Nanobody-targeted photodynamic therapy induces significant tumor regression of trastuzumab-resistant HER2-positive breast cancer, after a single treatment session.

Autor: Deken MM; Dept. of Surgery, Leiden University Medical Center, Leiden, the Netherlands., Kijanka MM; Division of Cell Biology, Neurobiology and Biophysics, Dept. of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands., Beltrán Hernández I; Pharmaceutics, Dept. of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands., Slooter MD; Dept. of Radiology, Division of Molecular Imaging, Leiden University Medical Center, Leiden, the Netherlands., de Bruijn HS; Dept. of Otorhinolaryngology & Head and Neck Surgery, Center for Optical Diagnostics and Therapy, Erasmus Medical Center, Rotterdam, the Netherlands., van Diest PJ; Dept. of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands., van Bergen En Henegouwen PMP; Division of Cell Biology, Neurobiology and Biophysics, Dept. of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands., Lowik CWGM; Dept. of Radiology, Optical Molecular Imaging, Erasmus University Medical Center, Rotterdam, the Netherlands., Robinson DJ; Dept. of Surgery, Leiden University Medical Center, Leiden, the Netherlands; Dept. of Otorhinolaryngology & Head and Neck Surgery, Center for Optical Diagnostics and Therapy, Erasmus Medical Center, Rotterdam, the Netherlands., Vahrmeijer AL; Dept. of Surgery, Leiden University Medical Center, Leiden, the Netherlands., Oliveira S; Division of Cell Biology, Neurobiology and Biophysics, Dept. of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands; Pharmaceutics, Dept. of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands. Electronic address: s.oliveira@uu.nl.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2020 Jul 10; Vol. 323, pp. 269-281. Date of Electronic Publication: 2020 Apr 21.
DOI: 10.1016/j.jconrel.2020.04.030
Abstrakt: Rationale: A substantial number of breast cancer patients with an overexpression of the human epidermal growth factor receptor 2 (HER2) have residual disease after neoadjuvant therapy or become resistant to trastuzumab. Photodynamic therapy (PDT) using nanobodies targeted to HER2 is a promising treatment option for these patients. Here we investigate the in vitro and in vivo antitumor efficacy of HER2-targeted nanobody-photosensitizer (PS) conjugate PDT.
Methods: Nanobodies targeting HER2 were obtained from phage display selections. Monovalent nanobodies were engineered into a biparatopic construct. The specificity of selected nanobodies was tested in immunofluorescence assays and their affinity was evaluated in binding studies, both performed in a panel of breast cancer cells varying in HER2 expression levels. The selected HER2-targeted nanobodies 1D5 and 1D5-18A12 were conjugated to the photosensitizer IRDye700DX and tested in in vitro PDT assays. Mice bearing orthotopic HCC1954 trastuzumab-resistant tumors with high HER2 expression or MCF-7 tumors with low HER2 expression were intravenously injected with nanobody-PS conjugates. Quantitative fluorescence spectroscopy was performed for the determination of the local pharmacokinetics of the fluorescence conjugates. After nanobody-PS administration, tumors were illuminated to a fluence of 100 J∙cm -2 , with a fluence rate of 50 mW∙cm -2 , and thereafter tumor growth was measured with a follow-up until 30 days.
Results: The selected nanobodies remained functional after conjugation to the PS, binding specifically and with high affinity to HER2-positive cells. Both nanobody-PS conjugates potently and selectively induced cell death of HER2 overexpressing cells, either sensitive or resistant to trastuzumab, with low nanomolar LD 50 values. In vivo, quantitative fluorescence spectroscopy showed specific accumulation of nanobody-PS conjugates in HCC1954 tumors and indicated 2 h post injection as the most suitable time point to apply light. Nanobody-targeted PDT with 1D5-PS and 1D5-18A12-PS induced significant tumor regression of trastuzumab-resistant high HER2 expressing tumors, whereas in low HER2 expressing tumors only a slight growth delay was observed.
Conclusion: Nanobody-PS conjugates accumulated selectively in vivo and their fluorescence could be detected through optical imaging. Upon illumination, they selectively induced significant tumor regression of HER2 overexpressing tumors with a single treatment session. Nanobody-targeted PDT is therefore suggested as a new additional treatment for HER2-positive breast cancer, particularly of interest for trastuzumab-resistant HER2-positive breast cancer. Further studies are now needed to assess the value of this approach in clinical practice.
Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists.
(Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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