Advertisement

Comparison of Al18F- and 68Ga-labeled NOTA-PEG4-LLP2A for PET imaging of very late antigen-4 in melanoma

  • Yongkang Gai
  • Lujie Yuan
  • Lingyi Sun
  • Huiling Li
  • Mengting Li
  • Hanyi Fang
  • Bouhari Altine
  • Qingyao Liu
  • Yongxue Zhang
  • Dexing ZengEmail author
  • Xiaoli LanEmail author
Original Paper
  • 27 Downloads

Abstract

Malignant melanoma is an aggressive cancer with poor prognosis. Very late antigen-4 (VLA-4) is overexpressed in melanoma and many other tumors, making it an attractive target for developing molecular diagnostic and therapeutic agents. We compared Al18F- and 68Ga-labeled LLP2A peptides for PET imaging of VLA-4 expression in melanoma. The peptidomimetic ligand LLP2A was modified with chelator 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), and the resulting NOTA-PEG4-LLP2A peptide was then radiolabeled with Al18F or 68Ga. The two labeled peptides were assayed for in vitro and in vivo VLA-4 targeting efficiency. Good Al18F and 68Ga radiolabeling yields were achieved, and the resulting PET tracers showed good serum stability. In the in vivo evaluation of the B16F10 xenograft mouse model, both tracers exhibited high accumulation with good contrast in static PET images. Compared with 68Ga-NOTA-PEG4-LLP2A, Al18F-NOTA-PEG4-LLP2A resulted in relatively higher background, including higher liver uptake (1 h: 20.1 ± 2.6 vs. 15.3 ± 1.7%ID/g, P < 0.05; 2 h: 11.0 ± 1.2 vs. 8.0 ± 0.8%ID/g, P < 0.05) and lower tumor-to-blood ratios (2.5 ± 0.4 vs. 3.3 ± 0.5 at 1 h, P < 0.05; 5.1 ± 0.9 vs. 7.3 ± 0.6 at 2 h, P < 0.01) at some time points. The results obtained from the mice blocked with unlabeled peptides and VLA-4-negative A375 xenografts groups confirmed the high specificity of the developed tracers. Despite the relatively high liver uptake, both Al18F-NOTA-PEG4-LLP2A and 68Ga-NOTA-PEG4-LLP2A exhibited high VLA-4 targeting efficacy with comparable in vivo performance, rendering them promising candidates for imaging tumors that overexpress VLA-4.

Graphic abstract

Keywords

VLA-4 Melanoma Al18F radiolabeling 68Ga PET imaging LLP2A 

Notes

Acknowledgements

This work was supported, in part, by the National Natural Science Foundation of China (Nos. 81801738 and 81630049), the Fundamental Research Fund for the Chinese Central Universities of Huazhong University of Science and Technology (2017KFYXJJ235), opening foundation of Hubei key laboratory of molecular imaging (02.03.2017-187) and research foundation of Wuhan Union Hospital (02.03.2017-12). We also acknowledge the support from the National Institute of Biomedical Imaging and Bioengineering grant R21-EB020737, and the American Cancer Society Research Scholar ACS-RSG-17-004-01-CCE.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

775_2019_1742_MOESM1_ESM.pdf (210 kb)
Supplementary material 1 (PDF 210 kb)

