Trastuzumab-Conjugated pH-Sensitive Micelles Exhibit Antitumor Activity and Induce Mesenchymal-to-Epithelial Transition in Triple-Negative Breast Cancer Cell Lines

Tiron, Crina Elena; Luta, Gabriel; Ghiarasim, Razvan; Tiron, Adrian; Nastasa, Valentin; Anita, Dragos Constantin; Iversen, Tore Geir; Skotland, Tore; Sandvig, Kirsten; Mares, Mihai; Dimofte, Mihail-Gabriel

doi:10.3390/pharmaceutics17121554

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Trastuzumab-Conjugated pH-Sensitive Micelles Exhibit Antitumor Activity and Induce Mesenchymal-to-Epithelial Transition in Triple-Negative Breast Cancer Cell Lines

by

Crina Elena Tiron

¹

,

Gabriel Luta

¹,

Razvan Ghiarasim

²

,

Adrian Tiron

^1,*

,

Valentin Nastasa

³

,

Dragos Constantin Anita

³

,

Tore Geir Iversen

^4,5,

Tore Skotland

^4,5,

Kirsten Sandvig

^4,5,6

,

Mihai Mares

³

and

Mihail-Gabriel Dimofte

^1,7

¹

TRANSCEND Centre, Regional Institute of Oncology, 2-4 General Henri Mathias Berthelot Street, 700483 Iasi, Romania

²

Centre of Advanced Research in Bionanoconjugates and Biopolymers, “Petru Poni” Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania

³

Translational Research Center for Antimicrobial and Anticancer Agents, Iasi, Faculty of Veterinary Medicine, University of life Sciences, 8 Aleea Mihail Sadoveanu, 700489 Iasi, Romania

⁴

Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway

⁵

Centre for Cancer Cell Reprogramming, University of Oslo, 0379 Oslo, Norway

⁶

Department of Biosciences, University of Oslo, 0316 Oslo, Norway

⁷

Department of Surgery, “Grigore T Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania

^*

Author to whom correspondence should be addressed.

Pharmaceutics 2025, 17(12), 1554; https://doi.org/10.3390/pharmaceutics17121554 (registering DOI)

Submission received: 6 October 2025 / Revised: 18 November 2025 / Accepted: 20 November 2025 / Published: 2 December 2025

(This article belongs to the Special Issue Biomedical Applications of Nanocarriers in Targeted Delivery of Bioactive Compounds)

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Abstract

Background: Despite improved knowledge on cancer prevention, progression, and treatment, the incidence of cancer is still increasing. Patients with highly aggressive triple-negative breast cancer benefit from chemotherapy as the only systemic therapeutic alternative. Here, we performed studies that demonstrate the effects of trastuzumab linked to nanostructures with pH-dependent release on triple-negative models. Methods: We assessed in vitro cell proliferation, migration, invasion, mammospheres, spheroids, and organoid formation of human and murine cell lines. Balb/c mice were used to investigate the in vivo anti-tumoral effects of functionalized nanostructures. Ex vivo samples and cell lines were used to investigate, using immunohistochemistry and Western blot, the modulation of key molecular pathways. Results: Using a human normal cell line and human and murine triple-negative breast cancer cell lines, we found that trastuzumab exhibits anti-tumoral properties on triple-negative breast cancer cell lines only when linked to pH-sensitive micelles. In addition, the data demonstrates that functionalized micelles induce mesenchymal-to-epithelial transitions, impairing the metastasis. Conclusions: Taken together, these results indicate that functionalization of micelles by linking trastuzumab may open the way of treating triple-negative patients with trastuzumab, a treatment which is currently in use for patients with Her2 overexpression. The functionalized micelles may be loaded with various molecules to further improve the anti-tumoral effects.

Keywords: TNBC; trastuzumab; drug delivery system; targeted delivery; EMT

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MDPI and ACS Style

Tiron, C.E.; Luta, G.; Ghiarasim, R.; Tiron, A.; Nastasa, V.; Anita, D.C.; Iversen, T.G.; Skotland, T.; Sandvig, K.; Mares, M.; et al. Trastuzumab-Conjugated pH-Sensitive Micelles Exhibit Antitumor Activity and Induce Mesenchymal-to-Epithelial Transition in Triple-Negative Breast Cancer Cell Lines. Pharmaceutics 2025, 17, 1554. https://doi.org/10.3390/pharmaceutics17121554

AMA Style

Tiron CE, Luta G, Ghiarasim R, Tiron A, Nastasa V, Anita DC, Iversen TG, Skotland T, Sandvig K, Mares M, et al. Trastuzumab-Conjugated pH-Sensitive Micelles Exhibit Antitumor Activity and Induce Mesenchymal-to-Epithelial Transition in Triple-Negative Breast Cancer Cell Lines. Pharmaceutics. 2025; 17(12):1554. https://doi.org/10.3390/pharmaceutics17121554

Chicago/Turabian Style

Tiron, Crina Elena, Gabriel Luta, Razvan Ghiarasim, Adrian Tiron, Valentin Nastasa, Dragos Constantin Anita, Tore Geir Iversen, Tore Skotland, Kirsten Sandvig, Mihai Mares, and et al. 2025. "Trastuzumab-Conjugated pH-Sensitive Micelles Exhibit Antitumor Activity and Induce Mesenchymal-to-Epithelial Transition in Triple-Negative Breast Cancer Cell Lines" Pharmaceutics 17, no. 12: 1554. https://doi.org/10.3390/pharmaceutics17121554

APA Style

Tiron, C. E., Luta, G., Ghiarasim, R., Tiron, A., Nastasa, V., Anita, D. C., Iversen, T. G., Skotland, T., Sandvig, K., Mares, M., & Dimofte, M.-G. (2025). Trastuzumab-Conjugated pH-Sensitive Micelles Exhibit Antitumor Activity and Induce Mesenchymal-to-Epithelial Transition in Triple-Negative Breast Cancer Cell Lines. Pharmaceutics, 17(12), 1554. https://doi.org/10.3390/pharmaceutics17121554

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Trastuzumab-Conjugated pH-Sensitive Micelles Exhibit Antitumor Activity and Induce Mesenchymal-to-Epithelial Transition in Triple-Negative Breast Cancer Cell Lines

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