Delivery of an ERK inhibitor using bioactive lipid nanoparticles reduces angiogenesis and prevents oral squamous cell carcinoma development.

Extracellular regulated protein kinases (ERK) signaling is aberrantly activated in oral squamous cell carcinoma (OSCC), and targeting ERK signaling with ERK1/2 inhibitors is a potential strategy for OSCC treatment. However, methods for the more efficient delivery of ERK inhibitors to improve drug utilization remains a pressing challenge. Notably, the application of antiangiogenic therapies to treat OSCC has received increasing attention, yet single therapies often have very limited efficacy. The combination of antiangiogenic therapies with strategies targeting ERK1/2 signaling for the treatment of OSCC is very promising. In this study, we utilized bioactive phospholipids (dipalmitoyl phosphatidic acid, DPPA) with antiangiogenic functions to encapsulate a small-molecule ERK inhibitor (called NP-AE) and constructed an intrinsically biotherapeutically active nanomedicine delivery platform with dual therapeutic efficacy. NP-AE effectively inhibited the proliferation and promoted the apoptosis of OSCC cell lines. A tongue orthotopic xenograft model and a patient-derived xenograft (PDX) model of OSCC were subsequently used to investigate its therapeutic effect. The nanoplatform was able to accumulate in tumor tissues and was internalized by tumor cells after intravenous administration. NP-AE effectively inhibited ERK1/2 phosphorylation and Angptl2 and VEGFA expression in OSCC in vitro and in vivo and significantly inhibited the growth of xenografts. Taken together, these findings suggest that targeting ERK1/2 signaling in combination with antiangiogenic therapy by NP-AE may be a promising strategy for the treatment of OSCC.