HER2-targeted multifunctional gold nanorods for imaging-guided combined chemotherapy and photothermal therapy

Conventional chemotherapy remains limited by nonspecific biodistribution, dose-limiting systemic toxicity, and poor control over drug delivery at tumor sites. To address these challenges, we developed a multifunctional nanoplatform based on doxorubicin (DOX)-conjugated gold nanorods (GNRs) functionalized with Herceptin (HER), an anti-HER2 antibody, to promote HER-associated tumor accumulation and chemo-photothermal therapy. Carboxylated poly(ethylene glycol)-modified GNRs were sequentially conjugated with DOX and HER via protein G to generate HER-DOX-PEG-GNRs. Surface-charge changes, ultraviolet-visible/near-infrared (UV-vis/NIR) spectroscopy, Fourier-transform infrared (FT-IR) analysis, and quantitative measurements of DOX and HER content supported stepwise surface functionalization. HER-DOX-PEG-GNRs retained strong NIR absorption near 805 nm and generated localized heat upon NIR irradiation. In HER2-overexpressing SK-BR-3 cells and xenografts, HER functionalization was associated with greater cellular uptake and tumor accumulation than non-targeted controls; however, because HER2-negative controls and receptor-blocking experiments were not performed, these findings are interpreted as HER-associated rather than definitive receptor-specific targeting. HER-DOX-PEG-GNRs exhibited greater apparent DOX-associated release at pH 6.8 than at pH 7.4. In SK-BR-3 xenograft-bearing mice, HER-DOX-PEG-GNRs combined with NIR irradiation produced marked tumor regression, with no measurable regrowth detected during the 28-day observation period. Histological analysis showed reduced PCNA staining and increased TUNEL-positive staining, consistent with reduced proliferative activity and increased treatment-associated DNA fragmentation/cell death. Zebrafish embryo testing and 28-day mouse observations, including body weight, major-organ histology, and hematological and serum biochemical parameters, revealed no obvious short-term treatment-associated toxicity under the tested conditions. Collectively, these findings support the feasibility of integrating NIR imaging, localized photothermal heating, HER-associated tumor accumulation, and pH-facilitated DOX release within a single GNR-based platform, while further receptor-specific targeting studies, quantitative synergy analyses, and longer-term safety evaluation remain warranted.