SpringerLink
Log in

The Effects of an Albumin Binding Moiety on the Targeting and Pharmacokinetics of an Integrin αvβ6-Selective Peptide Labeled with Aluminum [18F]Fluoride

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The αvβ6-BP peptide selectively targets the integrin αvβ6, a cell surface receptor recognized as a prognostic indicator for several challenging malignancies. Given that the 4-[18F]fluorobenzoyl (FBA)-labeled peptide is a promising PET imaging agent, radiolabeling via aluminum [18F]fluoride chelation and introduction of an albumin binding moiety (ABM) have the potential to considerably simplify radiochemistry and improve the pharmacokinetics by increasing biological half-life.

Procedures

The peptides NOTA-αvβ6-BP (1) and NOTA-K(ABM)-αvβ6-BP (2) were synthesized on solid phase, radiolabeled with aluminum [18F]fluoride, and evaluated in vitro (integrin ELISA, albumin binding, cell studies) and in vivo in mouse models bearing paired DX3puroβ6 [αvβ6(+)]/DX3puro [αvβ6(−)], and for [18F]AlF 2, BxPC-3 [αvβ6(+)] cell xenografts (PET imaging, biodistribution).

Results

The peptides were radiolabeled in 23.0 ± 5.7 % and 22.1 ± 4.4 % decay-corrected radiochemical yield, respectively, for [18F]AlF 1 and [18F]AlF 2. Both demonstrated excellent affinity and selectivity for integrin αvβ6 by ELISA (IC50(αvβ6) = 3–7 nM vs IC50(αvβ3) > 10 μM) and in cell binding studies (51.0 ± 0.7 % and 47.2 ± 0.7 % of total radioactivity bound to DX3puroβ6 cells at 1 h, respectively, vs. ≤ 1.2 % to DX3puro for both compounds). The radiotracer [18F]AlF 1 bound to human serum at 16.3 ± 1.9 %, compared to 67.5 ± 1.0 % for the ABM-containing [18F]AlF 2. In vivo studies confirmed the effect of the ABM on blood circulation (≤ 0.1 % ID/g remaining in blood for [18F]AlF 1 as soon as 1 h p.i. vs. > 2 % ID/g for [18F]AlF 2 at 6 h p.i.) and higher αvβ6(+) tumor uptake (4 h: DX3puroβ6; [18F]AlF 1: 3.0 ± 0.7 % ID/g, [18F]AlF 2: 7.2 ± 0.7 % ID/g; BxPC-3; [18F]AlF 2: 10.2 ± 0.1 % ID/g).

Conclusion

Both compounds were prepared using standard chemistries; affinity and selectivity for integrin αvβ6 in vitro remained unaffected by the albumin binding moiety. In vivo, the albumin binding moiety resulted in prolonged circulation and higher αvβ6-targeted uptake.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.

Similar content being viewed by others

References

  1. Chatalic KLS, Kwekkeboom DJ, de Jong M (2015) Radiopeptides for imaging and therapy: a radiant future. J Nucl Med 56:1809–1812

    CAS  PubMed  Google Scholar 

  2. Okarvi SM, Maecke HR (2018) 17 - Radiolabelled peptides in medical imaging A2 - Koutsopoulos, Sotirios. Peptide applications in biomedicine, biotechnology and bioengineering: Woodhead Publishing. pp. 431-483

  3. Correia JD, Paulo A, Raposinho PD, Santos I (2011) Radiometallated peptides for molecular imaging and targeted therapy. Dalton Trans 40:6144–6167

    CAS  PubMed  Google Scholar 

  4. Cives M, Strosberg J (2017) Radionuclide therapy for neuroendocrine tumors. Curr Oncol Rep 19:9

    PubMed  Google Scholar 

  5. Richter S, Wuest F (2014) 18F-labeled peptides: the future is bright. Molecules 19:20536–20556

    PubMed  PubMed Central  Google Scholar 

  6. Krishnan HS, Ma L, Vasdev N, Liang SH (2017) 18F-labeling of sensitive biomolecules for positron emission tomography. Chem Eur J 23:15553–15577

    CAS  PubMed  Google Scholar 

  7. Vaidyanathan G, Zalutsky MR (2006) Synthesis of N-succinimidyl 4-[18F]fluorobenzoate, an agent for labeling proteins and peptides with 18F. Nat Protoc 1:1655–1661

