Advertisement

Applied Microbiology and Biotechnology

, Volume 103, Issue 7, pp 3049–3059 | Cite as

A high-risk papillomavirus 18 E7 affibody-enabled in vivo imaging and targeted therapy of cervical cancer

  • Ledan Wang
  • Wangqi Du
  • Shanli Zhu
  • Pengfei Jiang
  • Lifang ZhangEmail author
Biotechnologically relevant enzymes and proteins

Abstract

High-risk papillomavirus (HPV) is one of the major reasons for cervical cancer, causing most lethal gynecologic malignancies worldwide. For cervical cancer progression, oncogene E7 plays vital roles and is used as one of the major targets for cervical tumor diagnosis and treatment. In the clinic, successful treatment of cervical cancer relies on diagnosing the disease at an early stage, where a late-stage diagnosis usually led to treatment failure. In this work, we designed and purified an HPV18 E7 oncogene targeting affibody, named as ZHPV18E7, for in vitro and in vivo imaging and targeted treatment of cervical cancer. In vitro, ZHPV18E7 showed a specific targeting effect against an HPV18 positive cell line; as a contrast, the affibody did not target the HPV18 negative cell line. In vivo, we tested the bio-distribution of the affibody in mice bearing cervical cancer. The whole animal imaging analysis indicated the affibody-targeted tumor tissue specifically with 10 min after injection, and the affibody reached the highest level at tumor tissues 45 min after injection. At the 24th hour after injection, the affibody still maintained a certain level in tumor tissues compared to other organs. To test the therapeutic effect of this affibody, we modified the affibody (i.e., ZHPV18E7) with a clinically used anti-cancer agent (i.e., Pseudomonas exotoxin). In a mice cervical cancer model, ZHPV18E7 was able to deliver Pseudomonas exotoxin to tumor tissues effectively, showing great potential for cancer treatment. This study indicated that ZHPV18E7 could be employed for in vitro imaging and targeted treatment of cervical cancer. Beyond the chemotherapeutic agent used in this work, the affibody could be extended for carrying other therapeutic agents for cervical cancer treatment.

Keywords

Affibody High-risk papillomavirus E7 oncogene Targeting Surface plasmon resonance In vivo distribution Cervical cancer treatment 

Notes

Funding

This work is supported by the National Nature Science Foundation (grant no. 81172463) and Zhejiang Province Natural Science Foundation (grant no.LQ16H160022.)

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

253_2019_9655_MOESM1_ESM.pdf (55 kb)
ESM 1 (PDF 54 kb)

