Abstract
The encapsulation of Glucocorticoids (GCs) into long-circulating liposomes (LCLs) is a proven strategy to reduce the side effects of glucocorticoids and improve the treatment of inflammatory diseases, such as rheumatoid arthritis (RA). With the aim of supporting the development of GC-loaded LCLs, and potentially predict patient response to therapy clinically, we evaluated a direct PET imaging radiolabelling approach for preformed GC-LCLs in an animal model of human inflammatory arthritis. Methods: A preformed PEGylated liposomal methylprednisolone hemisuccinate (NSSL-MPS) nanomedicine was radiolabelled using [89Zr]Zr(oxinate)4 (89Zr-oxine), characterised and tracked in vivo using PET imaging in a K/BxN serum-transfer arthritis (STA) mouse model of inflammatory arthritis and non-inflamed controls. Histology and joint size measurements were used to confirm inflammation. The biodistribution of 89Zr-NSSL-MPS was compared to that of free 89Zr in the same model. A therapeutic study using NSSL-MPS using the same time points as the PET/CT imaging was carried out. Results: The radiolabelling efficiency of NSSL-MPS with [89Zr]Zr(oxinate)4 was 69 ± 8 %. PET/CT imaging of 89Zr-NSSL-MPS showed high uptake (3.6 ± 1.5 % ID; 17.4 ± 9.3 % ID/mL) at inflamed joints, with low activity present in non-inflamed joints (0.5 ± 0.1 % ID; 2.7 ± 1.1 % ID/mL). Importantly, a clear correlation between joint swelling and high 89Zr-NSSL-MPS uptake was observed, which was not observed with free 89Zr. STA mice receiving a therapeutic dose of NSSL-MPS showed a reduction in inflammation at the time points used for the PET/CT imaging compared with the control group. Conclusions: PET imaging was used for the first time to track a liposomal glucocorticoid, showing high uptake at visible and occult inflamed sites and a good correlation with the degree of inflammation. A subsequent therapeutic response matching imaging time points in the same model demonstrated the potential of this radiolabeling method as a theranostic tool for the prediction of therapeutic response - with NSSL-MPS and similar nanomedicines - in the treatment of inflammatory diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 3867-3879 |
| Number of pages | 13 |
| Journal | Theranostics |
| Volume | 10 |
| Issue number | 9 |
| DOIs | |
| State | Published - 2020 |
Bibliographical note
Funding Information:The authors thank J. Bordoloi, A. Rigby, V. de Santis, E. Verger, I. Hungnes and G. Keeling for technical support and assistance during the in vivo work. Cryo-TEM work that was performed by Dr. Yael Kalisman, Staff Scientist at the Unit for Nanoscopic Characterization, Hebrew University Center for Nanoscience and Nanotechnology at HUJI Givaat Ram campus (Israel). This work was funded by the King’s College London & Imperial College London EPSRC Centre for Doctoral Training in Medical Imaging (EP/L015226/1), The Rosetrees Trust (CM606) and GlaxoSmithKline plc. We also acknowledge support from EPSRC (EP/R045046/1) and (EP/S032789/1), the KCL and UCL Comprehensive Cancer Imaging Centre funded by CRUK and EPSRC in association with the MRC and DoH (England). PET scanning equipment was funded by an equipment grant from the Wellcome Trust. The research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Funding Information:
Rafael T. M. de Rosales receives research funding from GlaxoSmithKline plc supporting a PhD studentship for PG. Yechezkel Barenholz is an inventor of two patents on NSSL-MPS owned by Yissum TTO of the Hebrew University. Yechezkel Barenholz, Yaacov Naparstack, Yuval Avnir and Rina Ulmansky: “The use of Liposomal Glucocorticoids for Treating Inflammatory States.” US Patent 7,744,920, 2010, June 29, 2010 and Yechezkel Barenholz, Alberto A. Gabizon and Yuval Avnir. “Liposomal Compositions of Glucocorticoid and Glucocorticoid Derivatives”. US Patent 8,932,627, January 13, 2015.
Funding Information:
The authors thank J. Bordoloi, A. Rigby, V. de Santis, E. Verger, I. Hungnes and G. Keeling for technical support and assistance during the in vivo work. Cryo-TEM work that was performed by Dr. Yael Kalisman, Staff Scientist at the Unit for Nanoscopic Characterization, Hebrew University Center for Nanoscience and Nanotechnology at HUJI Givaat Ram campus (Israel). This work was funded by the King's College London & Imperial College London EPSRC Centre for Doctoral Training in Medical Imaging (EP/L015226/1), The Rosetrees Trust (CM606) and GlaxoSmithKline plc. We also acknowledge support from EPSRC (EP/R045046/1) and (EP/S032789/1), the KCL and UCL Comprehensive Cancer Imaging Centre funded by CRUK and EPSRC in association with the MRC and DoH (England). PET scanning equipment was funded by an equipment grant from the Wellcome Trust. The research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Publisher Copyright:
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Keywords
- In vivo Liposome Imaging
- Nanomedicine
- Personalised Nanomedicine
- Positron Emission Tomography
- Rheumatoid Arthritis