    CAS  PubMed  Google Scholar 

  8. Bernard-Gauthier V, Lepage ML, Waengler B, Bailey JJ, Liang SH, Perrin DM, Vasdev N, Schirrmacher R (2018) Recent advances in 18F radiochemistry: a focus on B-18F, Si-18F, Al-18F, and C-18F radiofluorination via spirocyclic iodonium ylides. J Nucl Med 59:568–572

    CAS  PubMed  Google Scholar 

  9. McBride WJ, Sharkey RM, Goldenberg DM (2013) Radiofluorination using aluminum-fluoride (Al18F). EJNMMI Res 3:36

    PubMed  PubMed Central  Google Scholar 

  10. Kumar K (2018) 18F-AlF–labeled biomolecule conjugates as imaging pharmaceuticals. J Nucl Med 59:1208–1209

    PubMed  PubMed Central  Google Scholar 

  11. Hausner SH, Bauer N, Sutcliffe JL (2014) In vitro and in vivo evaluation of the effects of aluminum [18F]fluoride radiolabeling on an integrin alpha(v)beta(6)-specific peptide. Nucl Med Biol 41:43–50

    CAS  PubMed  Google Scholar 

  12. Kiesewetter DO, Guo N, Guo J, Gao H, Zhu L, Ma Y, Niu G, Chen X (2012) Evaluation of an [(18)F]AlF-NOTA analog of exendin-4 for imaging of GLP-1 receptor in insulinoma. Theranostics 2:999–1009

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kumar K, Ghosh A (2018) 18F-AlF labeled peptide and protein conjugates as positron emission tomography imaging pharmaceuticals. Bioconjug Chem 29:953–975

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Richter S, Wuest M, Bergman CN, Way JD, Krieger S, Rogers BE, Wuest F (2015) Rerouting the metabolic pathway of18F-labeled peptides: the influence of prosthetic groups. Bioconjug Chem 26:201–212

    CAS  PubMed  Google Scholar 

  15. Wetzler M, Hamilton P (2018) 8 - Peptides as therapeutics A2 - Koutsopoulos, Sotirios. Peptide applications in biomedicine, biotechnology and bioengineering: Woodhead Publishing. pp. 215-230

  16. Hausner SH, Kukis DL, Gagnon MKJ, Stanecki CE, Ferdani R, Marshall JF, Anderson CJ, Sutcliffe JL (2009) Evaluation of [64Cu]Cu-DOTA and [64Cu]Cu-CB-TE2A chelates for targeted positron emission tomography with an alpha(v)beta(6)-specific peptide. Mol Imaging 8:111–121

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Akizawa H, Arano Y, Uezono T, Ono M, Fujioka Y, Uehara T, Yokoyama A, Akaji K, Kiso Y, Koizumi M, Saji H (1998) Renal metabolism of 111In-DTPA-D-Phe1-octreotide in vivo. Bioconjug Chem 9:662–670

    CAS  PubMed  Google Scholar 

  18. Zhang F, Xue J, Shao J, Jia L (2012) Compilation of 222 drugs’ plasma protein binding data and guidance for study designs. Drug Discov Today 17:475–485

    CAS  PubMed  Google Scholar 

  19. Sleep D (2014) Albumin and its application in drug delivery. Expert Opin Drug Delivery 12:793–812

    Google Scholar 

  20. Dennis MS, Zhang M, Meng YG, Kadkhodayan M, Kirchhofer D, Combs D, Damico LA (2002) Albumin binding as a general strategy for improving the pharmacokinetics of proteins. J Biol Chem 277:35035–35043

    CAS  PubMed  Google Scholar 

  21. Lauffer RB, Parmelee DJ, Ouellet HS, Dolan RP, Sajiki H, Scott DM, Bernard PJ, Buchanan EM, Ong KY, Tyeklár Z, Midelfort KS, McMurry TJ, Walovitch RC (1996) MS-325: a small-molecule vascular imaging agent for magnetic resonance imaging. Acad Radiol 3:S356–S358

