Magnetoliposomes (MLs) were synthesized and tested for longitudinal monitoring of transplanted pancreatic islets using magnetic resonance imaging (MRI) in rat models. The rat insulinoma cell line INS-1E and isolated pancreatic islets from outbred and inbred rats were used to optimize labeling conditions in vitro. Strong MRI contrast was generated by islets exposed to 50 µg Fe/ml for 24 hours without any increased cell death, loss of function or other signs of toxicity. In vivo experiments showed that pancreatic islets (50-1000 units) labeled with MLs were detectable for up to 6 weeks post-transplantation in the kidney subcapsular space. Islets were also monitored for two weeks following transplantation through the portal vein of the liver. Hereby, islets labeled with MLs and transplanted under the left kidney capsule were able to correct hyperglycemia and had stable MRI signals until nephrectomy. Interestingly, in vivo MRI of streptozotocin induced diabetic rats transplanted with allogeneic islets demonstrated loss of MRI contrast between 7-16 days, indicative of loss of islet structure. MLs used in this study were not only beneficial for monitoring the location of transplanted islets in vivo with high sensitivity but also reported on islet integrity and hereby indirectly on islet function and rejection.

Biomedical MRI MoSAIC Department of Imaging and Pathology Biomedical Sciences Group KU LEUVEN Herestraat 49 3000 Leuven Belgium

Clinical and Experimental Endocrinology Department of Chronic Diseases Metabolism and Ageing KU LEUVEN Herestraat 49 3000 Leuven Belgium

Department of Biophysics Institute of Biophysics and Informatics 1st Faculty of Medicine Charles University Salmovska 1 120 00 Prague 2 Czech Republic

Diabetes Center Institute for Clinical and Experimental Medicine Videnska 1958 9 140 21 Prague Czech Republic

Diagnostic Tools and Methods Advanced Av Mestre José Veiga s n 4715 330 Braga Portugal

Lab of Histology Biomedical Research Institute Hasselt University Campus Diepenbeek Agoralaan B3590 Diepenbeek Belgium

Laboratory of BioNanoColloids Interdisciplinary Research Centre KULAK KU LEUVEN Etienne Sabbelaan 53 8500 Kortrijk Belgium

MR Spectroscopy Unit Institute for Clinical and Experimental Medicine Videnska 1958 9 140 21 Prague Czech Republic

Zobrazit více v PubMed

Olefsky JM. Prospects for research in diabetes mellitus. J.A.M.A. 2001;285(5):628–32. doi: 10.1001/jama.285.5.628. PubMed DOI

Bailes BK. Diabetes mellitus and its chronic complications. A.O.R.N. J. 2002;76:266–82. PubMed

Bloomgarden ZT. Diabetes complications. Diab. Care. 2004;27:1506–14. doi: 10.2337/diacare.27.6.1506. PubMed DOI

Shapiro AMJ, et al. Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen. N. Engl. J. Med. 2000;343:230–8. doi: 10.1056/NEJM200007273430401. PubMed DOI

Narang AS, Mahato RI. Biological and biomaterial approaches for improved islet transplantation. Pharm. Rev. 2006;58:194–243. doi: 10.1124/pr.58.2.6. PubMed DOI

Shapiro AM, et al. International trial of the Edmonton protocol for islet transplantation. N. Engl. J. Med. 2006;355:1318–30. doi: 10.1056/NEJMoa061267. PubMed DOI

Ryan EA, et al. Five-year follow-up after clinical islet transplantation. Diabetes. 2005;54:2060–9. doi: 10.2337/diabetes.54.7.2060. PubMed DOI

Robertson RP. Islet Transplantation a decade later and strategies for filling a half-full glass. Diabetes. 2010;59:1285–91. doi: 10.2337/db09-1846. PubMed DOI PMC

Vantyghen MC, et al. Primary graft function, metabolic control, and graft survival after islet transplantation. Diab. Care. 2009;28:1358–65. PubMed PMC

Barshes NR, Wyllie S, Goss JA. Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts. J. Leukoc. Biol. 2005;77:587–97. doi: 10.1189/jlb.1104649. PubMed DOI

Shapiro AM, et al. Islets Transplantation in Type 1 diabetes: ongoing challenges, refined procedures, and long-term outcome. Rev Diabet Stud. 2012;9:385–406. doi: 10.1900/RDS.2012.9.385. PubMed DOI PMC

Desai NM, et al. Elevated portal vein drug levels of sirolimus and tacrolimus in islet transplant recipients: local immunosuppression or islet toxicity? Transplantation. 2003;76:1623–5. doi: 10.1097/01.TP.0000081043.23751.81. PubMed DOI

