Longitudinal PET imaging of muscular inflammation using 18F-DPA-714 and 18F-Alfatide II and differentiation with tumors

Chenxi Wu, Xuyi Yue, Lixin Lang, Dale O Kiesewetter, Fang Li, Zhaohui Zhu, Gang Niu, Xiaoyuan Chen, Chenxi Wu, Xuyi Yue, Lixin Lang, Dale O Kiesewetter, Fang Li, Zhaohui Zhu, Gang Niu, Xiaoyuan Chen

Abstract

Aim: (18)F-DPA-714 is a PET tracer that recognizes macrophage translocator protein (TSPO), and (18)F-Alfatide II ((18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2) is specific for integrin αvβ3. This study aims to apply these two tracers for longitudinal PET imaging of muscular inflammation, and evaluate the value of (18)F-DPA-714 in differentiating inflammation from tumor.

Methods: RAW264.7 mouse macrophage cells were used for cell uptake analysis of (18)F-DPA-714. A mouse hind limb muscular inflammation model was established by intramuscular injection of turpentine oil. For the inflammation model, PET imaging was performed at different days using (18)F-DPA-714 and (18)F-Alfatide II. The specificity of the imaging probes was tested by co- or pre-injection of PK11195 or unlabeled RGD (Arg-Gly-Asp) peptide. PET imaging using (18)F-DPA-714 was performed in A549, HT29, U87MG, INS-1, and 4T1 xenograft models. Immunofluorescence staining was performed to evaluate infiltrated macrophages and angiogenesis in inflammation and/or tumors.

Results: Uptake of (18)F-DPA-714 in RAW264.7 cells was 45.5% at 1 h after incubation, and could be blocked by PK11195. PET imaging showed increased (18)F-DPA-714 and (18)F-Alfatide II uptake at inflammatory muscles. Peak uptake of (18)F-DPA-714 was seen on day 6 (4.02 ± 0.64 %ID/g), and peak uptake of (18)F-Alfatide II was shown on day 12 (1.87 ± 0.35 %ID/g) at 1 h p.i.. Tracer uptakes could be inhibited by PK11195 for (18)F-DPA-714 or cold RGD for (18)F-Alfatide II. Moreover, macrophage depletion with liposomal clodronate also reduced the local accumulation of both tracers. A549, HT29, U87MG, INS-1, and 4T1 tumor uptakes of (18)F-DPA-714 (0.46 ± 0.28, 0.91 ± 0.08, 1.69 ± 0.67, 1.13 ± 0.33, 1.22 ± 0.55 %ID/g at 1 h p.i., respectively) were significantly lower than inflammation uptake (All P < 0.05).

Conclusion: PET imaging using (18)F-DPA-714 as a TSPO targeting tracer could evaluate the dynamics of macrophage activation and infiltration in different stages of inflammatory diseases. The concomitant longitudinal PET imaging with both (18)F-DPA-714 and (18)F-Alfatide II matched the causal relationship between macrophage infiltration and angiogenesis. Moreover, we found (18)F-DPA-714 uptake in several types of tumors is significantly lower than that in inflammatory muscles, suggesting (18)F-DPA-714 PET has the potential for better differentiation of tumor and non-tumor inflammation.