References

  1. 1.
    Welch HG, Woloshin S, Schwartz LM (2005) Skin biopsy rates and incidence of melanoma: population based ecological study. BMJ 331(7515):481PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Trinh VA (2008) Current management of metastatic melanoma. Am J Health Syst Pharm 65(24 Suppl 9):S3–S9PubMedCrossRefGoogle Scholar
  3. 3.
    Mijnhout GS, Hoekstra OS, van Tulder MW, Teule GJ, Devillé WL (2001) Systematic review of the diagnostic accuracy of 18F-fluorodeoxyglucose positron emission tomography in melanoma patients. Cancer 91(8):1530–1542PubMedCrossRefGoogle Scholar
  4. 4.
    Pfannenberg C, Aschoff P, Schanz S, Eschmann SM, Plathow C, Eigentler TK, Garbe C, Brechtel K, Vonthein R, Bares R (2007) Prospective comparison of 18F-fluorodeoxyglucose positron emission tomography/computed tomography and whole-body magnetic resonance imaging in staging of advanced malignant melanoma. Eur J Cancer 43(3):557–564PubMedCrossRefGoogle Scholar
  5. 5.
    Rinne D, Baum RP, Hör G, Kaufmann R (1998) Primary staging and follow-up of high risk melanoma patients with whole-body 18F-fluorodeoxyglucose positron emission tomography. Cancer 82(9):1664–1671PubMedCrossRefGoogle Scholar
  6. 6.
    Strobel K, Bode B, Dummer R, Veit-Haibach P, Fischer D, Imhof L, Goldinger S, Steinert HC, Von Schulthess G (2009) Limited value of 18 F-FDG PET/CT and S-100B tumour marker in the detection of liver metastases from uveal melanoma compared to liver metastases from cutaneous melanoma. Eur J Nucl Med Mol Imaging 36(11):1774PubMedCrossRefGoogle Scholar
  7. 7.
    Servois V, Mariani P, Malhaire C, Petras S, Piperno-Neumann S, Plancher C, Levy-Gabriel C, Lumbroso-le Rouic L, Desjardins L, Salmon R (2010) Preoperative staging of liver metastases from uveal melanoma by magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET). Eur J Surg Oncol 36(2):189–194PubMedCrossRefGoogle Scholar
  8. 8.
    Choi EA, Gershenwald JE (2007) Imaging studies in patients with melanoma. Surg Oncol Clin N Am 16(2):403–430PubMedCrossRefGoogle Scholar
  9. 9.
    Wei W, Ehlerding EB, Lan X, Luo Q, Cai W (2018) PET and SPECT imaging of melanoma: the state of the art. Eur J Nucl Med Mol Imaging 45(1):132–150PubMedCrossRefGoogle Scholar
  10. 10.
    Xu X, Yuan L, Yin L, Jiang Y, Gai Y, Liu Q, Wang Y, Zhang Y, Lan X (2017) Synthesis and preclinical evaluation of 18F-PEG3-FPN for the detection of metastatic pigmented melanoma. Mol Pharm 14(11):3896–3905PubMedCrossRefGoogle Scholar
  11. 11.
    Feng H, Xia X, Li C, Song Y, Qin C, Liu Q, Zhang Y, Lan X (2016) Imaging malignant melanoma with 18F-5-FPN. Eur J Nucl Med Mol Imaging 43(1):113–122PubMedCrossRefGoogle Scholar
  12. 12.
    Ma X, Wang S, Wang S, Liu D, Zhao X, Chen H, Kang F, Yang W, Wang J, Cheng Z (2019) Biodistribution, radiation dosimetry, and clinical application of a melanin-targeted PET probe, 18F-P3BZA, in patients. J Nucl Med 60(1):16–22PubMedCrossRefGoogle Scholar
  13. 13.
    Xu X, Yuan L, Gai Y, Liu Q, Yin L, Jiang Y, Wang Y, Zhang Y, Lan X (2018) Targeted radiotherapy of pigmented melanoma with 131I-5-IPN. J Exp Clin Cancer Res 37(1):306PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Zhang C, Zhang Z, Lin K-S, Pan J, Dude I, Hundal-Jabal N, Colpo N, Bénard F (2017) Preclinical melanoma imaging with 68Ga-labeled α-melanocyte-stimulating hormone derivatives using PET. Theranostics 7(4):805PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Froidevaux S, Calame-Christe M, Schuhmacher J, Tanner H, Saffrich R, Henze M, Eberle AN (2004) A gallium-labeled DOTA-α-melanocyte-stimulating hormone analog for PET imaging of melanoma metastases. J Nucl Med 45(1):116–123PubMedGoogle Scholar
  16. 16.
