Trastuzumab Conjugation Enhances HER2-Positive Cell Association and Intratumoral Retention of Magnetite Nanoparticles for Magnetic Hyperthermia

Magnetic hyperthermia is a therapeutic strategy for cancer that utilizes the heat generated by magnetic nanoparticles exposed to an alternating magnetic field (AMF) to locally elevate tumor tissue temperature and induce cancer cell death. Effective treatment requires delivering an adequate amount of magnetic nanoparticles to the tumor. However, systemic administration is often constrained by insufficient tumor accumulation and potential safety concerns arising from off-target biodistribution, thereby hindering clinical translation. Although direct intratumoral administration can mitigate these limitations, nanoparticles may still rapidly diffuse or leak from the injection site, resulting in insufficient intratumoral retention. In this study, we engineered magnetite nanoparticles (MNPs) to enhance intratumoral retention in HER2-positive tumors via antibody-mediated interactions. Poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) brushes were grafted onto the surface of MNPs, followed by conjugation of the anti-HER2 antibody trastuzumab (Tmab), yielding antibody-modified nanoparticles (MNPs-PMPC-Tmab). In vitro experiments demonstrated increased cellular association of MNPs-PMPC-Tmab with HER2-positive cells compared with HER2-negative counterparts. Following intratumoral administration in nude mice bearing HER2-positive NCI-N87 tumors, MNPs-PMPC-Tmab exhibited higher intratumoral retention than non-antibody-modified controls and remained detectable for up to 72 h. Upon AMF exposure, these nanoparticles elevated tumor temperature to 46 °C and successfully suppressed tumor growth. Collectively, these results demonstrate that surface engineering integrating an antifouling polymer brush with a tumor-targeting antibody is an effective strategy for improving intratumoral retention of magnetic nanoparticles and enhancing therapeutic performance in magnetic hyperthermia.