Issue

Vol. 14 (2022)

Self-Assembled Nanomicelles of Affibody-Drug Conjugate with Excellent Therapeutic Property to Cure Ovary and Breast Cancers

https://doi.org/10.1007/s40820-021-00762-9
Xuelin Xia
School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, People’s Republic of China
Xiaoyuan Yang
School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, People’s Republic of China
Wei Huang
School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, People’s Republic of China
Xiaoxia Xia
State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, People’s Republic of China
Deyue Yan
School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, People’s Republic of China

Corresponding Author: Deyue Yan

dyyan@sjtu.edu.cn

Nano-Micro Letters, Vol. 14 (2022), Article Number: 33

Abstract

Affibody molecules are small non-immunoglobulin affinity proteins, which can precisely target to some cancer cells with specific overexpressed molecular signatures. However, the relatively short in vivo half-life of them seriously limited their application in drug targeted delivery for cancer therapy. Here an amphiphilic affibody-drug conjugate is self-assembled into nanomicelles to prolong circulation time for targeted cancer therapy. As an example of the concept, the nanoagent was prepared through molecular self-assembly of the amphiphilic conjugate of ZHER2:342-Cys with auristatin E derivate, where the affibody used is capable of binding to the human epidermal growth factor receptor 2 (HER2). Such a nanodrug not only increased the blood circulation time, but also enhanced the tumor targeting capacity (abundant affibody arms on the nanoagent surface) and the drug accumulation in tumor. As a result, this affibody-based nanoagent showed excellent antitumor activity in vivo to HER2-positive ovary and breast tumor models, which nearly eradicated both small solid tumors (about 100 mm3) and large established tumors (exceed 500  mm3). The relative tumor proliferation inhibition ratio reaches 99.8% for both models.


Highlights:


1 The nanoagent of affibody-drug conjugate made of ZHER2:342 and MMAE was successfully fabricated through molecular self-assembly of the conjugate in aqueous solution for targeted cancer therapy, which is recorded as Z-M ADCN for short.
2 Z-M ADCN shows extraordinary anticancer ability in HER2-positive ovary and breast tumor models with good biosecurity, that nearly eradicated both small solid tumors (about 100  mm3) and large tumors (exceed 500  mm3).

