Amphiphilic Metallodrug Assemblies with Red‐Light‐Enhanced Cellular Internalization and Tumor Penetration for Anticancer Phototherapy

Abstract Metallodrugs are widely used in cancer treatment. The modification of metallodrugs with polyethylene glycol (PEGylation) prolongs blood circulation and improves drug accumulation in tumors; it represents a general strategy for drug delivery. However, PEGylation hinders cellular internalization and tumor penetration, which reduce therapeutic efficacy. Herein, the red‐light‐enhanced cellular internalization and tumor penetration of a PEGylated anticancer agent, PEGylated Ru complex (Ru‐PEG), are reported upon. Ru‐PEG contains a red‐light‐cleavable PEG ligand, anticancer Ru complex moiety, and fluorescent pyrene group for imaging and self‐assembly. Ru‐PEG self‐assembles into vesicles that circulate in the bloodstream and accumulate in the tumors. Red‐light irradiation induces dePEGylation and changes the Ru‐PEG vesicles to large compound micelles with smaller diameters and higher zeta potentials, which enhance tumor penetration and cellular internalization. Red‐light irradiation also generates intracellular 1 O 2 , which induces the death of cancer cells. This work presents a new strategy to enhance the cellular internalization and tumor penetration of anticancer agents for efficient phototherapy.