A novel near-infrared fluorescent hERG potassium channel probe for glioblastoma therapy and imaging

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumor, and its therapy remains challenging. The hERG potassium channel represents a promising target for GBM therapy and imaging. However, there are currently few efficient hERG channel inhibitors with low toxicity for cancer therapy. In this work, a novel near-infrared fluorescent probe A8 with high binding affinity for the hERG channel was developed, and then it was encapsulated into an ApoE peptide-modified liposome to improve its transport across the blood–brain barrier and tumor targeting. The obtained liposome, ApoE-Lipo@A8, can significantly suppress the growth of orthotopic glioblastoma xenografts with reduced cardiac toxicity. Additionally, our studies unveil a novel molecular mechanism underlying the antitumor effect of hERG channel inhibition, including suppression of the CDK2-pRB-E2F axis and induction of ER-stress-dependent apoptosis and autophagy. Additionally, A8 is characterized by an aggregation-caused fluorescence quenching switch, and it can be used to light up the hERG channel and, further, for GBM imaging in vivo. Together, this study systematically explores the therapeutic and imaging potential of the hERG channel for glioblastomas using the probe A8, which would promote the development of the hERG channel as a therapeutic and imaging target for cancer.