Smart Nanomedicine Targeting Endocytosis Mediated by Cancer Cell Surface Neuraminidase-1

Human neuraminidase-1 (NEU1) plays a much more profound function in human cancers than previously considered. It is demonstrated that cancer cell surface NEU1 is a desired gatekeeper for an innovative anticancer therapeutic nanomedicine enabling active drug-targeting delivery by specific endocytosis into the cytoplasm. Nanosome, an antiadhesive nanoparticular shuttle, carrying multiple suicide substrates for NEU1 confers potent and universal inhibitory effects on the proliferation of human cancer cells, such as hepatocellular carcinoma (HCC) (HepG2, IC₅₀ = 13.5 nM), lung cancer (A549, IC₅₀ = 9.57 nM), and colon cancer (HT-29, IC₅₀ = 11.1 nM), in which irreversible inactivation of cell surface NEU1 is essential for the intracellular trafficking and subsequent lysosomal membrane permeabilization by nanosomal aggregation due to the formation of “sialidase corona” through irreversible inactivation of NEU1–NEU4 residing in lysosome. Nanomedicine targeting membrane-tethered NEU1 allows efficient delivery of hydrophobic sorafenib (Nexavar), a RAF family kinase inhibitor for the treatment of advanced renal cell carcinoma and unresectable HCC at the recommended dose of 400 mg orally twice daily, into endolysosome, resulting in a potent and sustainable inhibition (IC₅₀ = 3.1–6.2 nM at 24–96 h after coincubation) against HepG2 cell growth.