A Modular Approach to Obtain HER2-Targeting DM1-Loaded Nanoparticles for Gastric Cancer Therapy

Antibody-based tumor-targeting nanomedicines, despite their high efficacy, present significant challenges in preparation and long-term storage. We introduce a novel approach for the synthesis of durable, ready-to-use, antibody-coupled nanomedical drugs. Our research centers on the development of HER2-targeting DM1-loaded nanoparticles for gastric cancer treatment using a modular methodology. We synthesized Fc-PLG-Mal, conjugated DM1 through a "click" reaction, and subsequently bound the resultant compound with the HER2 antibody trastuzumab. The nanoparticles demonstrated a high drug loading content, stable particle size, and effective HER2 targeting. HER2-PLG-DM1 exhibited significant cytotoxicity against NCI-N87 gastric cancer cells, with an IC₅₀ of 0.35 nM. Biodistribution revealed rapid and substantial tumor accumulation, 6-fold higher than that of nontargeting IgG-PLG-DM1. HER2-PLG-DM1 significantly inhibited tumor growth in NCI-N87 tumor-bearing mice, achieving a 90.8% tumor inhibition rate, and displayed dose-dependent effects without significant liver and kidney toxicity. These studies offer an efficient and stable method for the preparation of antibody-coupled drugs.