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

Abstract

Liposomal nanoparticles are versatile drug delivery vehicles that show great promise in cancer therapy. In an effort to quantitatively measure their in vivo pharmacokinetics, we developed a highly efficient 89 Zr liposome-labeling method based on a rapid ligand exchange reaction between the membrane-permeable 89 Zr(8-hydroxyquinolinate) 4 complex and the hydrophilic liposomal cavity-encapsulated deferoxamine (DFO). This novel 89 Zr-labeling strategy allowed us to prepare radiolabeled forms of a folic acid (FA)-decorated active targeting 89 Zr-FA-DFO-liposome, a thermosensitive 89 Zr-DFO-liposome, and a renal avid 89 Zr-PEG-DFO-liposome at room temperature with near-quantitative isolated radiochemical yields of 98%±1% (n=6), 98%±2% (n=5), and 97%±1% (n=3), respectively. These 89 Zr-labeled liposomal nanoparticles showed remarkable stability in phosphate-buffered saline and serum at 37°C without leakage of radioactivity for 48 h. The uptake of 89 Zr-FA-DFO-liposome by the folate receptor-overexpressing KB cells was almost 15-fold higher than the 89 Zr-DFO-liposome in vitro. Positron emission tomography imaging and ex vivo biodistribution studies enabled us to observe the heterogeneous distribution of the 89 Zr-FA-DFO-liposome and 89 Zr-DFO-liposome in the KB tumor xenografts, the extensive kidney accumulation of the 89 Zr-FA-DFO-liposome and 89 Zr-PEG-DFO-liposome, and the different metabolic fate of the free and liposome-encapsulated 89 Zr-DFO. It also unveiled the poor resistance of all three liposomes against endothelial uptake resulting in their catabolism and high uptake of free 89 Zr in the skeleton. Thus, this technically simple 89 Zr-labeling method would find widespread use to guide the development and clinical applications of novel liposomal nanomedicines.

Recent Advances in Zirconium-89 Chelator Development

“…However, the introduction of zirconium-89 ( 89 Zr) more than three decades ago has reinvigorated this rapidly expanding area of research known as immuno-PET [ 18 , 19 ]. Its impact on antibody and nanoparticle development, clinical trials and precision medicine strategies has been reviewed extensively [ 14 , 15 , 16 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

Liposomes: Clinical Applications and Potential for Image-Guided Drug Delivery

“…PET imaging is an outstanding tool to derive a quantitative measure and real time monitoring of the biomarker uptake in vivo. Various researchers have studied the feasibility of PET imaging by conjugating PET isotopes in long circulating liposomes [ 83 , 86 , 87 , 88 , 89 , 90 , 91 ]. Wong et al [ 92 ] evaluated the clinical utility of 64 Cu (T 1/2 = 12.7 h) labeled liposomes as diagnostic and therapeutic tools to measure tumor volume, as a contrast agent, and compared the biodistribution of 64 Cu-labeled liposomes to the clinical tracer 18 F-FDG.…”

Nanoparticulate formulations of radiopharmaceuticals: Strategy to improve targeting and biodistribution properties

“…Active targeting can thus potentially augment passive targeting effects. Examples of active‐targeted nanoparticles include 64 Cu‐radiolabelled TRC105 antibodies (for CD105/endoglin binding), mesoporous silica (mSiO 2 ) nanoparticles 88 experimented in breast tumours, folic acid [ 89 Zr]Zr‐FA‐DFO‐liposomes used for in vivo pharmacokinetics and targeting in KB cells, and 64 Cu‐labelled quantum dots binding to integrin α v β 3 of tumour vasculature, 166 amongst others 167 …”