Tumor penetrating Janus prodrug nanoassemblies for enhanced synergistic chemotherapy and photodynamic therapy of colon cancer

[Display omitted] •Acetylated gelatin possessed great potential as a biocompatible and biodegradable drug carrier.•A facile approach was developed to prepare tumor-targeting nanoprodrugs using click chemistry.•The nanoassemblies exhibited exceptional tumor penetration capability attributed to their inherent shrinkage property. Intelligent nanodrug delivery systems that respond to tumor microenvironment have been extensively utilized in cancer therapy research. However, the passive diffusion of prodrug nanoparticles is hindered due to the absence of capillaries and dense extracellular matrix in the tumor microenvironment, resulting in low efficiency of anti-tumor drug delivery. In this study, we developed a metal matrix proteinase 2 (MMP2) and glutathione (GSH) responsive Janus prodrug nanoassemblies targeted towards tumors. The Janus prodrug nanoassemblies consist of targeted micelles and prodrug nanoaggregates linked by click chemistry. The size of the nanoassemblies can be reduced within the tumor microenvironment of high concentrations of MMP2. Active targeting and size shrinkage synergistically enhance cell uptake efficiency and tumor penetration capacity of nanoassemblies. The release of camptothecin (CPT) occurs in a GSH-dependent manner, while under irradiation with 660-nm red light, the photosensitizer introduced in the prodrug generates reactive oxygen species (ROS) to induce tumor cell death. Fluorescence imaging results demonstrate enhanced tumor targeting capabilities of Janus prodrug assemblies. As a theranostic agent for tumors, Janus prodrug assemblies achieve desirable synergistic chemotherapy and photodynamic therapy for colon cancer treatment. This work would provide a novel strategy for cancer diagnosis and treatment.