Evgenov NV, et al. In vivo imaging of immune rejection in transplanted pancreatic islets. Diabetes. 2006;55:2419–28. doi: 10.2337/db06-0484. PubMed DOI

Chen X, Zhang X, Larson CS, Baker MS, Kaufman DB. In vivo bioluminescence imaging of transplanted islets and early detection of graft rejection. Transplantation. 2006;81:1421–7. doi: 10.1097/01.tp.0000206109.71181.bf. PubMed DOI

Mattsson G, Jansson L, Carlsson PO. Decreased vascular density in mouse pancreatic islets after transplantation. Diabetes. 2002;51:1362–6. doi: 10.2337/diabetes.51.5.1362. PubMed DOI

Korsgren O, et al. Optimising islet engraftment is critical for successful clinical islet transplantation. Diabetologia. 2008;51:227–32. doi: 10.1007/s00125-007-0868-9. PubMed DOI

Carlsson PO, Palm F, Mattsson G. Low revascularization of experimentally transplanted human pancreatic islets. J. Clin. Endocrinol. Metab. 2002;87:5418–23. doi: 10.1210/jc.2002-020728. PubMed DOI

Fiorina P, Secchi A. Pancreatic islet cell transplant for treatment of diabetes. Endocrinol. Metab. Clin. North Am. 2007;36:999–1013. doi: 10.1016/j.ecl.2007.07.004. PubMed DOI

Saudek F, et al. Magnetic resonance imaging of pancreatic islets transplanted into the liver in humans. Transplantation. 2010;90:1602–6. doi: 10.1097/TP.0b013e3181ffba5e. PubMed DOI

Calafiore R, et al. Microencapsulated pancreatic islet allografts into nonimmunosupressed patients with type 1 diabetes: first two cases. Diab Care. 2006;29:137–8. doi: 10.2337/diacare.29.01.06.dc05-1270. PubMed DOI

Jirak D, et al. Monitoring the survival of islet transplants by MRI using a novel technique for their automated detection and quantification. Magma. 2009;22:257–65. doi: 10.1007/s10334-009-0172-4. PubMed DOI

Jirak D, et al. MRI of transplanted pancreatic islets. Magn. Reson. Med. 2004;52:1228–33. doi: 10.1002/mrm.20282. PubMed DOI

Berkova Z, et al. Labeling of pancreatic islets with iron oxide nanoparticles for in vivo detection with magnetic resonance. Transplantation. 2008;85:155–9. doi: 10.1097/01.tp.0000297247.08627.ff. PubMed DOI

Himmelreich U, Dresselaers T. Cell labeling and tracking for experimental models using Magn. Reson. Imag. Meth. 2009;48:112–24. PubMed

Cromer Berman SM, Walczak P, Bulte JW. Tracking stem cells using magnetic nanoparticles. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2011;3:343–55. doi: 10.1002/wnan.140. PubMed DOI PMC

Bulte J, Duncan I, Frank J. In vivo magnetic resonance tracking of magnetically labeled cells after transplantation. J. Cereb. Blood Flow Metab. 2002;22:899–907. doi: 10.1097/00004647-200208000-00001. PubMed DOI

Wilhelm C, Gazeau F. Universal cell labelling with anionic magnetic nanoparticles. Biomaterials. 2008;29:3161–74. doi: 10.1016/j.biomaterials.2008.04.016. PubMed DOI

Wang YX. Superparamagnetic iron oxide based MRI contrast agents: Current status of clinical application. Quant. Imaging Med. Surg. 2011;1:35–40. PubMed PMC

Arbab AS, et al. model of lysosomal metabolism of dextran coated superparamagnetic iron oxide (SPIO) nanoparticles: implications for cellular magnetic resonance imaging. NMR Biomed. 2005;18:383–9. doi: 10.1002/nbm.970. PubMed DOI

Soenen SJ, et al. Stable long-term intracellular labelling with fluorescently tagged cationic magnetoliposomes. Chembiochem. 2009;10(2):257–67. doi: 10.1002/cbic.200800510. PubMed DOI

Soenen SJ, Vande Velde G, Ketkar-Atre A, Himmelreich U, De Cuyper M. Magnetoliposomes as MRI contrast agent. WIREs Nanomed Nanobiotechnol. 2011;3:197–211. doi: 10.1002/wnan.122. PubMed DOI

Soenen SJ, et al. Intracellular nanoparticle coating stability determines nanoparticle diagnostics efficacy and cell functionality. Small. 2010;6:2136–45. doi: 10.1002/smll.201000763. PubMed DOI