    Zhang C, Zhang Z, Lin K-S, Lau J, Zeisler J, Colpo N, Perrin DM, Bénard F (2018) Melanoma imaging using 18F-labeled α-melanocyte-stimulating hormone derivatives with positron emission tomography. Mol Pharm 15(6):2116–2122PubMedCrossRefGoogle Scholar
  17. 17.
    Pohle K, Notni J, Bussemer J, Kessler H, Schwaiger M, Beer AJ (2012) 68Ga-NODAGA-RGD is a suitable substitute for 18F-Galacto-RGD and can be produced with high specific activity in a cGMP/GRP compliant automated process. Nucl Med Biol 39(6):777–784PubMedCrossRefGoogle Scholar
  18. 18.
    Notni J, Pohle K, Wester H-J (2013) Be spoilt for choice with radiolabelled RGD peptides: preclinical evaluation of 68Ga-TRAP (RGD) 3. Nucl Med Biol 40(1):33–41PubMedCrossRefGoogle Scholar
  19. 19.
    D’Alessandria C, Pohle K, Rechenmacher F, Neubauer S, Notni J, Wester H-J, Schwaiger M, Kessler H, Beer AJ (2016) In vivo biokinetic and metabolic characterization of the 68Ga-labelled α5β1-selective peptidomimetic FR366. Eur J Nucl Med Mol Imaging 43(5):953–963PubMedCrossRefGoogle Scholar
  20. 20.
    Holzmann B, Gosslar U, Bittner M (1998) α4 integrins and tumor metastasis. In: Leukocyte integrins in the immune system and malignant disease. Springer, Berlin, pp 125–141CrossRefGoogle Scholar
  21. 21.
    Moretti S, Martini L, Berti E, Pinzi C, Giannotti B (1993) Adhesion molecule profile and malignancy of melanocytic lesions. Melanoma Res 3(4):235–239PubMedGoogle Scholar
  22. 22.
    Garmy-Susini B, Jin H, Zhu Y, Sung R-J, Hwang R, Varner J (2005) Integrin α4β1-VCAM-1-mediated adhesion between endothelial and mural cells is required for blood vessel maturation. J Clin Investig 115(6):1542–1551PubMedCrossRefGoogle Scholar
  23. 23.
    Schlesinger M, Bendas G (2015) Contribution of very late antigen-4 (VLA-4) integrin to cancer progression and metastasis. Cancer Metastasis Rev 34(4):575–591PubMedCrossRefGoogle Scholar
  24. 24.
    Peng L, Liu R, Marik J, Wang X, Takada Y, Lam KS (2006) Combinatorial chemistry identifies high-affinity peptidomimetics against α4β1 integrin for in vivo tumor imaging. Nat Chem Biol 2(7):381PubMedCrossRefGoogle Scholar
  25. 25.
    Jiang M, Ferdani R, Shokeen M, Anderson CJ (2013) Comparison of two cross-bridged macrocyclic chelators for the evaluation of 64Cu-labeled-LLP2A, a peptidomimetic ligand targeting VLA-4-positive tumors. Nucl Med Biol 40(2):245–251PubMedCrossRefGoogle Scholar
  26. 26.
    Gai Y, Sun L, Hui W, Ouyang Q, Anderson CJ, Xiang G, Ma X, Zeng D (2016) New bifunctional chelator p-SCN-PhPr-NE3TA for copper-64: synthesis, peptidomimetic conjugation, radiolabeling, and evaluation for PET imaging. Inorg Chem 55(14):6892–6901PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Beaino W, Anderson CJ (2014) PET imaging of very late antigen-4 in melanoma: comparison of 68Ga-and 64Cu-labeled NODAGA and CB-TE1A1P-LLP2A conjugates. J Nucl Med 55(11):1856–1863PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Gai Y, Sun L, Lan X, Zeng D, Xiang G, Ma X (2018) Synthesis and evaluation of new bifunctional chelators with phosphonic acid arms for Gallium-68 based PET imaging in melanoma. Bioconjug Chem 29(10):3483–3494PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Roxin Á, Zhang C, Huh S, Lepage ML, Zhang Z, Lin K-S, Bénard F, Perrin DM (2018) Preliminary evaluation of 18F-labeled LLP2A-trifluoroborate conjugates as VLA-4 (α4β1 integrin) specific radiotracers for PET imaging of melanoma. Nucl Med Biol 61:11–20PubMedCrossRefGoogle Scholar
  30. 30.
    Roxin A, Zhang C, Huh S, Lepage M, Zhang Z, Lin K, Bénard F, Perrin D (2019) A metal-free DOTA-conjugated 18F-labeled radiotracer: [18F] DOTA-AMBF3-LLP2A for imaging VLA-4 over-expression in murine melanoma with improved tumor uptake and greatly enhanced renal clearance. Bioconjug Chem.  https://doi.org/10.1021/acs.bioconjchem.9b00146 (just accepted manuscript)PubMedCrossRefGoogle Scholar
