Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma

Abstract

PURPOSE: Losartan, an angiotensin II receptor blocker, can reduce desmoplasia and enhance drug delivery and efficacy through improving interstitial transport and vascular perfusion in pancreatic ductal adenocarcinoma (PDAC) models in mice. The purpose of this study was to determine whether magnetic resonance imaging (MRI) of magnetic iron oxide nanoparticles (MNPs) and micro–positron emission tomography (PET) measurements could respectively detect improvements in tumor vascular parameters and drug uptake in orthotopic PDAC in mice treated with losartan. METHOD AND MATERIALS: All experiments were approved by the local Institutional Animal Care and Use Committee. FVB mice with orthotopic PDAC were treated daily with an i.p. injection of losartan (70 mg/kg) or saline (control vehicle) for 5 days. In order to calculate the fractional blood volume, vessel size index, and vessel density index, MRI was performed at 4.7 T following the injection of 3 mg/kg iron ferumoxytol (i.v.). Dynamic PET images were also acquired for 60 minutes using an 18F-5FU tracer dose of 200 μCi and analyzed for time activity curves normalized to muscle. Statistical analyses compared both cohorts using an unpaired two-tailed t test. RESULTS: In comparison to the control treatment, the losartan administration significantly increased the fractional blood volume (mean ± SEM) [12.1 ± 1.7 (n = 19) vs 6.7 ± 1.1 (n = 20); P < .02] and vessel size index (128.2 ± 35.6 vs 57.5 ± 18; P < .05). Losartan also induced a significant increase in the intratumoral uptake of 18F-5FU by 53% (P < .0001). CONCLUSION: MRI using FDA-approved MNPs provides a noninvasive, translatable means of assaying microvascular parameters induced by losartan in pancreatic cancer. PET measurements demonstrated that losartan significantly increased the uptake of 18F-5FU.

Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts

“…This receptor is a leading target in active clinical investigations for patients with PDAC (NCT01821729 and NCT03563248). An inhibitor of this receptor, Losartan, was shown to reduce intratumoral solid stress, leading to increased vascular perfusion and improved drug delivery (48,78). A major source of solid stress in PDAC tumors is hyaluronan (7), and the enzymes responsible for hyaluronan production are uniquely and specifically expressed in iCAFs (HAS1 and HAS2 in the human data; Has1 and Has2 in the mouse data).…”

Multi‐parametric T2* magnetic resonance fingerprinting using variable echo times

“…In addition to tissue composition, the introduction of contrast agents, including magnetic iron nanoparticles such as ferumoxytol, reduces the T 1 , T 2 , and T 2 * of surrounding blood and tissue . Previous studies have demonstrated that comparing T 2 and T 2 * relaxation time constants before and after ferumoxytol can produce quantitative biomarkers of vessel density and size, with T 2 * being critical for calculation of these parameters. However, in organs that are subject to motion and require breath hold imaging for precise relaxometry, it is difficult to gather simultaneous acquisition of all relaxation parameters.…”

Clinical Application of Oncolytic Viruses: A Systematic Review

“…However, collagenase cannot be used systemically, which limits its application. One of many systemic agents under investigation includes the antihypertensive agent losartan, which reportedly decreased collagen deposition, increased blood flow as well as uptake of the cytotoxic agent in pancreatic cancer [ 40 ].…”