Noninvasive Visualization of Obesity-Boosted Inflammation in Orthotopic Pancreatic Ductal Adenocarcinoma Using an Octapod Iron Oxide Nanoparticle

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment and promote the progression of tumors, including pancreatic ductal adenocarcinoma (PDAC). Obesity is a metabolic disease and a significant factor that affects tumor immunity and immunotherapy, contributing to a poorer tumor prognosis. However, TAMs as the link between obesity and poorer tumor prognosis has been less addressed and remains unclear. The current study aimed to noninvasively determine the effect of obesity on TAMs in orthotopic PDAC animal models, leptin-deficient transgenic obese (ob/ob) mice. Iron oxide nanoparticles, Octapod-30, with ultra high r₂ values, were utilized for in vivo consecutive T₂-weighted MR imaging. After Octapod-30 injection, the T₂-weighted signal intensity of the tumor area of both lean wild-type (WT) and ob/ob mice decreased rapidly, and the signal intensity significantly decreased as early as 0.5 h after injection compared with preinjection. The signal intensity continually decreased until 2 h and sustained for 4 h. In addition, the quantified signal intensity in obese ob/ob mice bearing PDAC significantly decreased compared with that in lean WT mice. Further histopathological analysis demonstrated that CD68-marked TAMs were highly colocalized with Prussian blue-stained Octapod-30, which were significantly more infiltrated in the tumor tissue of ob/ob mice than in the WT group, in parallel with larger size of tumor, higher levels of Ki67-marked proliferation and CD31-marked angiogenesis. Our results suggested that obesity increased TAMs infiltration and Octopad-30 can rapidly noninvasively detect TAMs in vivo in orthotopic PDAC with high spatial resolution and temporal resolution. Furthermore, the application of ultra high r₂ octagonal iron oxide nanoparticles with powerful clinical conversion potential could allow noninvasive and efficient quantitative analysis of TAMs in PDAC with or without obesity, providing a promising inspection approach for early detection, treatment management, and efficacy evaluation of tumors for clinical application.