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.
Highlights
The overexpression or gene amplification of human epidermal growth factor receptor 2 (HER2) characterizes 20–30% of all breast cancers, which are classified as the HER2-positive subtype[1]
MNP-half-chain antibody portions (HCs) were assessed for their capability to interact with multiple human breast cancer cell lines, classified as distinct carcinoma subtypes with different levels of HER2 expression (Table 1)[14]
MNP-HC exhibited ≥ 97% binding to all the tested cell lines when incubated at a dose equal to 0.2 μg mL−1 of trastuzumab, while decreasing the dosage different outcomes were observed depending on the cell type
Summary
The overexpression or gene amplification of human epidermal growth factor receptor 2 (HER2) characterizes 20–30% of all breast cancers, which are classified as the HER2-positive subtype[1]. Target specificity and biological activity of TZ-derived half chains immobilized on multivalent colloidal nanoparticles were investigated on breast cancer cell lines. Direct comparison with free TZ was made in order to characterize the efficacy of nanoparticles with respect to the same dosage of drug, following the idea that the spatial arrangement of the targeting moieties could be the key for antibody-ligand interaction and subsequent activity modulation. As the conjugation with colloidal nanoparticles seems to affect the therapeutic efficacy of TZ13, we explored the anticancer activity of MNP-HC both in HER2+ TZ-sensitive and resistant breast cancer cells
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