A Precise and Intelligent Nanomedicine for Salivary Adenoid Cystic Carcinoma Treatment by Combining Antivascular Photodynamic Therapy and Neuroinhibitory Chemotherapy

Abstract Salivary adenoid cystic carcinoma (SACC) is one of the most common salivary gland malignancies. Current clinical therapies have limitations and cannot efficiently prevent the SACC development and metastasis. Hematogenous and neural spread are the two major routes of SACC metastasis. In this study, a precise and intelligent nanomedicine, RCDT, is designed to combine antivascular photodynamic therapy and neuroinhibitory chemotherapy against SACC. A tumor vessel‐targeted and reactive oxygen species (ROS)‐responsive photosensitizer (RC) is synthesized by linking cRGD to chlorin e6 (Ce6) via a bridge between the poly(ethylene glycol) and diselenide bonds. A neural‐targeted and pH‐responsive cytotoxic prodrug (DT) is synthesized by conjugating doxorubicin (DOX) with Tet1, a neural‐targeting peptide, via an acidic‐cleavable hydrazone bond. RC and DT are assembled to form RCDT via hydrophobic interactions, thereby shielding Tet1. Under the guidance of cRGD and the photodynamic action of Ce6, RCDT can precisely disrupt the tumor vasculature and simultaneously disintegrate to expose Tet1 by rupturing the diselenide bond. Guided by Tet1, disintegrated RCDT can be specifically internalized into neurons and release DOX to exert neuroinhibitory effects by cleaving the hydrazone bond. Using these stepwise dual‐targeting and dual‐responsive strategies, RCDT can efficiently suppress the growth and metastasis of SACC.