    PubMed  Google Scholar 

  22. Kratz F (2008) Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release 132:171–183

    CAS  PubMed  Google Scholar 

  23. Yamasaki K, Chuang VTG, Maruyama T, Otagiri M (2013) Albumin–drug interaction and its clinical implication. Biochim Biophys Acta Gen Subj 1830:5435–5443

    CAS  Google Scholar 

  24. Gunnoo SB, Madder A (2016) Bioconjugation – using selective chemistry to enhance the properties of proteins and peptides as therapeutics and carriers. Org Biomol Chem 14:8002–8013

    CAS  PubMed  Google Scholar 

  25. Muller C, Struthers H, Winiger C, Zhernosekov K, Schibli R (2013) DOTA conjugate with an albumin-binding entity enables the first folic acid-targeted Lu-177-radionuclide tumor therapy in mice. J Nucl Med 54:124–131

    CAS  PubMed  Google Scholar 

  26. Benešová M, Umbricht CA, Schibli R, Müller C (2018) Albumin-binding PSMA ligands: optimization of the tissue distribution profile. Mol Pharm 15:934–946

    PubMed  Google Scholar 

  27. Zhang J, Lang L, Zhu Z, Li F, Niu G, Chen X (2015) Clinical translation of an albumin-binding PET radiotracer 68Ga-NEB. J Nucl Med 56:1609–1614

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Tian R, Jacobson O, Niu G, Kiesewetter DO, Wang Z, Zhu G, Ma Y, Liu G, Chen X (2018) Evans blue attachment enhances somatostatin receptor subtype-2 imaging and radiotherapy. Theranostics 8:735–745

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Choy CJ, Ling X, Geruntho JJ, Beyer SK, Latoche JD, Langton-Webster B, Anderson CJ, Berkman CE (2017) 177Lu-labeled phosphoramidate-based PSMA inhibitors: the effect of an albumin binder on biodistribution and therapeutic efficacy in prostate tumor-bearing mice. Theranostics 7:1928–1939

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mindt TL, Struthers H, S**ler B, Brans L, Tourwe D et al (2010) Molecular assembly of multifunctional 99mTc radiopharmaceuticals using “clickable” amino acid derivatives. ChemMedChem 5:2026–2038

    CAS  PubMed  Google Scholar 

  31. Kelly JM, Amor-Coarasa A, Nikolopoulou A, Wüstemann T, Barelli P, Kim D, Williams C Jr, Zheng X, Bi C, Hu B, Warren JD, Hage DS, DiMagno SG, Babich JW (2017) Dual-target binding ligands with modulated pharmacokinetics for endoradiotherapy of prostate cancer. J Nucl Med 58:1442–1449

    CAS  PubMed  Google Scholar 

  32. Manaenko A, Chen H, Kammer J, Zhang JH, Tang J (2011) Comparison Evans Blue injection routes: intravenous versus intraperitoneal, for measurement of blood–brain barrier in a mice hemorrhage model. J Neurosci Methods 195:206–210

    PubMed  Google Scholar 

  33. Hausner S, Bold RJ, Cheuy LY, Chew HK, Daly ME, et al. (2019) Preclinical development and first-in-human imaging of the integrin αvβ6 with [18F]αvβ6-binding peptide in metastatic carcinoma. Clin Cancer Res 25:1206–1215

  34. Bandyopadhyay A, Raghavan S (2009) Defining the role of integrin alpha(v)beta(6) in cancer. Curr Drug Targets 10:645–652

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Niu J, Li Z (2017) The roles of integrin αvβ6 in cancer. Cancer Lett 403:128–137

    CAS  PubMed  Google Scholar 

  36. de Geus SWL, Boogerd LSF, Swijnenburg R-J, Mieog JSD, Tummers WSFJ, Prevoo HAJM, Sier CFM, Morreau H, Bonsing BA, van de Velde CJH, Vahrmeijer AL, Kuppen PJK (2016) Selecting tumor-specific molecular targets in pancreatic adenocarcinoma: paving the way for image-guided pancreatic surgery. Mol Imaging Biol 18:807–819

    PubMed  PubMed Central  Google Scholar 

  37. Hausner SH, DiCara D, Marik J, Marshall JF, Sutcliffe JL (2007) Use of a peptide derived from foot-and-mouth disease virus for the noninvasive imaging of human cancer: generation and evaluation of 4-[18F]fluorobenzoyl A20FMDV2 for in vivo imaging of integrin alpha(v)beta(6) expression with positron emission tomography. Cancer Res 67:7833–7840

