CER-001

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.

CER-001 is an HDL mimetic that has been tested in different pathological conditions, but never with LCAT deficiency. This study was designed to investigate whether the absence of LCAT affects the catabolic fate of CER-001, and to evaluate the effects of CER-001 on kidney disease associated with LCAT deficiency.

Lcat^-/- and wild-type mice received CER-001 (2.5, 5, 10 mg/kg) intravenously for 2 weeks. The plasma lipid/ lipoprotein profile and HDL subclasses were analyzed. In a second set of experiments, Lcat^-/- mice were injected with LpX to induce renal disease and treated with CER-001 and then the plasma lipid profile, lipid accumulation in the kidney, albuminuria and glomerular podocyte markers were evaluated.

In Lcat^-/- mice a decrease in total cholesterol and triglycerides, and an increase in HDL-c was observed after CER-001 treatment. While in wild-type mice CER-001 entered the classical HDL remodeling pathway, in the absence of LCAT it disappeared from the plasma shortly after injection and ended up in the kidney. In a mouse model of renal disease in LCAT deficiency, treatment with CER-001 at 10 mg/kg for one month had beneficial effects not only on the lipid profile, but also on renal disease, by limiting albuminuria and podocyte dysfunction.

Treatment with CER-001 ameliorates the dyslipidemia typically associated with LCAT deficiency and more importantly limits renal damage in a mouse model of renal disease in LCAT deficiency. The present results provide a rationale for using CER-001 in FLD patients.