Keywords: 18F-Alfatide II; 18F-DPA-714; TSPO; inflammation; positron emission tomography; tumor.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
(A) Cell uptake and efflux of 18F-DPA-714 in RAW264.7 cells with or without blocking agent PK11195 (n = 3, mean ± SD). (B) Cell uptake of 18F-Alfatide II in RAW264.7 cells (n = 3, mean ± SD).
Figure 2
Figure 2
(A) 18F-DPA-714 PET imaging of mouse muscular inflammation model on day 1, 6 and 26 after turpentine oil injection. White boxes indicate inflammatory muscles. (B) PET images based quantitative analysis of 18F-DPA-714 uptake in inflammatory muscles on day 1, 3, 6, 10, 14, 19 and 26 after turpentine oil injection. Peak uptake was seen on day 6 (4.02 ± 0.64 %ID/g). (C) Time activity curves (TACs) of inflammatory muscles from 1 h 18F-DPA-714 dynamic PET imaging with PK11195 displacement. (D) Representative transaxial PET images of 18F-DPA-714 uptake in inflammatory muscle before and after K11195 displacement.
Figure 3
Figure 3
(A) 18F-Alfatide II PET imaging of mouse muscular inflammation model on day 1, 12 and 26 after turpentine oil injection. White boxes indicate inflammatory muscles. (B) PET images based quantitative analysis of 18F-Alfatide II uptake in inflammatory muscles on day 1, 2, 4, 8, 12, 16 and 26 after turpentine oil injection. Peak uptake was seen on day 12 (1.87 ± 0.35 %ID/g). (C) Quantification of 18F-Alfatide II uptake in inflammatory muscles on day 9 after turpentine injection with or without cold RGD blocking. (D) Representative transaxial PET images of 18F-Alfatide II uptake in inflammatory muscle without and with cold RGD blocking.
Figure 4
Figure 4
(A) PET imaging based quantification of 18F-DPA-714 uptake in inflammatory muscles at day 6, 10 and 14 after turpentine oil injection with or without macrophage depletion. The mice received 1.4mg (200µl) liposomal clodronate on day 3 after turpentine oil injection and then 0.7 mg (100 µl) every 2-3 days (Scheme 1). (B) Quantification of 18F-Alfatide II uptake in inflammatory muscles on day 12 after turpentine oil injection under different macrophage depletion methods. Mice with treatment scheme 2 (1.4 mg liposomal clodronate started 2 days before turpentine oil injection and then 0.7 mg every 2-3 days) showed even lower uptake compared to mice with treatment scheme 1 (1.4 mg liposomal clodronate started on day 3 and then 0.7 mg every 2-3 days).
Figure 5
Figure 5
(A) 18F-DPA-714 PET imaging of mice bearing A549, HT29, U87MG, INS-1, 4T1 tumors. (B) Quantitative analysis of different tumor uptakes of 18F-DPA-714 compared to inflammation 18F-DPA-714 uptake on day 6 after turpentine injection.