Keywords

Molecular self-assembly Affibody-drug conjugate Nanoagent Targeted cancer therapy
Xia, Xuelin, Xiaoyuan Yang, Wei Huang, Xiaoxia Xia, and Deyue Yan. 2021. “Self-Assembled Nanomicelles of Affibody-Drug Conjugate With Excellent Therapeutic Property to Cure Ovary and Breast Cancers”. Nano-Micro Letters 14 (December):33. https://doi.org/10.1007/s40820-021-00762-9.
Download Citation
Endnote/Zotero/Mendeley (RIS)
BibTeX
References
  1. F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca-Cancer J. Clin. 68, 394–424 (2018). https://doi.org/10.3322/caac.21492
  2. K.A. Cronin, L.C. Harlan, K.W. Dodd, J.S. Abrams, R. Ballard-Barbash, Population-based estimate of the prevalence of HER-2 positive breast cancer tumors for early stage patients in the US. Cancer Invest. 28, 963–968 (2010). https://doi.org/10.3109/07357907.2010.496759
  3. S.M. Swain, D. Miles, S. Kim, Y. Im, S. Im et al., Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 21, 519–530 (2020). https://doi.org/10.1016/S1470-2045(19)30863-0
  4. J.R. Junutula, H. Raab, S. Clark, S. Bhakta, D.D. Leipold et al., Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat. Biotechnol. 26, 925–932 (2008). https://doi.org/10.1038/nbt.1480
  5. W. Mu, Q. Chu, Y. Liu, N. Zhang, A review on nano based drug delivery system for cancer chemoimmunotherapy. Nano-Micro Lett. 12, 142 (2020). https://doi.org/10.1007/s40820-020-00482-6
  6. R.V.J. Chari, M.L. Miller, W.C. Widdison, Antibody–drug conjugates: an emerging concept in cancer therapy. Angew. Chem. Int. Ed. 53, 3796–3827 (2014). https://doi.org/10.1002/anie.201307628
  7. N. Krall, J. Scheuermann, D. Neri, Small targeted cytotoxics: current state and promises from DNA-encoded chemical libraries. Angew. Chem. Int. Ed. 52, 1384–1402 (2013). https://doi.org/10.1002/anie.201204631
  8. G.P. Adams, L.M. Weiner, Monoclonal antibody therapy of cancer. Nat. Biotechnol. 23, 1147–1157 (2005). https://doi.org/10.1038/nbt1137
  9. P. Chames, M.V. Regenmortel, E. Weiss, D. Baty, Therapeutic antibodies: Successes, limitations and hopes for the future. Br. J. Pharmacol. 157, 220–233 (2009). https://doi.org/10.1111/j.1476-5381.2009.00190.x
  10. G.N. Hatzopoulos, T. Kükenshöner, N. Banterle, T. Favez, I. Flückiger et al., Tuning SAS-6 architecture with monobodies impairs distinct steps of centriole assembly. Nat. Commun. 12, 3805 (2021). https://doi.org/10.1038/s41467-021-23897-0
  11. Z. Miao, J. Levi, Z. Cheng, Protein scaffold-based molecular probes for cancer molecular imaging. Amino Acids 41, 1037–1047 (2011). https://doi.org/10.1007/s00726-010-0503-9
  12. F. Kast, M. Schwill, J.C. Stüber, S. Pfundstein, G. Nagy-Davidescu et al., Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action. Nat. Commun. 12, 3790 (2021). https://doi.org/10.1038/s41467-021-23948-6
  13. K.T. Xenaki, B. Dorresteijn, J.A. Muns, K. Adamzek, S. Doulkeridou et al., Homogeneous tumor targeting with a single dose of HER2-targeted albumin-binding domain-fused nanobody-drug conjugates results in long-lasting tumor remission in mice. Theranostics 11, 5525–5538 (2021). https://doi.org/10.7150/thno.57510
  14. K. Nord, E. Gunneriusson, J. Ringdahl, S. Ståhl, M. Uhlén et al., Binding proteins selected from combinatorial libraries of an α-helical bacterial receptor domain. Nat. Biotechnol. 15, 772–777 (1997). https://doi.org/10.1038/nbt0897-772
  15. A. Orlova, M. Magnusson, T. Eriksson, M. Nilsson, B. Larsson et al., Tumor imaging using a picomolar affinity HER2 binding affibody molecule. Cancer Res. 66, 4339–4348 (2006). https://doi.org/10.1158/0008-5472.CAN-05-3521
  16. S. Ståhl, T. Gräslund, A. Karlström, F. Frejd, P. Nygren et al., Affibody molecules in biotechnological and medical applications. Trends Biotechnol. 35, 691–712 (2017). https://doi.org/10.1016/j.tibtech.2017.04.007