References

  1. Alavizadeh SH, Akhtari J, Badiee A, Golmohammadzadeh S, Jaafari MR (2016) Improved therapeutic activity of HER2 Affibody-targeted cisplatin liposomes in HER2-expressing breast tumor models. Expert Opin Drug Deliv 13(3):325–336.  https://doi.org/10.1517/17425247.2016.1121987 CrossRefGoogle Scholar
  2. Altai M, Liu H, Orlova A, Tolmachev V, Graslund T (2016) Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin. Int J Oncol 49(3):1185–1194.  https://doi.org/10.3892/ijo.2016.3614 CrossRefGoogle Scholar
  3. Baldwin A, Grueneberg DA, Hellner K, Sawyer J, Grace M, Li WL, Harlow E, Munger K (2010) Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3. Proc Natl Acad Sci U S A 107(28):12463–12468.  https://doi.org/10.1073/pnas.1007462107 CrossRefGoogle Scholar
  4. Behr TM, Goldenberg DM, Becker W (1998) Reducing the renal uptake of radiolabeled antibody fragments and peptides for diagnosis and therapy: present status, future prospects and limitations. Eur J Nucl Med 25(2):201–212CrossRefGoogle Scholar
  5. Bosch FX, Broker TR, Forman D, Moscicki AB, Gillison ML, Doorbar J, Stern PL, Stanley M, Arbyn M, Poljak M, Cuzick J, Castle PE, Schiller JT, Markowitz LE, Fisher WA, Canfell K, Denny LA, Franco EL, Steben M, Kane MA, Schiffman M, Meijer CJ, Sankaranarayanan R, Castellsague X, Kim JJ, Brotons M, Alemany L, Albero G, Diaz M, de Sanjose S, authors of ICOMCCoHPVI, Related Diseases Vaccine Volume S (2013) Comprehensive control of human papillomavirus infections and related diseases. Vaccine 31(Suppl 7):H1–H31.  https://doi.org/10.1016/j.vaccine.2013.10.003 CrossRefGoogle Scholar
  6. Chellappan S, Kraus VB, Kroger B, Munger K, Howley PM, Phelps WC, Nevins JR (1992) Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci U S A 89(10):4549–4553CrossRefGoogle Scholar
  7. De Luca A, Esposito V, Baldi A, Giordano A (1996) The retinoblastoma gene family and its role in proliferation, differentiation and development. Histol Histopathol 11(4):1029–1034Google Scholar
  8. de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, Tous S, Felix A, Bravo LE, Shin HR, Vallejos CS, de Ruiz PA, Lima MA, Guimera N, Clavero O, Alejo M, Llombart-Bosch A, Cheng-Yang C, Tatti SA, Kasamatsu E, Iljazovic E, Odida M, Prado R, Seoud M, Grce M, Usubutun A, Jain A, Suarez GA, Lombardi LE, Banjo A, Menendez C, Domingo EJ, Velasco J, Nessa A, Chichareon SC, Qiao YL, Lerma E, Garland SM, Sasagawa T, Ferrera A, Hammouda D, Mariani L, Pelayo A, Steiner I, Oliva E, Meijer CJ, Al-Jassar WF, Cruz E, Wright TC, Puras A, Llave CL, Tzardi M, Agorastos T, Garcia-Barriola V, Clavel C, Ordi J, Andujar M, Castellsague X, Sanchez GI, Nowakowski AM, Bornstein J, Munoz N, Bosch FX, Retrospective International S, Group HPVTTS (2010) Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 11(11):1048–1056.  https://doi.org/10.1016/S1470-2045(10)70230-8 CrossRefGoogle Scholar
  9. Feldwisch J, Tolmachev V (2012) Engineering of affibody molecules for therapy and diagnostics. Methods Mol Biol 899:103–126.  https://doi.org/10.1007/978-1-61779-921-1_7 CrossRefGoogle Scholar
  10. Hagenbuch B (2010) Drug uptake systems in liver and kidney: a historic perspective. Clin Pharmacol Ther 87(1):39–47.  https://doi.org/10.1038/clpt.2009.235 CrossRefGoogle Scholar
  11. Jiang P, Wang L, Hou B, Zhu J, Zhou M, Jiang J, Wang L, Chen S, Zhu S, Chen J, Zhang L (2018) A novel HPV16 E7-affitoxin for targeted therapy of HPV16-induced human cervical cancer. Theranostics 8(13):3544–3558.  https://doi.org/10.7150/thno.24607 CrossRefGoogle Scholar
  12. Jones DL, Munger K (1996) Interactions of the human papillomavirus E7 protein with cell cycle regulators. Semin Cancer Biol 7(6):327–337.  https://doi.org/10.1006/scbi.1996.0042 CrossRefGoogle Scholar
