Multivalent exposure of trastuzumab on iron oxide nanoparticles improves antitumor potential and reduces resistance in HER2-positive breast cancer cells

Marta Truffi, Miriam Colombo, Luca Sorrentino, Laura Pandolfi, Serena Mazzucchelli, Francesco Pappalardo, Chiara Pacini, Raffaele Allevi, Arianna Bonizzi, Fabio Corsi, Davide Prosperi

Research output: Contribution to journalArticle

Abstract

Targeted therapies have profoundly changed the clinical prospect in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In particular, the anti-HER2 monoclonal antibody trastuzumab represents the gold standard for the treatment of HER2+ breast cancer patients. Its contribution in dampening cancer progression is mainly attributed to the antibody-dependent cell-mediated cytotoxicity (ADCC) rather than HER2 blockade. Here, multiple half chains of trastuzumab were conjugated onto magnetic iron oxide nanoparticles (MNP-HC) to develop target-specific and biologically active nanosystems to enhance anti-HER2 therapeutic potential. HER2 targeting was assessed in different human breast cancer cell lines, where nanoparticles triggered site-specific phosphorylation in the catalytic domain of the receptor and cellular uptake by endocytosis. MNP-HC induced remarkable antiproliferative effect in HER2+ breast cancer cells, exhibiting enhanced activity compared to free drug. Accordingly, nanoparticles induced p27kip1 expression and cell cycle arrest in G1 phase, without loosing capability to prime ADCC. Finally, MNP-HC affected viability of trastuzumab-resistant cells, suggesting interference with the resistance machinery. Our findings indicate that multiple arrangement of trastuzumab half chain on the nanoparticle surface enhances anticancer efficacy in HER2+ breast cancer cells. Powerful inhibition of HER2 signaling could promote responsiveness of resistant cells, thus suggesting ways for drug sensitization.

Original languageEnglish
Pages (from-to)6563
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Apr 26 2018

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Nanoparticles
Breast Neoplasms
Antibody-Dependent Cell Cytotoxicity
Trastuzumab
human ERBB2 protein
ferric oxide
G1 Phase
Endocytosis
Cell Cycle Checkpoints
Pharmaceutical Preparations
Catalytic Domain
Therapeutics
Monoclonal Antibodies
Phosphorylation
Cell Line

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Multivalent exposure of trastuzumab on iron oxide nanoparticles improves antitumor potential and reduces resistance in HER2-positive breast cancer cells. / Truffi, Marta; Colombo, Miriam; Sorrentino, Luca; Pandolfi, Laura; Mazzucchelli, Serena; Pappalardo, Francesco; Pacini, Chiara; Allevi, Raffaele; Bonizzi, Arianna; Corsi, Fabio; Prosperi, Davide.

In: Scientific Reports, Vol. 8, No. 1, 26.04.2018, p. 6563.

Research output: Contribution to journalArticle

Truffi, M, Colombo, M, Sorrentino, L, Pandolfi, L, Mazzucchelli, S, Pappalardo, F, Pacini, C, Allevi, R, Bonizzi, A, Corsi, F & Prosperi, D 2018, 'Multivalent exposure of trastuzumab on iron oxide nanoparticles improves antitumor potential and reduces resistance in HER2-positive breast cancer cells', Scientific Reports, vol. 8, no. 1, pp. 6563. https://doi.org/10.1038/s41598-018-24968-x
Truffi, Marta ; Colombo, Miriam ; Sorrentino, Luca ; Pandolfi, Laura ; Mazzucchelli, Serena ; Pappalardo, Francesco ; Pacini, Chiara ; Allevi, Raffaele ; Bonizzi, Arianna ; Corsi, Fabio ; Prosperi, Davide. / Multivalent exposure of trastuzumab on iron oxide nanoparticles improves antitumor potential and reduces resistance in HER2-positive breast cancer cells. In: Scientific Reports. 2018 ; Vol. 8, No. 1. pp. 6563.
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