guan1, Xin Huang2, Zhiyong Wang3, Guoxi Xie2, and Ci He4
1Department of Radiology, Jinan University, Guangzhou, China, 2School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, China, 3School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, China, 4Department of Radiology, The Sixth Affiliated Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Guangzhou, China

Keywords: Small Animals, Cancer, cancer immunotherapy, gas-photothermal therapy, magnetic resonance imaging, stimulator of interferon genes pathways, triple-negative breast cancer

Motivation: Breast cancer exhibits high incidence and mortality rates. We reports a functional nanosystem composed of Pluronic F127, manganese chloride (MnCl2), and IR780 dye. The nanosystem possesses multimodal imaging capabilities using near-infrared II (NIR-II) and T1-T2 dual-enhanced MRI, guiding photothermal therapy, and enhancing the STING pathway to combat triple-negative breast cancer.

Goal(s): Effectively suppress TNBC growth and metastasis, with good biocompatibility..

Approach: MC@NS nanosystem could diagnose the tumor and confirm the time window of treatment via NIR II/MRI dual-modal imaging, and effectively suppress tumor growth thought phototherapy, STING pathway and anti-tumor immunity.

Results: It effectively suppress tumor growth thought phototherapy, STING pathway and immunotherapy. 

Impact: This nanosystem, through T1-T2 dual-enhanced MRI and NIR II multimodal imaging, enabled tumor diagnosis and guided photothermal therapy, effectively suppressing tumor growth by combining photothermal therapy and STING pathway to enhance immunogenic cell death, providing a novel theranostic strategy.

15:210170.
Acidic Tumor Microenvironment-Activated MRI Nanoprobes for Modulation and Visualization of Anti-PD-L1 Immunotherapy
Kai Fan1 and Shenghong Ju1
1Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 DingJiaQiao Road, Nanjing, 210009, P. R. China., Jiangsu,Nanjing, China

Keywords: Probes & Targets, Cancer

Motivation: Molecular imaging holds revolutionary significance in the diagnosis and treatment of tumors. 

Goal(s): Clinical trials targeting immune checkpoint receptors with immune checkpoint blockade (ICB) therapies has encountered limited efficacy in pancreatic cancer.

Approach: MRI-guide ICB therapy (MRGIT) strategy for enhancing and guiding anti-PD-L1 therapy was proposed.

Results: The successful inhibition of tumor growth via MRGIT strategy in pancreatic tumor models demonstrates that it may be efficiently reverse the immunosuppressive PDAC and improve the ICB therapy with the employment of MRI technology.

Impact: The MRGIT strategy bridging the antitumor immune response with the MRI technique, which devised a potent tool that holds great promise for improving cancer diagnosis and facilitating the development of personalized treatment strategies tailored to individual patients.

15:330171.
Magnetic resonance imaging-based radiomic for predicting infiltration levels of CD68+ tumor-associated macrophages in Glioblastomas
Qing Zhou1 and Junlin Zhou1
1Lanzhou University Second Hospital, Lanzhou, China

Keywords: Preclinical Image Analysis, Nervous system

Motivation: Predicting Tumor-Associated Macrophages (TAMs)  levels using preoperative non-invasive imaging can influence patients with Glioblastoma (Gb) treatment decision-making and evaluate prognosis.

Goal(s): This study aimed to combine imaging and radiomics features of preoperative for predicting CD68 + macrophage infiltration.

Approach: Retrospective collection 143 patients with Gb. Divided patients into high CD68+TAMs(≥14.8%)and low CD68+TAMs (<14.8%) groups. The radiomics features extraction were based on CE-T1WI and T2WI. Multi-parameter stepwise regression was used to create the models.

Results: The combined model, with ADCmin and radiomics features, had the best performance revealing AUCs of 0.865 and 0.825 for the training and testing sets, respectively. 

Impact: To provide imaging biomarkers for the evaluation of the TAMs infiltration of Gb by using machine learning combined with MR imaging parameters, reveal the relationship between images features and TAMs, and construct an evaluation model to predict macrophage before surgery.