  13. Li N, Franceschi S, Howell-Jones R, Snijders PJ, Clifford GM (2011) Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: variation by geographical region, histological type and year of publication. Int J Cancer 128(4):927–935.  https://doi.org/10.1002/ijc.25396 CrossRefGoogle Scholar
  14. Lipinski MM, Jacks T (1999) The retinoblastoma gene family in differentiation and development. Oncogene 18(55):7873–7882.  https://doi.org/10.1038/sj.onc.1203244 CrossRefGoogle Scholar
  15. Lofblom J, Feldwisch J, Tolmachev V, Carlsson J, Stahl S, Frejd FY (2010) Affibody molecules: engineered proteins for therapeutic, diagnostic and biotechnological applications. FEBS Lett 584(12):2670–2680.  https://doi.org/10.1016/j.febslet.2010.04.014 CrossRefGoogle Scholar
  16. Rejman J, Oberle V, Zuhorn IS, Hoekstra D (2004) Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J 377(Pt 1):159–169.  https://doi.org/10.1042/BJ20031253 CrossRefGoogle Scholar
  17. Ronco G, Dillner J, Elfstrom KM, Tunesi S, Snijders PJ, Arbyn M, Kitchener H, Segnan N, Gilham C, Giorgi-Rossi P, Berkhof J, Peto J, Meijer CJ, International HPVswg (2014) Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 383(9916):524–532.  https://doi.org/10.1016/S0140-6736(13)62218-7 CrossRefGoogle Scholar
  18. Santin AD, Zhan F, Bignotti E, Siegel ER, Cane S, Bellone S, Palmieri M, Anfossi S, Thomas M, Burnett A, Kay HH, Roman JJ, O'Brien TJ, Tian E, Cannon MJ, Shaughnessy J Jr, Pecorelli S (2005) Gene expression profiles of primary HPV16- and HPV18-infected early stage cervical cancers and normal cervical epithelium: identification of novel candidate molecular markers for cervical cancer diagnosis and therapy. Virology 331(2):269–291.  https://doi.org/10.1016/j.virol.2004.09.045 CrossRefGoogle Scholar
  19. Tolmachev V, Mume E, Sjoberg S, Frejd FY, Orlova A (2009) Influence of valency and labelling chemistry on in vivo targeting using radioiodinated HER2-binding affibody molecules. Eur J Nucl Med Mol Imaging 36(4):692–701.  https://doi.org/10.1007/s00259-008-1003-y CrossRefGoogle Scholar
  20. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108.  https://doi.org/10.3322/caac.21262 CrossRefGoogle Scholar
  21. Tran TA, Rosik D, Abrahmsen L, Sandstrom M, Sjoberg A, Wallberg H, Ahlgren S, Orlova A, Tolmachev V (2009) Design, synthesis and biological evaluation of a multifunctional HER2-specific Affibody molecule for molecular imaging. Eur J Nucl Med Mol Imaging 36(11):1864–1873.  https://doi.org/10.1007/s00259-009-1176-z CrossRefGoogle Scholar
  22. Vegt E, de Jong M, Wetzels JF, Masereeuw R, Melis M, Oyen WJ, Gotthardt M, Boerman OC (2010) Renal toxicity of radiolabeled peptides and antibody fragments: mechanisms, impact on radionuclide therapy, and strategies for prevention. J Nucl Med 51(7):1049–1058.  https://doi.org/10.2967/jnumed.110.075101 CrossRefGoogle Scholar
  23. Wang L, Cai Y, Xiong Y, Du W, Cen D, Zhang C, Song Y, Zhu S, Xue X, Zhang L (2017) DNA plasmid vaccine carrying Chlamydia trachomatis (Ct) major outer membrane and human papillomavirus 16L2 proteins for anti-Ct infection. Oncotarget 8(20):33241–33251.  https://doi.org/10.18632/oncotarget.16601
  24. Yim EK, Park JS (2005) The role of HPV E6 and E7 oncoproteins in HPV-associated cervical carcinogenesis. Cancer Res Treat 37(6):319–324.  https://doi.org/10.4143/crt.2005.37.6.319 CrossRefGoogle Scholar
  25. zur Hausen H (1991) Human papillomaviruses in the pathogenesis of anogenital cancer. Virology 184(1):9–13CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of GynecologyThe Second Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
  2. 2.Department of Microbiology and Immunology, Institute of Molecular Virology and ImmunologyWenzhou Medical UniversityWenzhouChina

Personalised recommendations