Impact of Arterial Input Function and Pharmacokinetic Models on DCE-MRI Biomarkers for Detection of Vascular Effect Induced by Stroma-Directed Drug in an Orthotopic Mouse Model of Pancreatic Cancer

Cao, Jianbo; Pickup, Stephen; Rosen, Mark; Zhou, Rong

doi:10.1007/s11307-023-01824-7

Cited by 2 publications

(2 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This capability will take advantage of MRI's capacity for temporal and spatial resolution during imaging, and thereby increase the potential to detect, stratify, and stage diseases; monitor treatment response; and study the biology of diseases at the molecular level in vivo, as well as correlate imaging results with histological analysis. Although dynamic contrast enhancement with dynamic changes of CAs has been approved for clinical applications, 28,29,114 it has low sensitivity due to arterial input function kinetic properties that interfere with quantification and low relaxivity. It is also important for the agent to reach the molecular biomarkers quickly to facilitate temporal imaging of dynamic molecular contrast enhancement that can provide important data related to disease vessel structure and subtle structural changes 52,115,116 .…”

Section: Criteria Of Ideal Mri Contrast Agents For Precision Mrimentioning

confidence: 99%

“…Macrocyclic Gd-DOTA, 12,13 Gd-HP-DO3A, 14 and Gd-BT-DO3A 15 chelate a Gd(III) in a rigid organized cavity whose size is preferable for Gd(III), 16,17 whereas linear Gd-DTPA, 11 Gd-DTPA-BMA, 18 Gd-BOPTA, 19 Gd-DTPA-BMEA, 20 and Gd-EOB-DTPA 21 have flexible open chains offering weaker protection of the Gd ion from endogenous metal ions 22,23 . Gadolinium-based contrast agents largely improve the sensitivity of MRI, and they also add functional information, such as perfusion 24 and cine 25,26 of heart, permeability of blood-brain barrier, 27 as well as perfusion and permeability in tumors 28,29 and inflamation 30 . Several significant GBCAs that have been developed recently include the following: gadopiclenol, which was approved by the FDA in 2022 31 ; gadoquatrane (Bayer), a tetramer of DOTA conjugates, 32 which is currently in phase 3 clinical trials 33,34 ; and HOPO and PCTA, which coordinate 2 and 3 water molecules, respectively, but have yet to be FDA approved 35 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Protein MRI Contrast Agents as an Effective Approach for Precision Molecular Imaging

Li,

Kirberger,

Qiao

et al. 2024

Invest Radiol

View full text Add to dashboard Cite

Cancer and other acute and chronic diseases are results of perturbations of common molecular determinants in key biological and signaling processes. Imaging is critical for characterizing dynamic changes in tumors and metastases, the tumor microenvironment, tumor-stroma interactions, and drug targets, at multiscale levels. Magnetic resonance imaging (MRI) has emerged to be a primary imaging modality for both clinical and preclinical applications due to its advantages over other modalities, including sensitivity to soft tissues, nondepth limitations, and the use of nonionizing radiation. However, extending the application of MRI to achieve both qualitative and quantitative precise molecular imaging with the capability to quantify molecular biomarkers for early detection, staging, and monitoring therapeutic treatment requires the capacity to overcome several major challenges including the trade-off between metal-binding affinity and relaxivity, which is an issue frequently associated with small chelator contrast agents. In this review, we will introduce the criteria of ideal contrast agents for precision molecular imaging and discuss the relaxivity of current contrast agents with defined first shell coordination water molecules. We will then report our advances in creating a new class of protein-targeted MRI contrast agents (ProCAs) with contributions to relaxivity largely derived from the secondary sphere and correlation time. We will summarize our rationale, design strategy, and approaches to the development and optimization of our pioneering ProCAs with desired high relaxivity, metal stability, and molecular biomarker-targeting capability, for precision MRI. From first generation (ProCA1) to third generation (ProCA32), we have achieved dual high r1 and r2 values that are 6- to 10-fold higher than clinically approved contrast agents at magnetic fields of 1.5 T, and their relaxivity values at high field are also significantly higher, which enables high resolution during small animal imaging. Further engineering of multiple targeting moieties enables ProCA32 agents that have strong biomarker-binding affinity and specificity for an array of key molecular biomarkers associated with various chronic diseases, while maintaining relaxation and exceptional metal-binding and selectivity, serum stability, and resistance to transmetallation, which are critical in mitigating risks associated with metal toxicity. Our leading product ProCA32.collagen has enabled the first early detection of liver metastasis from multiple cancers at early stages by mapping the tumor environment and early stage of fibrosis from liver and lung in vivo, with strong translational potential to extend to precision MRI for preclinical and clinical applications for precision diagnosis and treatment.

show abstract

Section: Criteria Of Ideal Mri Contrast Agents For Precision Mrimentioning

confidence: 99%

mentioning

confidence: 99%

Protein MRI Contrast Agents as an Effective Approach for Precision Molecular Imaging

Li,

Kirberger,

Qiao

et al. 2024

Invest Radiol

View full text Add to dashboard Cite

show abstract

Quantitative MRI Measurements Capture Pancreatic Cancer and Stroma Reactions to New KRAS Inhibitor

Gupta,

Choi,

Kemp

et al. 2024

Preprint

View full text Add to dashboard Cite

In pancreatic ductal adenocarcinoma (PDAC), KRAS mutations drive both cancer cell growth and formation of a dense stroma. Small molecule KRAS inhibitors (KRASi) represent a breakthrough for PDAC treatment hence clinical tools that can assess early response, detect resistance and/or predict prolonged survival are desirable for management of patients undergoing KRASi therapy. We hypothesized that diffusion-weighted MRI (DWI) can detect cell death while dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) imaging are sensitive to tumor microenvironment changes, and these metrics shed insights into tumor size (standard care assessment) change induced by KRASi treatment. We tested this hypothesis in multiple preclinical PDAC models receiving MRTX1133, an investigational new drug specific for KRASG12D mutation. Quantitative imaging markers corroborated by immunohistochemistry (IHC) revealed significant and profound changes related to cell death accompanied by changes in tumor cellularity, capillary perfusion /permeability and stromal matrix as early as 48h and day-7 after initiation of KRASi treatment, and greatly prolonged median survival over controls in a genetic engineered mouse model of PDAC (KPC). The MRI markers also captured distinct responses to KRASi therapy from PDAC tumors carrying KRASG12C versus KRASG12D mutation. In tumors developed resistance to MRTX1133, the imaging markers exhibited a reversal from those of responding tumors. Our findings have established that multiparametric MRI provide biological insights including cell death, reduced cellularity and tumor microenvironment changes induced by KRASi treatment and set the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy.

show abstract

Impact of Arterial Input Function and Pharmacokinetic Models on DCE-MRI Biomarkers for Detection of Vascular Effect Induced by Stroma-Directed Drug in an Orthotopic Mouse Model of Pancreatic Cancer

Cited by 2 publications

References 48 publications

Protein MRI Contrast Agents as an Effective Approach for Precision Molecular Imaging

Protein MRI Contrast Agents as an Effective Approach for Precision Molecular Imaging

Quantitative MRI Measurements Capture Pancreatic Cancer and Stroma Reactions to New KRAS Inhibitor

Contact Info

Product

Resources

About