    CAS  PubMed  Google Scholar 

  38. Hausner SH, Abbey CK, Bold RJ, Gagnon MK, Marik J, Marshall JF, Stanecki CE, Sutcliffe JL (2009) Targeted in vivo imaging of integrin alpha(v)beta(6) with an improved radiotracer and its relevance in a pancreatic tumor model. Cancer Res 69:5843–5850

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee S, **e J, Chen X (2010) Peptides and peptide hormones for molecular imaging and disease diagnosis. Chem Rev 110:3087–3111

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Banerjee S, Pillai MRA, Knapp FF (2015) Lutetium-177 therapeutic radiopharmaceuticals: linking chemistry, radiochemistry, and practical applications. Chem Rev 115:2934–2974

    CAS  PubMed  Google Scholar 

  41. Pollaro L, Raghunathan S, Morales-Sanfrutos J, Angelini A, Kontos S et al (2014) Bicyclic peptides conjugated to an albumin-binding tag diffuse efficiently into solid tumors. Mol Cancer Ther 14:151–161

    PubMed  Google Scholar 

  42. Dumelin CE, Trussel S, Buller F, Trachsel E, Bootz F et al (2008) A portable albumin binder from a DNA-encoded chemical library. Angew Chem Int Ed Engl 47:3196–3201

    CAS  PubMed  Google Scholar 

  43. Henoumont C, Laurent S, Muller RN, Elst LV (2012) Effect of nonenzymatic glycosylation on the magnetic resonance imaging (MRI) contrast agent binding to human serum albumin. J Med Chem 55:4015–4019

    CAS  PubMed  Google Scholar 

  44. Russell-Jones D (2009) Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue. Mol Cell Endocrinol 297:137–140

    CAS  PubMed  Google Scholar 

  45. Jenssen H, Aspmo SI (2008) Serum stability of peptides. In: Otvos L (ed) Peptide-based drug design. Humana Press, Totowa, NJ, pp 177–186

    Google Scholar 

  46. Umbricht CA, Benešová M, Schibli R, Müller C (2018) Preclinical development of novel PSMA-targeting radioligands: modulation of albumin-binding properties to improve prostate Cancer therapy. Mol Pharm 15:2297–2306

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the staff of the Center for Molecular and Genomic Imaging (Jennifer Fung, David Kukis, Charles Smith, Sarah Tam, and Josh Waltenburg), David L. Boucher, and Lina Y. Cheuy for technical assistance, scientific support, and discussions.

Funding

This study was funded in part by National Institute of Health awards # R01CA211554-01 and R50CA211556-01 and a UC Davis Research Investment in Science and Engineering grant.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis, Sacramento, CA, USA

    Sven H. Hausner, Nadine Bauer, Tanushree Ganguly, Sarah Y. C. Tang & Julie L. Sutcliffe

  2. Department of Biomedical Engineering, University of California Davis, Davis, CA, USA

    Ryan A. Davis & Julie L. Sutcliffe

  3. Center for Molecular and Genomic Imaging, University of California Davis, Davis, CA, USA

    Julie L. Sutcliffe

Authors
  1. Sven H. Hausner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nadine Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryan A. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tanushree Ganguly
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sarah Y. C. Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julie L. Sutcliffe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julie L. Sutcliffe.

Ethics declarations

Conflict of Interest

S. H. Hausner is a co-inventor of intellectual property related to [18F]αvβ6-BP.

J. L. Sutcliffe is founder of and holds ownership interest (including patents) in Luminance, Biosciences, Inc., and is a co-inventor of intellectual property related to [18F]αvβ6-BP. The other authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(DOCX 103 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hausner, S.H., Bauer, N., Davis, R.A. et al. The Effects of an Albumin Binding Moiety on the Targeting and Pharmacokinetics of an Integrin αvβ6-Selective Peptide Labeled with Aluminum [18F]Fluoride. Mol Imaging Biol 22, 1543–1552 (2020). https://doi.org/10.1007/s11307-020-01500-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-020-01500-0

Key words

Search

Navigation