  31. 31.
    DeNardo SJ, Liu R, Albrecht H, Natarajan A, Sutcliffe JL, Anderson C, Peng L, Ferdani R, Cherry SR, Lam KS (2009) 111In-LLP2A-DOTA polyethylene glycol–targeting α4β1 integrin: comparative pharmacokinetics for imaging and therapy of lymphoid malignancies. J Nucl Med 50(4):625–634 CrossRefGoogle Scholar
  32. 32.
    Zwingenberger AL, Kent MS, Liu R, Kukis DL, Wisner ER, DeNardo SJ, Taylor SL, Chen X, Lam KS (2012) In-vivo biodistribution and safety of 99mTc-LLP2A-HYNIC in canine non-Hodgkin lymphoma. PLoS One 7(4):e34404PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Beaino W, Nedrow JR, Anderson CJ (2015) Evaluation of 68Ga-and 177Lu-DOTA-PEG4-LLP2A for VLA-4-targeted PET imaging and treatment of metastatic melanoma. Mol Pharm 12(6):1929–1938PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Choi J, Beaino W, Fecek RJ, Fabian KP, Laymon CM, Kurland BF, Storkus WJ, Anderson CJ (2018) Combined VLA-4-targeted radionuclide therapy and immunotherapy in a mouse model of melanoma. J Nucl Med 59(12):1843–1849PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Koukouraki S, Strauss LG, Georgoulias V, Eisenhut M, Haberkorn U, Dimitrakopoulou-Strauss A (2006) Comparison of the pharmacokinetics of 68Ga-DOTATOC and [18F] FDG in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy. Eur J Nucl Med Mol Imaging 33(10):1115–1122PubMedCrossRefGoogle Scholar
  36. 36.
    Virgolini I, Ambrosini V, Bomanji JB, Baum RP, Fanti S, Gabriel M, Papathanasiou ND, Pepe G, Oyen W, De Cristoforo C (2010) Procedure guidelines for PET/CT tumour imaging with 68Ga-DOTA-conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE. Eur J Nucl Med Mol Imaging 37(10):2004–2010PubMedCrossRefGoogle Scholar
  37. 37.
    Haug A, Auernhammer CJ, Wängler B, Tiling R, Schmidt G, Göke B, Bartenstein P, Pöpperl G (2009) Intraindividual comparison of 68Ga-DOTA-TATE and 18F-DOPA PET in patients with well-differentiated metastatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging 36(5):765–770PubMedCrossRefGoogle Scholar
  38. 38.
    Prasad V, Ambrosini V, Hommann M, Hoersch D, Fanti S, Baum RP (2010) Detection of unknown primary neuroendocrine tumours (CUP-NET) using 68Ga-DOTA-NOC receptor PET/CT. Eur J Nucl Med Mol Imaging 37(1):67PubMedCrossRefGoogle Scholar
  39. 39.
    Gabriel M, Oberauer A, Dobrozemsky G, Decristoforo C, Putzer D, Kendler D, Uprimny C, Kovacs P, Bale R, Virgolini IJ (2009) 68Ga-DOTA-Tyr3-octreotide PET for assessing response to somatostatin-receptor-mediated radionuclide therapy. J Nucl Med 50(9):1427PubMedCrossRefGoogle Scholar
  40. 40.
    Hyduk SJ, Oh J, Xiao H, Chen M, Cybulsky MI (2004) Paxillin selectively associates with constitutive and chemoattractant-induced high-affinity α4β1 integrins: implications for integrin signaling. Blood 104(9):2818–2824PubMedCrossRefGoogle Scholar

Copyright information

© Society for Biological Inorganic Chemistry (SBIC) 2019

Authors and Affiliations

  • Yongkang Gai
    • 1
    • 2
  • Lujie Yuan
    • 1
    • 2
  • Lingyi Sun
    • 3
  • Huiling Li
    • 1
    • 2
  • Mengting Li
    • 1
    • 2
  • Hanyi Fang
    • 1
    • 2
  • Bouhari Altine
    • 1
    • 2
  • Qingyao Liu
    • 1
    • 2
  • Yongxue Zhang
    • 1
    • 2
  • Dexing Zeng
    • 3
    Email author
  • Xiaoli Lan
    • 1
    • 2
    Email author
  1. 1.Department of Nuclear Medicine, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Hubei Province Key Laboratory of Molecular ImagingWuhanChina
  3. 3.Center for Radiochemistry Research, Department of Diagnostic RadiologyOregon Health and Science UniversityPortlandUSA

Personalised recommendations