Abstract

Photothermal therapy (PTT) is an innovative cancer treatment that leverages heat generated from near-infrared light exposure to induce tumor cell death. A major challenge in PTT is achieving precise delivery of the photothermal agent to tumor tissues to maximize efficacy and minimize off-target effects. In this study, we introduce a novel ligand-coupled photothermal reagent that addresses this challenge by leveraging the high-affinity HER2 affibody Z_HER2:2891 (referred to as Z_HER2), conjugated with indocyanine green (ICG) for targeted delivery. Polyethylene glycol (PEG) was incorporated as a hydrophilic linker to further optimize photothermal conversion efficiency and enhance tumor-specific targeting. Among the conjugates tested, Z_HER2-PEG₁₀₀₀-ICG, modified with a PEG chain of 1000?Da molecular weight, demonstrated exceptional performance. In vitro studies revealed that Z_HER2-PEG₁₀₀₀-ICG specifically bound to HER2-expressing cells and effectively induced cell death. In vivo experiments using HER2-positive N87 tumor-bearing mice showed that Z_HER2-PEG₁₀₀₀-ICG accumulated highly and specifically in tumor tissues over an extended period. Upon light irradiation, this conjugate caused a significant rise in temperature at the tumor site, resulting in complete tumor elimination with a single photothermal treatment. This PEG-modified affibody-ICG conjugate represents a precise and effective approach to PTT, offering a promising new therapeutic strategy for cancer treatment with the potential to significantly impact future cancer therapies.