  17. R.N. Gilbreth, S. Koide, Structural insights for engineering binding proteins based on non-antibody scaffolds. Curr. Opin. Struct. Biol. 22, 413–420 (2012). https://doi.org/10.1016/j.sbi.2012.06.001
  18. M. Gebauer, A. Skerra, Engineered protein scaffolds as next-generation antibody therapeutics. Curr. Opin. Chem. Biol. 13, 245–255 (2009). https://doi.org/10.1016/j.cbpa.2009.04.627
  19. J. Lindgren, C. Ekblad, L. Abrahmsén, A.E. Karlström, A native chemical ligation approach for combinatorial assembly of affibody molecules. ChemBioChem 13, 1024–1031 (2012). https://doi.org/10.1002/cbic.201200052
  20. A. Perols, H. Honarvar, J. Strand, R. Selvaraju, A. Orlova et al., Influence of DOTA chelator position on biodistribution and targeting properties of 111In-labeled synthetic anti-HER2 affibody molecules. Bioconjugate Chem. 23, 1661–1770 (2012). https://doi.org/10.1021/bc3002369
  21. M. Rosestedt, K. Andersson, B. Mitran, V. Tolmachev, J. Löfblom et al., Affibody-mediated PET imaging of HER3 expression in malignant tumours. Sci. Rep. 5, 15226 (2015). https://doi.org/10.1038/srep15226
  22. H. Honarvar, C. Müller, S. Cohrs, S. Haller, K. Westerlund et al., Evaluation of the first 44Sc-labeled Affibody molecule for imaging of HER2-expressing tumors. Nucl. Med. Biol. 45, 15–21 (2017). https://doi.org/10.1016/j.nucmedbio.2016.10.004
  23. A.L. Antaris, H. Chen, K. Cheng, Y. Sun, G. Hong et al., A small-molecule dye for NIR-II imaging. Nat. Mater. 15, 235–242 (2016). https://doi.org/10.1038/nmat4476
  24. A. Nomani, G. Li, S. Yousefi, S. Wu, O.M. Malekshah et al., Gadolinium-labeled affibody-XTEN recombinant vector for detection of HER2+ lesions of ovarian cancer lung metastasis using quantitative MRI. J. Control. Release 337, 132–143 (2021). https://doi.org/10.1016/j.jconrel.2021.07.022
  25. A.L.R. de Souza, K. Marra, J. Gunn, K. Samkoe, P. Hoopes et al., Fluorescent affibody molecule administered in vivo at a microdose level labels EGFR expressing glioma tumor regions. Mol. Imaging Biol. 19, 41–48 (2017). https://doi.org/10.1007/s11307-016-0980-7
  26. R. Sun, Y. Zhao, Y. Wang, Q. Zhang, P. Zhao, An affibody-conjugated nanoprobe for IGF-1R targeted cancer fluorescent and photoacoustic dual-modality imaging. Nanotechnology 32, 205103 (2021). https://doi.org/10.1088/1361-6528/abe437
  27. G. Casi, D. Neri, Antibody–drug conjugates and small molecule–drug conjugates: opportunities and challenges for the development of selective anticancer cytotoxic agents. J. Med. Chem. 58, 8751–8761 (2015). https://doi.org/10.1021/acs.jmedchem.5b00457
  28. A.M. Sochaj-Gregorczyk, A.M. Serwotka-Suszczak, J. Otlewski, A novel affibody-auristatin E conjugate with a potent and selective activity against HER2+ cell lines. J. Immunother. 39, 223–232 (2016). https://doi.org/10.1097/CJI.0000000000000125
  29. A.M. Serwotka-Suszczak, A.M. Sochaj-Gregorczyk, J. Pieczykolan, D. Krowarsch, F. Jelen et al., A conjugate based on anti-HER2 diaffibody and auristatin E targets HER2-positive cancer cells. Int. J. Mol. Sci. 18, 401 (2017). https://doi.org/10.3390/ijms18020401
  30. M. Altai, H. Liu, H. Ding, B. Mitran, P. Edqvist et al., Affibody-derived drug conjugates: potent cytotoxic molecules for treatment of HER2 over-expressing tumors. J. Control. Release 288, 84–95 (2018). https://doi.org/10.1016/j.jconrel.2018.08.040
  31. J. Barreto, W. O’Malley, M. Kubeil, B. Graham, H. Stephan et al., Nanomaterials: applications in cancer imaging and therapy. Adv. Mater. 23, H18–H40 (2011). https://doi.org/10.1002/adma.201100140
