Systemic ligand-mimicking bioparticles cross the blood-brain barrier and reduce growth of intracranial triple-negative breast cancer using the human epidermal growth factor receptor 3 (HER3) to mediate both routes

Abstract

Crossing the blood-brain barrier (BBB) and reaching intracranial tumors is a significant clinical challenge for targeted therapeutics and contributes to the poor prognosis for most patients with brain malignancies. Triple-negative breast cancer (TNBC) has a high propensity for metastasis to the brain and lacks cell surface markers that can be recognized by current targeted therapies used in the clinic, thus limiting therapeutic options. The human epidermal growth factor receptor HER3 (or ErbB3) has emerged as a biomarker of therapeutic resistance and metastasis in a growing range of tumor types and may serve as a possible therapeutic target for TNBC. Accordingly, we have developed HER3-targeted biological particles (bioparticles) that assume polyhedral capsid shapes when encapsulating nucleic acid cargo, forming nano-nucleocapsids (NNCs). The NNCs exhibit systemic homing to resistant and metastatic breast tumors, including TNBC, due to the high cell surface densities of HER3 on these tumors. Here we describe our discovery that HER3 is also prominently expressed on the brain endothelium and can mediate the passage of HER3-targeted NNCs across the BBB and into triple-negative breast tumors localized in the brain. Our findings show that HER3 is present at high levels on the vasculature (but not extravascular parenchyma) of both mouse and human adult brain specimens and associates with the extravasation of systemic HER3-targeted NNCs in mice and in a human model of the BBB (BBB chip). Furthermore, systemically delivered NNCs carrying tumoricidal agents reduced the growth of intracranial TNBC tumors in mice (representing metastatic breast tumors that have established in the brain) and exhibited improved therapeutic profile compared to current therapeutic interventions (liposomal doxorubicin) used in the clinic. This study addresses the major clinical problem of systemically delivering targeted therapeutics across the blood-brain barrier (BBB), and demonstrates a new route for not only accomplishing this but also for reaching tumors localized in the brain.