Abstract
Rationale: Nanomedicine holds promise for delivery of therapeutic and imaging agents to improve cancer treatment outcome. Preclinical studies demonstrated that high-density lipoprotein (HDL) nanoparticles accumulate in tumor tissue upon intravenous administration. Whether this HDL-based nanomedicine concept is feasible in patients is unexplored. Using a multi-modal imaging approach, we aimed to assess tumor uptake of exogenously administered HDL nanoparticles in patients with esophageal cancer. Methods: The HDL mimetic CER-001 was radiolabeled using Zirconium-89 (89Zr) to allow for PET/CT imaging. Patients with primary esophageal cancer staged T2 and above were recruited for serial 89Zr-HDL PET/CT imaging prior to starting chemoradiation therapy. In addition, patients underwent routine 18F-FDG PET/CT and 3T MRI scanning (DWI/IVIM and DCE-MRI) to assess tumor glucose metabolism, tumor cellularity and microcirculation perfusion, and tumor vascular permeability. Tumor biopsies were analyzed for expression of the HDL scavenger receptor class B1 (SR-B1) and macrophage marker CD68 using immunofluorescent staining. Results: Nine patients with adenocarcinoma or squamous cell carcinoma underwent all study procedures. Following injection of 89Zr-HDL, tumor uptake increased over time (SUVpeak t=1h: 3.5±1.1; t=24h: 5.5±2.1 (P = 0.016); t=72h: 5.7±1.4 (P = 0.001)). PET/CT and 3T MRI measures of tumor glucose metabolism, tumor cellularity and microcirculation perfusion, and tumor vascular permeability did not correlate with tumor uptake of 89Zr-HDL, suggesting a specific mechanism to mediate the accumulation of 89Zr-HDL. Immunofluorescent staining of clinical biopsies demonstrated SR-B1 and CD68 positivity in tumor tissue, establishing a potential cellular mechanism of action. Conclusion: 89Zr-HDL PET/CT imaging demonstrates that intravenously administered HDL nanoparticles accumulate in tumors of patients with esophageal cancer. These findings support the development of HDL nanoparticles as a clinical delivery platform for drug agents. 89Zr-HDL imaging may guide drug development and serve as biomarker for individualized therapy.
- Copyright © 2022 by the Society of Nuclear Medicine and Molecular Imaging, Inc.