⁸⁹Zr-oxine labelling and PET imaging shows lung delivery of a cell/gene cancer therapy

Abstract

PurposeMSCTRAIL is a new stem cell-based therapy for lung cancer, currently in phase I evaluation (ClinicalTrials.gov ref: NCT03298763). Biodistribution of cell therapies is rarely assessed in clinical trials, despite cell delivery to the target site often being critical to presumed mechanism of action. This preclinical study demonstrates that MSCTRAIL biodistribution dynamics can be detected non-invasively using 89Zr-oxine labelling and PET imaging, thus supporting use of this cell tracking technology in phase II evaluation.MethodsMSCTRAIL were radiolabelled with a range of 89Zr-oxine doses, and assayed for cell viability, phenotype and therapeutic efficacy post-labelling. Cell biodistribution was imaged in a mouse model of lung cancer using PET imaging and bioluminescence imaging (BLI) to confirm cell viability and location in vivo up to 1 week post-injection.ResultsMSCTRAIL retained therapeutic efficacy and MSC phenotype at doses up to and above those required for clinical imaging. The effect of 89Zr-oxine labelling on cell proliferation rate was dose and time-dependent. PET imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer, with PET signal correlating with the presence of viable cells as assessed by bioluminescence imaging, ex vivo autoradiography and matched fluorescence imaging on lung tissue sections. Human dosimetry estimates were produced using simulations and preclinical biodistribution data.Conclusion89Zr-oxine labelling and PET imaging present an attractive method of evaluating the biodistribution of new cell-therapies, such as MSCTRAIL. This offers to improve understanding of mechanism of action, migration dynamics and interpatient variability of MSCTRAIL and other cell-based therapies.

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

“…Sato and colleagues published a more complex process that obtained 89 ZrCl 4 from 89 Zr-oxalate, including an ion exchange step prior to solvent extraction [ 3 ]. Weist et al reached an 82–92% labeling yield [ 4 ], while Patrick and colleagues achieved around 74% efficiency [ 5 ] using variable buffer and extraction settings. Man et al reached [ 89 Zr]Zr(oxinate) 4 -labeling yields similar to those achieved in the present study by applying the formulation of a more complex kit prior to cell labeling studies [ 6 ].…”

“…Reactions were performed at RT, 50 • C or 60 • C, respectively. The [ 89 Zr]Zr(oxinate) 4 -labeling yield was calculated from the measured activities of the separated aqueous raffinates and chloroform extracts after different times (5,10,15,20,30, 60 min, 2 h and24 h) of extensive mixing in glass reaction vessels. After extraction, [ 89 Zr]Zr(oxinate) 4 was crystallized by evaporation of chloroform at 60 • C under a N 2 stream and was redissolved in ethanol and dimethyl sulfoxide (DMSO).…”

“…Oxinates of the transition radiometals gallium-68, zirconium-89 and indium-111 ([ 68 Ga]Ga(oxinate) 3 , [ 89 Zr]Zr(oxinate) 4 , [ 111 In]In(oxinate) 3 ) are highly lipophilic molecules that can be incorporated into lipid-bilayered nanovesicles (liposomes) and living cells under neutral conditions. Using this mechanism, more recent studies disseminated [ 89 Zr]Zr(oxinate) 4 -related cell tracing by applying various labeling protocols from 60% to 97% labeling efficiency of the prelabeled oxinate [2][3][4][5][6] and complex liposome labeling by combining this method with a liposome-incorporated bifunctional chelator [7].…”

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

“…As a result, the use of radiotracers that selectively target inflammatory cells could greatly enhance the noninvasive detection of inflammatory activity. 68 Ga-pentixafor is an agent that exhibits high affinity and selectivity for the C-X-C chemokine receptor type 4 (CXCR4), which is involved in various biological processes, including HIV entry, metastasis development, and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis [37,38] In addition to the detection of various tumors, 68 Ga-pentixafor proved to be a promising candidate for detecting high-risk atherosclerotic plaques that exhibit intense inflammatory reactions and hypoxic conditions [36]. CXCR4 plays a crucial role in the trafficking of inflammatory cells, mediating the homing of progenitor cells in the bone marrow, regulating their mobilization into peripheral tissues upon injury [38].…”

Biodistribution of Mesenchymal Stromal Cells Labeled with [89Zr]Zr-Oxine in Local Radiation Injuries in Laboratory Animals

“…The liquid-liquid extraction (LLE) method (with chloroform and later with octanol-1) is recommended by European Pharmacopoeia to determine the RCP of the commonly used [ 111 In]In-oxine [22]. This method (using chloroform) is applicable for Zr-oxine complexes [23,24].…”