Inhibiting HER3 Hyperphosphorylation in HER2‐Overexpressing Breast Cancer through Multimodal Therapy with Branched Gold Nanoshells

Abstract

Treatment failure in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2) is associated mainly to the upregulation of human epidermal growth factor receptor 3 (HER3) oncoprotein linked to chemoresitence. Therefore, to increase patient survival, here a multimodal theranostic nanoplatform targeting both HER2 and HER3 is developed. This consists of doxorubicin‐loaded branched gold nanoshells functionalized with the near‐infrared (NIR) fluorescent dye indocyanine green, a small interfering RNA (siRNA) against HER3, and the HER2‐specific antibody Transtuzumab, able to provide a combined therapeutic outcome (chemo‐ and photothermal activities, RNA silencing, and immune response). In vitro assays in HER2+/HER3+ SKBR‐3 breast cancer cells have shown an effective silencing of HER3 by the released siRNA and an inhibition of HER2 oncoproteins provided by Trastuzumab, along with a decrease of the serine/threonine protein kinase Akt (p‐AKT) typically associated with cell survival and proliferation, which helps to overcome doxorubicin chemoresistance. Conversely, adding the NIR light therapy, an increment in p‐AKT concentration is observed, although HER2/HER3 inhibitions are maintained for 72 h. Finally, in vivo studies in a tumor‐bearing mice model display a significant progressively decrease of the tumor volume after nanoparticle administration and subsequent NIR light irradiation, confirming the potential efficacy of the hybrid nanocarrier.

Noble Metal Nanoparticle-Based Photothermal Therapy: Development and Application in Effective Cancer Therapy

“…Particularly, HER3 overexpression contributes to resistance mechanisms against conventional antitumor agents. To address these hurdles, Eva Villar-Alvarez et al [ 34 ] devised a multifunctional, biocompatible nanoplatform integrating diagnostic and therapeutic modalities. This platform comprises branched gold nanoshells loaded with doxorubicin, conjugated with the near-infrared (NIR) fluorescent dye indocyanine green, and further functionalized with small interfering RNA (siRNA) targeting HER3, along with the HER2-specific antibody trastuzumab.…”

A Multifunctional Bimetallic Nanoplatform for Synergic Local Hyperthermia and Chemotherapy Targeting HER2‐Positive Breast Cancer

“…As an alternative approach, nanoparticle-based drug delivery has gained increasing attention in breast cancer treatment. [11] In recent years, numerous stimuli-responsive nanocarriers have been developed to facilitate controlled release and sustained delivery of biologically active substances. These carriers are also used to implement specific novel therapies in tandem with external physical stimuli such as phototherapy, acoustic therapy, and magnetotherapy.…”