Sandwich-Structured Upconversion Nanoprobes Coated with a Thin Silica Layer for Mitochondria-Targeted Cooperative Photodynamic Therapy for Solid Malignant Tumors

Abstract

Upconversion nanoparticles-based photodynamic nanotheranostic agents (UCNPs-PDT) have received great interest due to improved tissue penetration, weak autofluorescence, and low biotoxicity. However, conventional UCNPs-PDT are often limited by low energy transfer efficiency from UCNPs to photosensitizer (PS) molecules and insufficient generation and limited diffusion distance of reactive oxygen species (ROSs). Herein, an "all in one" nanotheranostic agent has been developed which has multicolor sandwich-structured UCNPs (SWUCNPs) as the core, a thin silica layer with a mitochondria-targeted group for loading dual PS as the medium layer, and polyethylene glycol-folic acid (PEG-FA) chains as the outer layer. Multicolor SWUCNPs simultaneously achieve two-photon fluorescence imaging and serve as energy donor for dual PS molecules. The thin luminescence layer and silica layer control most UCNPs activators and PS molecules in the effective energy transfer distance to guarantee a high energy transfer efficiency. Via FA-mediated endocytosis, the nanotheranostic agent is selectively endocytosed by cancer cells, is released from the endosome/lysosome, targets the mitochondria, and in situ produces ROSs under excitation from NIR, leading to significant mitochondria-mediated cell apoptosis. Furthermore, the established nanotheranostic agent shows tumor targetability, increased generation of ROSs, high PDT efficacy, significant cell apoptosis, minimal systemic cytotoxicity, and efficacious in vivo tumor inhibition.