An antibody-photosensitiser bioconjugate overcomes trastuzumab resistance in HER2-positive breast cancer
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Author
Other authors
Publication date
2025-06-05ISSN
1768-3254
Abstract
HER2-positive breast cancer, characterized by the overexpression of HER2 receptors, often develops resistance to trastuzumab, limiting its therapeutic efficacy. In this study, we explore the use of photodynamic therapy (PDT) with a trastuzumab-IRDye700DX photoimmunoconjugate (Tz-IR700) as a strategy to overcome trastuzumab resistance. Tz-IR700 combines the antibody's selectivity for the tumoral cells with the cytotoxic effect of IR700, induced by red light. Our results demonstrate that Tz-IR700 selectively accumulates in trastuzumab-resistant HER2-positive tumours (HCC1954) thereby enabling precise tumour localization by fluorescence imaging. Upon irradiation with red light, Tz-IR700 induces significant HCC1954 cell viability reduction both in vitro and in vivo, notably overcoming trastuzumab resistance in this HER2-positive breast cancer cell line. Mechanistic studies unequivocally demonstrate that the primary cytotoxic species is singlet oxygen. These findings suggest that Tz-IR700 could serve as a valuable treatment option for trastuzumab-resistant HER2-positive breast cancer and may also be used as an adjuvant to fluorescence-guided surgery, improving surgical outcomes and reducing the likelihood of tumour recurrence and metastasis.
Document Type
Article
Document version
Accepted version
Language
English
Subject (CDU)
615 - Pharmacology. Therapeutics. Toxicology
616 - Pathology. Clinical medicine
618 - Gynaecology. Obstetrics
Keywords
Breast cancer
Photodynamic therapy
Antibody-drug conjugates
Trastuzumab
Singlet oxygen
Mama--Càncer
Fototeràpia
Fàrmacs immunoconjugats
Oxigen singlet
Pages
p.35
Publisher
Elsevier
Is part of
European Journal of Medicinal Chemistry 2025, 290
Grant agreement number
info:eu-repo/grantAgreement/MCI/PN I+D/ PID2020-115801RB-C22
info:eu-repo/grantAgreement/MCIU/PN I+D/PID2023-149483NB-C22
info:eu-repo/grantAgreement/SUR del DEC/SGR/2021-SGR-01023
info:eu-repo/grantAgreement/MCI/RYC/RYC2021-032773-I
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Rights
© Elsevier Masson SAS
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-nd/4.0/