A Modular Labeling Strategy for In Vivo PET and Near-Infrared Fluorescence Imaging of Nanoparticle Tumor Targeting

Abstract

Advances in preclinical molecular imaging have generated new opportunities to noninvasively visualize the biodistribution and tumor targeting of nanoparticle therapeutics. Capitalizing on recent achievements in this area, we sought to develop an 89Zr-based labeling strategy for liposomal nanoparticles that accumulate in tumors via passive targeting mechanisms. Methods 89Zr-labeled liposomes were prepared using 2 different approaches: click labeling and surface chelation. Pharmacokinetic and biodistribution studies, as well as PET/CT imaging of the radiolabeled nanoparticles, were performed on a mouse model of breast cancer. In addition, a dual PET/optical probe was prepared by incorporation of a near-infrared fluorophore and tested in vivo by PET and near-infrared fluorescence imaging. Results The surface chelation approach proved to be superior in terms of radiochemical yield and stability, as well as in vivo performance. Accumulation of these liposomes in tumor peaked at 24 h after injection and was measured to be 13.7 ± 1.8 percentage injected dose per gram. The in vivo performance of this probe was not essentially perturbed by the incorporation of a near-infrared fluorophore. Conclusion We have developed a highly modular and efficient strategy for the labeling of liposomal nanoparticles with 89Zr. In xenograft and orthotopic mouse models of breast cancer, we demonstrated that the biodistribution of these nanoparticles can be visualized by PET imaging. In combination with a near-infrared dye, these liposomal nanoparticles can serve as bimodal PET/optical imaging agents. The liposomes target malignant growth, and their bimodal features may be useful for simultaneous PET and intraoperative imaging.

Exploiting the Metal-Chelating Properties of the Drug Cargo for In Vivo Positron Emission Tomography Imaging of Liposomal Nanomedicines

“…Similar bone uptake values have been found with long-circulating (>24 h) 89 Zr-labeled antibodies and liposomes, suggesting that these bone-targeting species are nonchelated 89 Zr released after liposome disassembly. 19,41−43 Highly vascular organs such as the lungs and kidneys followed the same decreasing trend in signal as the heart/blood, as expected for long-circulating nanoparticles that are cleared via the reticuloendothelial system (RES). One animal from the group was further imaged at 168 h to confirm the biodistribution trend.…”

PET Imaging of Tumor-Associated Macrophages with 89Zr-Labeled High-Density Lipoprotein Nanoparticles

“…The first one was synthesized by conjugation of DFO to apoA-I via reaction of the rHDL particles with DFO- p -NCS. The second one, the phospholipid-based chelator DSPE-DFO, was prepared as recently described by us (21). These modifications had no measurable effect on the size, compared with plain rHDL (Fig.…”

A generic ⁸⁹Zr labeling method to quantify the in vivo pharmacokinetics of liposomal nanoparticles with positron emission tomography

“…Pérez-Medina et al employed a copper-free click reaction to label 89 Zr with a DFO azide and then couple the corresponding 89 Zr-DFO azide to the lipid-bonded dibenzocyclooctynyl group on the liposome surface. 10 Low isolated RCY of 14% was observed in this two-step method with a prolonged preparation time of 16 h. As an alternative to the lipid membrane-labeling strategy, the radioisotopes can also be localized in the liposomal cavity. In 2011, Petersen et al reported a remote loading approach to label liposomes with 64 Cu.…”