Simplified 89Zr-Labeling Protocol of Oxine (8-Hydroxyquinoline) Enabling Prolonged Tracking of Liposome-Based Nanomedicines and Cells

Abstract

In this work, a method for the preparation of the highly lipophilic labeling synthon [89Zr]Zr(oxinate)4 was optimized for the radiolabeling of liposomes and human induced pluripotent stem cells (hiPSCs). The aim was to establish a robust and reliable labeling protocol for enabling up to one week positron emission tomography (PET) tracing of lipid-based nanomedicines and transplanted or injected cells, respectively. [89Zr]Zr(oxinate)4 was prepared from oxine (8-hydroxyquinoline) and [89Zr]Zr(OH)2(C2O4). Earlier introduced liquid–liquid extraction methods were simplified by the optimization of buffering, pH, temperature and reaction times. For quality control, thin-layer chromatography (TLC), size-exclusion chromatography (SEC) and centrifugation were employed. Subsequently, the 89Zr-complex was incorporated into liposome formulations. PET/CT imaging of 89Zr-labeled liposomes was performed in healthy mice. Cell labeling was accomplished in PBS using suspensions of 3 × 106 hiPSCs, each. [89Zr]Zr(oxinate)4 was synthesized in very high radiochemical yields of 98.7% (96.8% ± 2.8%). Similarly, high internalization rates (≥90%) of [89Zr]Zr(oxinate)4 into liposomes were obtained over an 18 h incubation period. MicroPET and biodistribution studies confirmed the labeled nanocarriers’ in vivo stability. Human iPSCs incorporated the labeling agent within 30 min with ~50% efficiency. Prolonged PET imaging is an ideal tool in the development of lipid-based nanocarriers for drug delivery and cell therapies. To this end, a reliable and reproducible 89Zr radiolabeling method was developed and tested successfully in a model liposome system and in hiPSCs alike.

Preparation and PET/CT imaging of implant directed 68Ga-labeled magnetic nanoporous silica nanoparticles

“…In a study using the same location of the implants and the same type of nanoparticles an accumulation of nanoparticles at the implant after 24 h could be seen [ 34 ]. Zirconium-89 ( 89 Zr) which is commonly used in clinical nuclear imaging, and due to its longer half-life of 78.4 h it allows longer tracking periods of up to several days [ 85 ]. This would allow repeated scanning of the animals at later time points without additional injections, which might reveal any later changes in particle distribution.…”

“…Additionally, it can also be attached via a chelator molecule which might make it easy to transmit to the here presented nanoparticles [ 86 ]. Labeling nanoparticular systems with 89 Zr is already described in the literature [ 85 , 87 ]. However, as long as the blood circulation time of the nanoparticles is not increased it is questionable whether a longer study time would reveal any changes in nanoparticle distribution because a redistribution of particles caught in the RES organs is not likely to happen.…”

Radiolabeled Liposomes for Nuclear Imaging Probes

“…Radiolabeling method optimization of 89 Zr, PET imaging probe [129] Although extensive efforts have been devoted to pharmacokinetic studies of radioliposomes, the research outcomes have been unsatisfactory in the last few decades due to various factors, such as rapid blood clearance, early drug release, low bioavailability, and non-targeted delivery. For example, 99m Tc-labeled liposomes failed to accumulate in several types of tumors even though similar tissue distributions of radioliposomes were found in these models (particularly high in the liver and spleen, moderate accumulation in the kidney and bone marrow) [75,86].…”

“…Additionally, results showed that 89 Zr-labeled liposomes accumulated in the lymph node at a later time point since 89 Zr has a high affinity for macrophages [128,133]. However, these supporting documents were insufficient for 89 Zr-labeled liposomes to be approved for use as a diagnostic probe in future clinical settings; hence, further optimization of labeling strategies for liposome labeling with 89 Zr should be prioritized to overcome the downsides [129].…”

Implant Imaging: Perspectives of Nuclear Imaging in Implant, Biomaterial, and Stem Cell Research

“…The long half-life of 89 Zr, offering a biologically more meaningful prolonged cell tracking time (even one or two weeks), deserves a special mention. Given its widespread commercial availability, [ 89 Zr]Zr(oxinate) 4 was already used for the labelling of the following various cell types: tumor cell lines, bone marrow and dendritic cells, therapeutic T cells, and stem cells (seen in Figure 3) [68][69][70][71][72][73][74][75][76][77][78][79].…”