De Cuyper M, Soenen SJ. Cationic Magnetoliposomes. Methods in Molecular Biology. 2010;605:97–111. doi: 10.1007/978-1-60327-360-2_6. PubMed DOI

Garcia Ribeiro R.S., et al. Improved Labeling of Pancreatic Islets Using Cationic Magnetoliposomes. J. Pers. Med. 2018;8:12. doi: 10.3390/jpm8010012. PubMed DOI PMC

Soenen SJ, Baert J, De Cuyper M. Optimal conditions for labelling of 3T3 fibroblasts with magnetoliposomes without affecting cellular viability. Chembiochem. 2007;8:2067–77. doi: 10.1002/cbic.200700327. PubMed DOI

Moore A, Weissleder R, Bogdanov A., Jr. Uptake of dextran-coated monocrystalline iron oxides in tumor cells and macrophages. J. Magn. Reson. Imaging. 1997;7:1140–5. doi: 10.1002/jmri.1880070629. PubMed DOI

Bulte JW, et al. Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol. 2001;19:1141–7. doi: 10.1038/nbt1201-1141. PubMed DOI

Biacone L, et al. Magnetic resonance imaging of gadolinium-labeled pancreatic islets for experimental transplantation. NMR Biomed. 2007;20:40–8. doi: 10.1002/nbm.1088. PubMed DOI

Evgenov NV, Medarova Z, Dai G, Bonner-Weir S, Moore A. In vivo imaging of islet transplantation. Nat Med. 2006;12:144–8. doi: 10.1038/nm1316. PubMed DOI

Jin SM, et al. Feasibility of islet magnetic resonance imaging using ferumoxytol in intraportal islet transplantation. Biomaterials. 2015;52:272–80. doi: 10.1016/j.biomaterials.2015.02.055. PubMed DOI

Jung MJ, et al. MRI of transplanted surface-labeled pancreatic islets with heparinized superparamagnetic iron oxide nanoparticles. Biomaterials. 2011;32:9391–400. doi: 10.1016/j.biomaterials.2011.08.070. PubMed DOI

Korosoglou G, et al. Noninvasive detection of macrophage-rich atherosclerotic plaque in hyperlipidemic rabbits using “positive contrast” magnetic resonance imaging. J. Am. Coll. Cardiol. 2008;52:483–491. doi: 10.1016/j.jacc.2008.03.063. PubMed DOI PMC

Stuber M, et al. Positive contrast visualization of iron oxide-labeled stem cells using inversion-recovery with ON-resonant water suppression (IRON) Magn Reson Med. 2007;58:1072–1077. doi: 10.1002/mrm.21399. PubMed DOI

Zhang L, et al. T(1)-weighted ultrashort echo time method for positive contrast imaging of magnetic nanoparticles and cancer cells bound with the targeted nanoparticles. J. Magn. Reson. Imaging. 2011;33:194–202. doi: 10.1002/jmri.22412. PubMed DOI PMC

Bottino R, et al. Transplantation of allogeneic islets of Langerhans in the rat liver: effects of macrophage depletion on graft survival and microenvironment activation. Diabetes. 1998;47:316–23. doi: 10.2337/diabetes.47.3.316. PubMed DOI

Davalli A, et al. Vulnerability of islets in the immediate post transplantation period: dynamic changes in structure and function. Diabetes. 1996;45:1161–7. doi: 10.2337/diab.45.9.1161. PubMed DOI

Merani S, Toso C, Emamaullee J, Shapiro AM. Optimal implantation site for pancreatic islet transplantation. Br. J. Surg. 2008;12:1449–1461. doi: 10.1002/bjs.6391. PubMed DOI

Zacharovova K, et al. Processing of superparamagnetic iron contrast agent ferucarbotran in transplanted pancreatic islets. Cont. Med. Mol. Imaging. 2012;7:485–493. doi: 10.1002/cmmi.1477. PubMed DOI

Kriz J, et al. Detection of pancreatic islet allograft impairment in advance of functional failure using magnetic resonance imaging. Transpl. Int. 2012;25:250–260. doi: 10.1111/j.1432-2277.2011.01403.x. PubMed DOI

Hoo HT, et al. Imaging islets labeled with magnetic nanoparticles at 1.5 Tesla. Diabetes. 2006;55(11):2931–8. doi: 10.2337/db06-0393. PubMed DOI

Boonen K, et al. Neuropeptides of the islets of Langerhans: A peptidomics study. Gen. Comp. 2007;152:231–41. doi: 10.1016/j.ygcen.2007.05.002. PubMed DOI