A self-enhanced chemiexcited PDT system for targeted and efficient treatment of deeply seated tumors

Abstract

Traditional photodynamic therapy (PDT) is almost ineffective against deeply seated tumors due to the limited penetration depth of external light. The development of chemiexcited PDT is promising to address this issue, but it is still challenging to construct simple, efficient and targeted chemiexcited PDT systems. In this work, CPPO (bio(3,5,6-trichloro-2-n-pentyloxycarbonylphenyl) oxalate) and [Ru(phen)₂(PIP-OCH₃)](PF₆)₂ (Ru3, where phen = 1,10-phenanthroline, PIP-OCH₃ = 2-(4-methoxy phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) with efficient photocatalytic NADH (reduced nicotinamide adenine dinucleotide) oxidation were co-encapsulated with DSPE-PEG 2000 to form Ru3/CPPO@PEG nanoparticles (NP3). Once internalized by cancer cells, Ru3 can be excited with the chemical energy produced by the reaction between CPPO and endogenous H₂O₂. The subsequent oxidation of intracellular NADH and generation of H₂O₂in situ by excited Ru3 will further promote the sustained occurrence of the chemical reaction, realizing self-enhanced chemiexcited PDT. NP3 could effectively deplete intracellular NADH, inhibit ATP synthesis, increase the H₂O₂ content, and produce reactive oxygen species (ROS) within cancer cells, thus exhibiting efficient chemiexcited PDT activity against various cancer cells. Notably, minimal cytotoxicity was observed towards normal cells. Good therapeutic effects against subcutaneously implanted and lung metastatic tumors were also observed for NP3. The current findings may provide new insights for development of novel chemiexcited PDT.