PET imaging of liposomes labeled with an [¹⁸F]-fluorocholesteryl ether probe prepared by automated radiosynthesis

Abstract

A novel [¹⁸F]-labeled cholesteryl ether lipid probe was prepared by synthesis of the corresponding mesylate, which was [¹⁸F]-fluorinated by a [¹⁸F]KF, Kryptofix-222, K₂CO₃ procedure. Fluorination was done for 10 minutes at 165^°C and took place with conversion between 3 and 17%, depending on conditions. Radiolabelling of the probe and subsequent in situ purification on SEP-Paks were done on a custom-built, fully automatic synthesis robot. Long-circulating liposomes were prepared by hydration (magnetic stirring) of a lipid film containing the radiolabeled probe, followed by fully automated extrusion through 100-nm filters. The [¹⁸F]-labeled liposomes were injected into nude, tumor-bearing mice, and positron emission tomography (PET) scans were performed several times over 8 hours to investigate the in vivo biodistribution. Clear tumor accumulation, as well as hepatic and splenic uptake, was observed, corresponding to expected liposomal pharmacokinetics. The tumor accumulation 8 hours postinjection accounted for 2.25 ± 0.23 (mean ± standard error of the mean) percent of injected dose per gram (%ID/g), and the tumor-to-muscle ratio reached 2.20 ± 0.24 after 8 hours, which is satisfactorily high for visualization of pathological lesions. Moreover, the blood concentration was still at a high level (13.9 ± 1.5 %ID/g) at the end of the 8-hour time frame. The present work demonstrates the methodology for automated preparation of radiolabeled liposomes, and shows that [¹⁸F]-labeled liposomes could be suitable as a methodology for visualization of tumors and obtaining short-term pharmacokinetics in vivo.

Keywords::

• Liposomal trafficking
• cancer diagnostics
• nanomedicine
• pharmacokinetics
• radiolabeling

Acknowledgments

The authors thank the staff at the Hevesy Laboratory for their fruitful discussions and for their daily assistance, in particular, Dr. Sorin Aburel, Dr. Martin F. Pedersen, Lene Niebuhr, and Professor Michael Jensen. Also, the authors thank Alex Givskov for carrying out the ROOT calculations used in this study. The authors thank the staff at the Hevesy Laboratory for providing [¹⁸F]fluoride.

Declaration of interest

Financial support was kindly provided by the National Advanced Technology Foundation, the Danish Medical Research Council, Rigshospitalets Research Foundation, the Svend Andersen Foundation, the AP Møller Foundation, the Novo Nordisk Foundation, the Lundbeck Foundation, and the Danish Cancer Society.