TY - JOUR
T1 - PET Imaging of Small Extracellular Vesicles via [89Zr]Zr(oxinate)4 Direct Radiolabeling
AU - Khan, Azalea
AU - Man, Francis
AU - Muhammad Faruqu, Farid
AU - Kim, Jana
AU - Al-Salemee, Fahad
AU - Minino, Amaia
AU - Volpe, Alessia
AU - Liam-Or, Revadee
AU - Simpson, Paul
AU - Fruhwirth, Gilbert
AU - Al-Jamal, Khuloud
AU - T. M. de Rosales, Rafael
N1 - Funding Information:
The authors declare the following competing financial interest(s): RTMR receives funding from AstraZeneca plc (50% co-funding of a PhD studentship). FM and RTMR are co-inventors in a patent related to the synthesis of 89Zr-oxine (GB patent application 2009512.1). Acknowledgments
Funding Information:
A.K. is supported by the UK Medical Research Council (MRC) (MR/N013700/1) and King’s College London MRC Doctoral Training Partnership in Biomedical Sciences. F.N.F. is funded by the Malaysian government agency Majlis Amanah Rakyat (MARA). This work was also funded by EPSRC programme grants EP/S032789/1 and EP/R045046/1 and the Wellcome/EPSRC Centre for Medical Engineering (WT/203148/Z/16/Z). We also acknowledge support from the KCL and UCL Comprehensive Cancer Imaging Centre funded by CRUK and EPSRC in association with the MRC and DoH (England). PET scanning equipment at KCL was funded by an equipment grant from the Wellcome Trust under grant no WT 084052/Z/07/Z. Radioanalytical equipment was funded by a Wellcome Trust Multi User Equipment grant: a multiuser radioanalytical facility for molecular imaging and radionuclide therapy research. The authors finally acknowledge support from the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and KCL (grant no IS-BRC-1215-20006). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. This research was funded in whole, or in part, by the Wellcome Trust [WT/203148/Z/16/Z] [WT 084052/Z/07/Z|. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/3/16
Y1 - 2022/3/16
N2 - Exosomes or small extracellular vesicles (sEVs) are increasingly gaining attention for their potential as drug delivery systems and biomarkers of disease. Therefore, it is important to understand their in vivo biodistribution using imaging techniques that allow tracking over time and at the whole-body level. Positron emission tomography (PET) allows short- and long-term whole-body tracking of radiolabeled compounds in both animals and humans and with excellent quantification properties compared to other nuclear imaging techniques. In this report, we explored the use of [89Zr]Zr(oxinate)4 (a cell and liposome radiotracer) for direct and intraluminal radiolabeling of several types of sEVs, achieving high radiolabeling yields. The radiosynthesis and radiolabeling protocols were optimized for sEV labeling, avoiding sEV damage, as demonstrated using several characterizations (cryoEM, nanoparticle tracking analysis, dot blot, and flow cytometry) and in vitro techniques. Using pancreatic cancer sEVs (PANC1) in a healthy mouse model, we showed that it is possible to track 89Zr-labeled sEVs in vivo using PET imaging for at least up to 24 h. We also report differential biodistribution of intact sEVs compared to intentionally heat-damaged sEVs, with significantly reduced spleen uptake for the latter. Therefore, we conclude that 89Zr-labeled sEVs using this method can reliably be used for in vivo PET tracking and thus allow efficient exploration of their potential as drug delivery systems.
AB - Exosomes or small extracellular vesicles (sEVs) are increasingly gaining attention for their potential as drug delivery systems and biomarkers of disease. Therefore, it is important to understand their in vivo biodistribution using imaging techniques that allow tracking over time and at the whole-body level. Positron emission tomography (PET) allows short- and long-term whole-body tracking of radiolabeled compounds in both animals and humans and with excellent quantification properties compared to other nuclear imaging techniques. In this report, we explored the use of [89Zr]Zr(oxinate)4 (a cell and liposome radiotracer) for direct and intraluminal radiolabeling of several types of sEVs, achieving high radiolabeling yields. The radiosynthesis and radiolabeling protocols were optimized for sEV labeling, avoiding sEV damage, as demonstrated using several characterizations (cryoEM, nanoparticle tracking analysis, dot blot, and flow cytometry) and in vitro techniques. Using pancreatic cancer sEVs (PANC1) in a healthy mouse model, we showed that it is possible to track 89Zr-labeled sEVs in vivo using PET imaging for at least up to 24 h. We also report differential biodistribution of intact sEVs compared to intentionally heat-damaged sEVs, with significantly reduced spleen uptake for the latter. Therefore, we conclude that 89Zr-labeled sEVs using this method can reliably be used for in vivo PET tracking and thus allow efficient exploration of their potential as drug delivery systems.
UR - http://www.scopus.com/inward/record.url?scp=85126094094&partnerID=8YFLogxK
U2 - 10.1021/acs.bioconjchem.1c00597
DO - 10.1021/acs.bioconjchem.1c00597
M3 - Article
SN - 1043-1802
VL - 33
SP - 473
EP - 485
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 3
ER -