  32. D. Xu, Z. Hu, J. Su, F. Wu, W. Yuan, Micro and nanotechnology for intracellular delivery therapy protein. Nano-Micro Lett. 4, 118–123 (2012). https://doi.org/10.1007/BF03353702
  33. C. Eigenbrot, M. Ultsch, A. Dubnovitsky, L. Abrahmsén, T. Härd, Structural basis for high-affinity HER2 receptor binding by an engineered protein. Proc. Natl. Acad. Sci. USA 107, 15039–15044 (2010). https://doi.org/10.1073/pnas.1005025107
  34. P. Senter, E. Sievers, The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat. Biotechnol. 30, 631–637 (2012). https://doi.org/10.1038/nbt.2289
  35. G. Pettit, Y. Kamano, C. Herald, A. Tuinman, F. Boettner et al., The isolation and structure of a remarkable marine animal antineoplastic constituent: dolastatin 10. J. Am. Chem. Soc. 109, 6883–6885 (1987). https://doi.org/10.1021/ja00256a070
  36. J. Choi, M.K. Shim, S. Yang, H.S. Hwang, H. Cho et al., Visible-light-triggered prodrug nanoparticles combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. ACS Nano 15, 12086–12098 (2021). https://doi.org/10.1021/acsnano.1c03416
  37. S. Doronina, B. Toki, M. Torgov, B. Mendelsohn, C. Cerveny et al., Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat. Biotechnol. 21, 778–784 (2003). https://doi.org/10.1038/nbt832
  38. V. Dincbas-Renqvist, C. Lendel, J. Dogan, E. Wahlberg, T. Härd, Thermodynamics of folding, stabilization, and binding in an engineered protein−protein complex. J. Am. Chem. Soc. 126, 11220–11230 (2004). https://doi.org/10.1021/ja047727y
  39. A. Orlova, V. Tolmachev, R. Pehrson, M. Lindborg, T. Tran et al., Synthetic affibody molecules: a novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors. Cancer Res. 67, 2178–2186 (2007). https://doi.org/10.1158/0008-5472.CAN-06-2887
  40. M. Srinivasarao, C.V. Galliford, P.S. Low, Principles in the design of ligand targeted cancer therapeutics and imaging agents. Nat. Rev. Drug Discov. 14, 203–219 (2015). https://doi.org/10.1038/nrd4519
  41. R. Zielinski, I. Lyakhov, M. Hassan, M. Kuban, K. Shafer-Weaver et al., HER2-affitoxin: a potent therapeutic agent for the treatment of HER2-overexpressing tumors. Clin. Cancer Res. 17, 5071–5081 (2011). https://doi.org/10.1158/1078-0432.CCR-10-2887
  42. S. Hoppmann, Z. Miao, S. Liu, H. Liu, G. Ren et al., Radiolabeled affibody-albumin bioconjugates for HER2-positive cancer targeting. Bioconjugate Chem. 22, 413–421 (2011). https://doi.org/10.1021/bc100432h
  43. D. Gao, T. Chen, S. Chen, X. Ren, Y. Han et al., Targeting hypoxic tumors with hybrid nanobullets for oxygen-independent synergistic photothermal and thermodynamic therapy. Nano-Micro Lett. 13, 99 (2021). https://doi.org/10.1007/s40820-021-00616-4
  44. J. Seijsing, M. Lindborg, I. Höidén-Guthenberg, H. Bönisch, E. Guneriusson et al., An engineered affibody molecule with pH-dependent binding to FcRn mediates extended circulatory half-life of a fusion protein. Proc. Natl. Acad. Sci. USA 111, 17110–17115 (2014). https://doi.org/10.1073/pnas.1417717111
  45. P. Huang, D. Wang, Y. Su, W. Huang, Y. Zhou et al., Combination of small molecule prodrug and nanodrug delivery: amphiphilic drug-drug conjugate for cancer therapy. J. Am. Chem. Soc. 136, 11748–11756 (2014). https://doi.org/10.1021/ja505212y
  46. Q. Zhou, S. Shao, J. Wang, C. Xu, J. Xiang et al., Enzyme-activatable polymer–drug conjugate augments tumour penetration and treatment efficacy. Nat. Nanotechnol. 14, 799–809 (2019). https://doi.org/10.1038/s41565-019-0485-z
  47. A. Wushou, X. Miao, Tumor size predicts prognosis of head and neck synovial cell sarcoma. Oncol. Lett. 9, 381–386 (2015). https://doi.org/10.3892/ol.2014.2634
Read More
Author biographies are not available.
Download this PDF file
PDF SUPPLEMENTARY MATERIAL
Statistic
Read Counter : 4196 Download : 3146

Most read articles by the same author(s)