References

    1. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7. doi:10.1038/nature05485.
    1. Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease--a double-edged sword. Neuron. 2002;35:419–32.
    1. Libby P. Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr. 2006;83:456S–60S.
    1. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7. doi:10.1038/nature01322.
    1. Kostakoglu L, Agress H Jr, Goldsmith SJ. Clinical role of FDG PET in evaluation of cancer patients. Radiographics: a review publication of the Radiological Society of North America, Inc. 2003;23:315–40. quiz 533. doi:10.1148/rg.232025705.
    1. Haroon A, Zumla A, Bomanji J. Role of fluorine 18 fluorodeoxyglucose positron emission tomography-computed tomography in focal and generalized infectious and inflammatory disorders. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2012;54:1333–41. doi:10.1093/cid/cis193.
    1. van Waarde A, Cobben DC, Suurmeijer AJ, Maas B, Vaalburg W, de Vries EF. et al. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model. J Nucl Med. 2004;45:695–700.
    1. van der Laken CJ, Elzinga EH, Kropholler MA, Molthoff CF, van der Heijden JW, Maruyama K. et al. Noninvasive imaging of macrophages in rheumatoid synovitis using 11C-(R)-PK11195 and positron emission tomography. Arthritis Rheum. 2008;58:3350–5. doi:10.1002/art.23955.
    1. Gent YY, Voskuyl AE, Kloet RW, van Schaardenburg D, Hoekstra OS, Dijkmans BA. et al. Macrophage positron emission tomography imaging as a biomarker for preclinical rheumatoid arthritis: findings of a prospective pilot study. Arthritis Rheum. 2012;64:62–6. doi:10.1002/art.30655.
    1. Boutin H, Prenant C, Maroy R, Galea J, Greenhalgh AD, Smigova A. et al. [18F]DPA-714: direct comparison with [11C]PK11195 in a model of cerebral ischemia in rats. PLoS One. 2013;8:e56441.. doi:10.1371/journal.pone.0056441.
    1. Harhausen D, Sudmann V, Khojasteh U, Muller J, Zille M, Graham K. et al. Specific imaging of inflammation with the 18 kDa translocator protein ligand DPA-714 in animal models of epilepsy and stroke. PLoS One. 2013;8:e69529.. doi:10.1371/journal.pone.0069529.
    1. Yu I, Inaji M, Maeda J, Okauchi T, Nariai T, Ohno K. et al. Glial cell-mediated deterioration and repair of the nervous system after traumatic brain injury in a rat model as assessed by positron emission tomography. J Neurotrauma. 2010;27:1463–75. doi:10.1089/neu.2009.1196.
    1. Maeda J, Zhang MR, Okauchi T, Ji B, Ono M, Hattori S. et al. In vivo positron emission tomographic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer's disease and related disorders. J Neurosci. 2011;31:4720–30. doi:10.1523/JNEUROSCI.3076-10.2011.
    1. Gaemperli O, Shalhoub J, Owen DR, Lamare F, Johansson S, Fouladi N. et al. Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography. Eur Heart J. 2012;33:1902–10. doi:10.1093/eurheartj/ehr367.
    1. Lamare F, Hinz R, Gaemperli O, Pugliese F, Mason JC, Spinks T. et al. Detection and quantification of large-vessel inflammation with 11C-(R)-PK11195 PET/CT. J Nucl Med. 2011;52:33–9. doi:10.2967/jnumed.110.079038.
    1. Chauveau F, Boutin H, Van Camp N, Dolle F, Tavitian B. Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging. 2008;35:2304–19. doi:10.1007/s00259-008-0908-9.
    1. Doorduin J, Klein HC, Dierckx RA, James M, Kassiou M, de Vries EF. [11C]-DPA-713 and [18F]-DPA-714 as new PET tracers for TSPO: a comparison with [11C]-(R)-PK11195 in a rat model of herpes encephalitis. Mol Imaging Biol. 2009;11:386–98. doi:10.1007/s11307-009-0211-6.
    1. Chauveau F, Van Camp N, Dolle F, Kuhnast B, Hinnen F, Damont A. et al. Comparative evaluation of the translocator protein radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation. J Nucl Med. 2009;50:468–76. doi:10.2967/jnumed.108.058669.
    1. Kinne RW, Brauer R, Stuhlmuller B, Palombo-Kinne E, Burmester GR. Macrophages in rheumatoid arthritis. Arthritis Res. 2000;2:189–202. doi:10.1186/ar86.
    1. Meleth AD, Agron E, Chan CC, Reed GF, Arora K, Byrnes G. et al. Serum inflammatory markers in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2005;46:4295–301. doi:10.1167/iovs.04-1057.
