Repurposing iron chelators for accurate positron emission tomography imaging tracking of radiometal-labeled cell transplants

Qian Xu, Xinyu Wang, Ziqian Mu, Yixiang Zhou, Xiang Ding, Xin Ji, Junjie Yan, Donghui Pan, Chongyang Chen, Yuping Xu, Lizhen Wang, Jing Wang, Guangji Wang, Min Yang

PDF
MedComm ›› 2024, Vol. 5 ›› Issue (2) : e473. DOI: 10.1002/mco2.473
ORIGINAL ARTICLE

Repurposing iron chelators for accurate positron emission tomography imaging tracking of radiometal-labeled cell transplants

Author information +
History +

Abstract

The use of radiolabeled cells for positron emission tomography (PET) imaging tracking has been a promising approach for monitoring cell-based therapies. However, the presence of free radionuclides released from dead cells during tracking can interfere with the signal from living cells, leading to inaccurate results. In this study, the effectiveness of the iron chelators deferoxamine (DFO) and deferiprone in removing free radionuclides 89Zr and 68Ga, respectively, was demonstrated in vivo utilizing PET imaging. The use of DFO during PET imaging tracking of 89Zr-labeled mesenchymal stem cells (MSCs) significantly reduced uptake in bone while preserving uptake in major organs, resulting in more accurate and reliable tracking. Furthermore, the clearance of free 89Zr in vivo resulted in a significant reduction in radiation dose from 89Zr-labeled MSCs. Additionally, the avoidance of free radionuclide accumulation in bone allowed for more precise observation of the homing process and persistence during bone marrow transplantation. The efficacy and safety of this solution suggest this finding has potential for widespread use in imaging tracking studies involving various cells. Moreover, since this method employed iron chelator drugs in clinical use, which makes it is a good prospect for clinical translation.

Keywords

cell therapy / cell tracking / iron chelator / PET imaging / radiolabel

Cite this article

Download citation ▾
Qian Xu, Xinyu Wang, Ziqian Mu, Yixiang Zhou, Xiang Ding, Xin Ji, Junjie Yan, Donghui Pan, Chongyang Chen, Yuping Xu, Lizhen Wang, Jing Wang, Guangji Wang, Min Yang. Repurposing iron chelators for accurate positron emission tomography imaging tracking of radiometal-labeled cell transplants. MedComm, 2024, 5(2): e473 https://doi.org/10.1002/mco2.473

References

[1]
Weber EW, Maus MV, Mackall CL. The emerging landscape of immune cell therapies. Cell. 2020;181(1):46-62.
[2]
Parmar M, Grealish S, Henchcliffe C. The future of stem cell therapies for Parkinson disease. Nat Rev Neurosci. 2020;21(2):103-115.
[3]
Yamanaka S. Pluripotent stem cell-based cell therapy—promise and challenges. Cell Stem Cell. 2020;27(4):523-531.
[4]
Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69.
[5]
Zhang J, Wang L. The emerging world of TCR-T cell trials against cancer: a systematic review. Technol Cancer Res Treat. 2019;18:1533033819831068.
[6]
Paijens ST, Vledder A, de Bruyn M, Nijman HW. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol. 2021;18(4):842-859.
[7]
Brown C, McKee C, Bakshi S, et al. Mesenchymal stem cells: cell therapy and regeneration potential. J Tissue Eng Regen Med. 2019;13(9):1738-1755.
[8]
Eddershaw PJ, Beresford AP, Bayliss MK. ADME/PK as part of a rational approach to drug discovery. Drug Discov Today. 2000;5(9):409-414.
[9]
Lucas AJ, Sproston JL, Barton P, Riley RJ. Estimating human ADME properties, pharmacokinetic parameters and likely clinical dose in drug discovery. Expert Opin Drug Discov. 2019;14(12):1313-1327.
[10]
Lang K, Matys K, Bennett P, Kakkanaiah VN. Flow cytometry and pharmacokinetics. Bioanalysis. 2021;13(21):1645-1651.
[11]
Yamamoto S, Matsumoto S-i, Goto A, et al. Quantitative PCR methodology with a volume-based unit for the sophisticated cellular kinetic evaluation of chimeric antigen receptor T cells. Sci Rep. 2020;10(1):17884.
[12]
Wu Q, Wang Y, Wang X, et al. Pharmacokinetic and pharmacodynamic studies of CD19 CAR T cell in human leukaemic xenograft models with dual-modality imaging. J Cell Mol Med. 2021;25(15):7451-7461.
[13]
Shim G, Lee S, Han J, et al. Pharmacokinetics and in vivo fate of intra-articularly transplanted human bone marrow-derived clonal mesenchymal stem cells. Stem Cells Dev. 2015;24(9):1124-1132.
[14]
Creane M, Howard L, O'Brien T, Coleman CM. Biodistribution and retention of locally administered human mesenchymal stromal cells: quantitative polymerase chain reaction–based detection of human DNA in murine organs. Cytotherapy. 2017;19(3):384-394.
[15]
Ford JW, Welling III TH, Stanley JC, Messina LM. PKH26 and125I-PKH95: characterization and efficacy as labels forin vitroandin vivoendothelial cell localization and tracking. J Surg Res. 1996;62(1):23-28.
[16]
Park B-N, Shim W, Lee G, et al. Early distribution of intravenously injected mesenchymal stem cells in rats with acute brain trauma evaluated by 99mTc-HMPAO labeling. Nucl Med Biol. 2011;38(8):1175-1182.
[17]
Khot A, Matsueda S, Thomas VA, Koya RC, Shah DK. Measurement and quantitative characterization of whole-body pharmacokinetics of exogenously administered T cells in mice. J Pharmacol Exp Ther. 2019;368(3):503-513.
[18]
Roca M, de Vries EF, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with 111 In-oxine. Eur J Nucl Med Mol Imaging. 2010;37:835-841.
[19]
Weist MR, Starr R, Aguilar B, et al. PET of adoptively transferred chimeric antigen receptor T cells with 89Zr-oxine. J Nucl Med. 2018;59(10):1531-1537.
[20]
Gawne PJ, Man F, Blower PJ, TM de Rosales R. Direct cell radiolabeling for in vivo cell tracking with PET and SPECT imaging. Chem Rev. 2022;122(11):10266-10318.
[21]
Morimoto-Ishikawa D, Hanaoka K, Watanabe S, et al. Evaluation of the performance of a high-resolution time-of-flight PET system dedicated to the head and breast according to NEMA NU 2–2012 standard. EJNMMI Phys. 2022;9(1):88.
[22]
Ritt P. Recent developments in SPECT/CT. Elsevier; 2022:276-285.
[23]
Cherry SR, Jones T, Karp JS, Qi J, Moses WW, Badawi RD. Total-body PET: maximizing sensitivity to create new opportunities for clinical research and patient care. J Nucl Med. 2018;59(1):3-12.
[24]
Prachayasittikul V, Prachayasittikul S, Ruchirawat S, Prachayasittikul V. 8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications. Drug Des Devel Ther. 2013;7:1157-1178.
[25]
Charoenphun P, Meszaros LK, Chuamsaamarkkee K, et al. [89 Zr] Oxinate 4 for long-term in vivo cell tracking by positron emission tomography. Eur J Nucl Med Mol Imaging. 2015;42:278-287.
[26]
Sato N, Wu H, Asiedu KO, Szajek LP, Griffiths GL, Choyke PL. 89Zr-oxine complex PET cell imaging in monitoring cell-based therapies. Radiology. 2015;275(2):490-500.
[27]
Sato N, Stringaris K, Davidson-Moncada JK, et al. In vivo tracking of adoptively transferred natural killer cells in rhesus macaques using 89zirconium-oxine cell labeling and PET imagingin vivo tracking of NK cells in macaques using 89Zr-oxine PET. Clin Cancer Res. 2020;26(11):2573-2581.
[28]
Wang X-y, Wang Y, Wu Q, et al. Feasibility study of 68Ga-labeled CAR T cells for in vivo tracking using micro-positron emission tomography imaging. Acta Pharmacol Sin. 2021;42(5):824-831.
[29]
Gawne P, Man F, Fonslet J, et al. Manganese-52: applications in cell radiolabelling and liposomal nanomedicine PET imaging using oxine (8-hydroxyquinoline) as an ionophore. Dalton Trans. 2018;47(28):9283-9293.
[30]
Socan A, Petrik M, Peitl PK, et al. On-cartridge preparation and evaluation of 68Ga-, 89Zr-and 64Cu-precursors for cell radiolabelling. Nucl Med Biol. 2019;71:23-31.
[31]
Lechermann LM, Manavaki R, Attili B, et al. Detection limit of 89Zr-labeled T cells for cellular tracking: an in vitro imaging approach using clinical PET/CT and PET/MRI. EJNMMI Res. 2020;10(1):1-12.
[32]
Man F, Lim L, Volpe A, et al. In vivo PET tracking of 89Zr-labeled Vγ9Vδ2 T cells to mouse xenograft breast tumors activated with liposomal alendronate. Mol Ther. 2019;27(1):219-229.
[33]
Hider RC, Hoffbrand AV. The role of deferiprone in iron chelation. N Engl J Med. 2018;379(22):2140-2150.
[34]
Brittenham GM. Iron-chelating therapy for transfusional iron overload. N Engl J Med. 2011;364(2):146-156.
[35]
Liu ZD, Hider RC. Design of iron chelators with therapeutic application. Coord Chem Rev. 2002;232(1-2):151-171.
[36]
Zhou T, Ma Y, Kong X, Hider RC. Design of iron chelators with therapeutic application. Dalton Trans. 2012;41(21):6371-6389.
[37]
Habib HM, Ibrahim S, Zaim A, Ibrahim WH. The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators. Biomed Pharmacother. 2021;136:111228.
[38]
Kontoghiorghes GJ, Pattichi K, Hadjigavriel M, Kolnagou A. Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1). Transfus Sci. 2000;23(3):211-223.
[39]
Piga A, Roggero S, Salussolia I, Massano D, Serra M, Longo F. Deferiprone. Ann N Y Acad Sci. 2010;1202(1):75-78.
[40]
Deri MA, Zeglis BM, Francesconi LC, Lewis JS. PET imaging with 89Zr: from radiochemistry to the clinic. Nucl Med Biol. 2013;40(1):3-14.
[41]
Yan G, Wang X, Fan Y, et al. Immuno-PET imaging of TNF-α in colitis using 89Zr-DFO-infliximab. Mol Pharm. 2022;19(10):3632-3639.
[42]
Dijkers EC, Kosterink JG, Rademaker AP, et al. Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu immunoPET imaging. J Nucl Med. 2009;50(6):974-981.
[43]
Shah NR. Advances in iron chelation therapy: transitioning to a new oral formulation. Drugs Context. 2017;6:212502.
[44]
Hamilton KO, Stallibrass L, Hassan I, Jin Y, Halleux C, Mackay M. The transport of two iron chelators, desferrioxamine B and L1, across Caco-2 monolayers. Br J Haematol. 1994;86(4):851-857.
[45]
Mobarra N, Shanaki M, Ehteram H, et al. A review on iron chelators in treatment of iron overload syndromes. Int J Hematol Oncol Stem Cell Res. 2016;10(4):239-247.
[46]
Yang J, Moyana T, MacKenzie S, Xia Q, Xiang J. One hundred seventy-fold increase in excretion of an FV fragment-tumor necrosis factor alpha fusion protein (sFV/TNF-α) from Escherichia coli caused by the synergistic effects of glycine and Triton X-100. Appl Environ Microbiol. 1998;64(8):2869-2874.
[47]
Hoetelmans RW, Prins FA, Cornelese-ten Velde I, van der Meer J, van de Velde CJ, van Dierendonck JH. Effects of acetone, methanol, or paraformaldehyde on cellular structure, visualized by reflection contrast microscopy and transmission and scanning electron microscopy. Appl Immunohistochem Mol Morphol. 2001;9(4):346-351.
[48]
Wynn RF, Hart CA, Corradi-Perini C, et al. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood. 2004;104(9):2643-2645.
[49]
Goldman JM, Apperley JF, Jones L, et al. Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med. 1986;314(4):202-207.
[50]
Ikehara S. Bone marrow transplantation for autoimmune diseases. Acta Haematol. 1998;99(3):116-132.
[51]
Lin H, Sohn J, Shen H, Langhans MT, Tuan RS. Bone marrow mesenchymal stem cells: aging and tissue engineering applications to enhance bone healing. Biomaterials. 2019;203:96-110.
[52]
Oliveira FA, Nucci MP, Filgueiras IS, et al. Noninvasive tracking of hematopoietic stem cells in a bone marrow transplant model. Cells. 2020;9(4):939.
[53]
Asaithamby A, Chen DJ. Cellular responses to DNA double-strand breaks after low-dose γ-irradiation. Nucleic Acids Res. 2009;37(12):3912-3923.
[54]
Robbins M, Zhao W. Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int J Radiat Biol. 2004;80(4):251-259.
[55]
Heylmann D, Rödel F, Kindler T, Kaina B. Radiation sensitivity of human and murine peripheral blood lymphocytes, stem and progenitor cells. Biochim Biophys Acta Rev Cancer. 2014;1846(1):121-129.
[56]
Entezari S, Haghi SM, Norouzkhani N, et al. Iron chelators in treatment of iron overload. J Toxicol. 2022;2022:4911205.

RIGHTS & PERMISSIONS

2024 2024 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.
PDF

Accesses

Citations

Detail

Sections
Recommended

/