89Zr-Labeled High-Density Lipoprotein Nanoparticle PET Imaging Reveals Tumor Uptake in Patients with Esophageal Cancer

Abstract

Nanomedicine holds promise for the delivery of therapeutic and imaging agents to improve cancer treatment outcomes. Preclinical studies have demonstrated that high-density lipoprotein (HDL) nanoparticles accumulate in tumor tissue on intravenous administration. Whether this HDL-based nanomedicine concept is feasible in patients is unexplored. Using a multimodal 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 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 before starting chemoradiation therapy. In addition, patients underwent routine ¹⁸F-FDG PET/CT and 3-T MRI scanning (diffusion-weighted imaging/intravoxel incoherent motion imaging and dynamic contrast-enhanced MRI) to assess tumor glucose metabolism, tumor cellularity and microcirculation perfusion, and tumor vascular permeability. Tumor biopsies were analyzed for the expression of HDL scavenger receptor class B1 and macrophage marker CD68 using immunofluorescence staining. Results: Nine patients with adenocarcinoma or squamous cell carcinoma underwent all study procedures. After injection of ⁸⁹Zr-HDL (39.2 ± 1.2 [mean ± SD] MBq), blood-pool SUV_mean decreased over time (11.0 ± 1.7, 6.5 ± 0.6, and 3.3 ± 0.5 at 1, 24, and 72 h, respectively), whereas liver and spleen SUV_mean remained relatively constant (4.1 ± 0.6, 4.0 ± 0.8, and 4.3 ± 0.8 at 1, 24, and 72 h, respectively, for the liver; 4.1 ± 0.3, 3.4 ± 0.3, and 3.1 ± 0.4 at 1, 24, and 72 h, respectively, for the spleen) and kidney SUV_mean markedly increased over time (4.1 ± 0.9, 9.3 ± 1.4, and 9.6 ± 2.0 at 1, 24, and 72 h, respectively). Tumor uptake (SUV_peak) increased over time (3.5 ± 1.1 and 5.5 ± 2.1 at 1 and 24 h, respectively [P = 0.016]; 5.7 ± 1.4 at 72 h [P = 0.001]). The effective dose of ⁸⁹Zr-HDL was 0.523 ± 0.040 mSv/MBq. No adverse events were observed after the administration of ⁸⁹Zr-HDL. PET/CT and 3-T 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 that a specific mechanism mediated the accumulation of ⁸⁹Zr-HDL. Immunofluorescence staining of clinical biopsies demonstrated scavenger receptor class B1 and CD68 positivity in tumor tissue, establishing a potential cellular mechanism of action. Conclusion: To our knowledge, this was the first ⁸⁹Zr-HDL study in human oncology. ⁸⁹Zr-HDL PET/CT imaging demonstrated that intravenously administered HDL nanoparticles accumulated in tumors of patients with esophageal cancer. The administration of ⁸⁹Zr-HDL was safe. These findings may support the development of HDL nanoparticles as a clinical delivery platform for drug agents. ⁸⁹Zr-HDL imaging may guide drug development and serve as a biomarker for individualized therapy.

Keywords: PET/CT; esophageal cancer; high-density lipoprotein; nanomedicine; zirconium.

Graphical abstract

FIGURE 1.

Maximum-intensity projections of serial ⁸⁹Zr-HDL PET images from patient 1.

FIGURE 2.

PET/CT images from patient 6 with esophageal adenocarcinoma. (A and B) ¹⁸F-FDG uptake was clearly increased in tumors. On administration of ⁸⁹Zr-HDL, signal intensity in esophageal tumor increased over time, and focal uptake pattern was clearly visualized at 72 h. (C) Tumor SUVs and target–to–blood pool ratios increased over time, indicating accumulation of ⁸⁹Zr-HDL particles in tumors. (D) There was no association between ¹⁸F-FDG uptake and ⁸⁹Zr-HDL uptake in tumors. Ao = aorta, He = heart, Li = liver; TBR = target–to–blood pool ratio.

FIGURE 3.

DWI/IVIM and DCE-MRI scanning of patient 7. (A) (Left) T2-weighted (T2w) turbo spin-echo images were obtained to localize tumors. Yellow arrow indicates tumor. (Right) Corresponding ⁸⁹Zr-HDL PET/CT at 72 h, with focal uptake in tumor delineated with white line, as well as intravascular signal from adjacent pulmonary vein (PV). (B) DWI/IVIM images were acquired to generate diffusivity (D) and perfusion fraction (f) maps. (C) Mean D and f values calculated from parameter maps were not associated with tumor uptake of ⁸⁹Zr-HDL. (D) Quantitative AUC maps resulting from DCE-MRI time series. (E) Mean AUC values were not associated with tumor uptake of ⁸⁹Zr-HDL. AU = arbitrary units.

FIGURE 4.

HDL receptor expression and macrophage presence in tumor biopsies, as shown by histology and immunofluorescence (IF) of tumor biopsies before chemoradiation therapy, in patient 3. (A and B) Hematoxylin and eosin (H&E) staining (A) with corresponding confocal microscopy image for 4,6-diamidino-2-phenylindole (DAPI) (blue), SR-B1 (green), and CD68 (red) (B). (C) Pixel count of SR-B1 and CD68 normalized (norm.) to DAPI. (D) Percentage area with double positivity for SR-B1 and CD68. AU = arbitrary units.