    1. Lue H, Kleemann R, Calandra T, Roger T, Bernhagen J. Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microbes Infect. 2002;4:449–60.
    1. Beer AJ, Kessler H, Wester HJ, Schwaiger M. PET Imaging of Integrin alphaVbeta3 Expression. Theranostics. 2011;1:48–57.
    1. Lee J, Lee TS, Ryu J, Hong S, Kang M, Im K. et al. RGD peptide-conjugated multimodal NaGdF4:Yb3+/Er3+ nanophosphors for upconversion luminescence, MR, and PET imaging of tumor angiogenesis. J Nucl Med. 2013;54:96–103. doi:10.2967/jnumed.112.108043.
    1. Cao Q, Cai W, Li ZB, Chen K, He L, Li HC. et al. PET imaging of acute and chronic inflammation in living mice. Eur J Nucl Med Mol Imaging. 2007;34:1832–42. doi:10.1007/s00259-007-0451-0.
    1. Laitinen I, Saraste A, Weidl E, Poethko T, Weber AW, Nekolla SG. et al. Evaluation of alphavbeta3 integrin-targeted positron emission tomography tracer 18F-galacto-RGD for imaging of vascular inflammation in atherosclerotic mice. Circ Cardiovasc Imaging. 2009;2:331–8. doi:10.1161/CIRCIMAGING.108.846865.
    1. Guo J, Lang L, Hu S, Guo N, Zhu L, Sun Z, Comparison of Three Dimeric F-AlF-NOTA-RGD Tracers. Mol Imaging Biol. 2013. doi:10.1007/s11307-013-0668-1.
    1. Hamazawa Y, Koyama K, Okamura T, Wada Y, Wakasa T, Okuma T. et al. Comparison of dynamic FDG-microPET study in a rabbit turpentine-induced inflammatory model and in a rabbit VX2 tumor model. Ann Nucl Med. 2007;21:47–55.
    1. Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Front Biosci. 1997;2:d12–26.
    1. Koneru R, Kobiler D, Lehrer S, Li J, van Rooijen N, Banerjee D. et al. Macrophages play a key role in early blood brain barrier reformation after hypothermic brain injury. Neurosci Lett. 2011;501:148–51. doi:10.1016/j.neulet.2011.06.062.
    1. Villalta SA, Rinaldi C, Deng B, Liu G, Fedor B, Tidball JG. Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype. Hum Mol Genet. 2011;20:790–805. doi:10.1093/hmg/ddq523.
    1. Tidball JG, Wehling-Henricks M. Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo. J Physiol. 2007;578:327–36. doi:10.1113/jphysiol.2006.118265.
    1. Li J, Hsu HC, Yang P, Wu Q, Li H, Edgington LE. et al. Treatment of arthritis by macrophage depletion and immunomodulation: testing an apoptosis-mediated therapy in a humanized death receptor mouse model. Arthritis Rheum. 2012;64:1098–109. doi:10.1002/art.33423.
    1. Denkinger CM, Denkinger M, Kort JJ, Metz C, Forsthuber TG. In vivo blockade of macrophage migration inhibitory factor ameliorates acute experimental autoimmune encephalomyelitis by impairing the homing of encephalitogenic T cells to the central nervous system. J Immunol. 2003;170:1274–82.
    1. Ohkawara T, Nishihira J, Takeda H, Hige S, Kato M, Sugiyama T. et al. Amelioration of dextran sulfate sodium-induced colitis by anti-macrophage migration inhibitory factor antibody in mice. Gastroenterology. 2002;123:256–70.
    1. Wu C, Li F, Niu G, Chen X. PET imaging of inflammation biomarkers. Theranostics. 2013;3:448–66. doi:10.7150/thno.6592.
    1. Howard KA, Paludan SR, Behlke MA, Besenbacher F, Deleuran B, Kjems J. Chitosan/siRNA nanoparticle-mediated TNF-alpha knockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model. Mol Ther. 2009;17:162–8. doi:10.1038/mt.2008.220.
    1. Black KL, Ikezaki K, Santori E, Becker DP, Vinters HV. Specific high-affinity binding of peripheral benzodiazepine receptor ligands to brain tumors in rat and man. Cancer. 1990;65:93–7.
    1. Zheng J, Boisgard R, Siquier-Pernet K, Decaudin D, Dolle F, Tavitian B. Differential expression of the 18 kDa translocator protein (TSPO) by neoplastic and inflammatory cells in mouse tumors of breast cancer. Mol Pharm. 2011;8:823–32. doi:10.1021/mp100433c.
    1. Schmieder A, Michel J, Schonhaar K, Goerdt S, Schledzewski K. Differentiation and gene expression profile of tumor-associated macrophages. Seminars in cancer biology. 2012;22:289–97. doi:10.1016/j.semcancer.2012.02.002.
    1. Quatromoni JG, Eruslanov E. Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. American journal of translational research. 2012;4:376–89.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit