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

• Published in: Molecular imaging and biology Vol. 25; no. 4; pp. 638 - 647
• Main Authors: Cao, Jianbo, Pickup, Stephen, Rosen, Mark, Zhou, Rong
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2023; Springer Nature B.V
• Subjects: Adenocarcinoma; Animal models; Animals; Biomarkers; Cancer; Carcinoma, Pancreatic Ductal - diagnostic imaging; Carcinoma, Pancreatic Ductal - drug therapy; Contrast Media - pharmacokinetics; Disease Models, Animal; Fluid pressure; Gadolinium; Hyaluronic acid; Image Enhancement - methods; Imaging; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Medicine; Medicine & Public Health; Mice; Microvasculature; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - diagnostic imaging; Pancreatic Neoplasms - drug therapy; Pharmacokinetics; Radiology; Reproducibility of Results; Research Article; Retrospective Studies; Stroma; Hyaluronidase; DCE-MRI; Arterial input function; Mouse; Pancreatic cancer; Microvascular permeability; Orthotopic model; Stroma; Gadolinium; Pharmacokinetic model
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-023-01824-7

Purpose We demonstrated earlier in mouse models of pancreatic ductal adenocarcinoma (PDA) that K trans derived from dynamic contrast-enhanced (DCE) MRI detected microvascular effect induced by PEGPH20, a hyaluronidase which removes stromal hyaluronan, leading to reduced interstitial fluid pressure in the tumor (Clinical Cancer Res (2019) 25: 2314–2322). How the choice of pharmacokinetic (PK) model and arterial input function (AIF) may impact DCE-derived markers for detecting such an effect is not known. Procedures Retrospective analyses of the DCE-MRI of the orthotopic PDA model are performed to examine the impact of individual versus group AIF combined with Tofts model (TM), extended-Tofts model (ETM), or shutter-speed model (SSM) on the ability to detect the microvascular changes induced by PEGPH20 treatment. Results Individual AIF exhibit a marked difference in peak gadolinium concentration. However, across all three PK models, k ep values show a significant correlation between individual versus group-AIF ( p < 0.01). Regardless individual or group AIF, when k ep is obtained from fitting the DCE-MRI data using the SSM, k ep shows a significant increase after PEGPH20 treatment ( p < 0.05 compared to the baseline); %change of k ep from baseline to post-treatment is also significantly different between PEGPH20 versus vehicle group ( p < 0.05). In comparison, when k ep is derived from the TM, only the use of individual AIF leads to a significant increase of k ep after PEGPH20 treatment, whereas the %change of k ep is not different between PEGPH20 versus vehicle group. Group AIF but not individual AIF allows detection of a significant increase of V p (derived from the ETM) in PEGPH20 versus vehicle group ( p < 0.05). Increase of V p is consistent with a large increase of mean capillary lumen area estimated from immunostaining. Conclusion Our results suggest that k ep derived from SSM and V p from ETM, both using group AIF, are optimal for the detection of microvascular changes induced by stroma-directed drug PEGPH20. These analyses provide insights in the choice of PK model and AIF for optimal DCE protocol design in mouse pancreatic cancer models.