Carbon-Dot-Decorated Carbon Nitride Nanoparticles for Enhanced Photodynamic Therapy against Hypoxic Tumor <i>via</i> Water Splitting

TLDR

Hypoxia in solid tumors limits the effectiveness of photodynamic therapy. The study aims to employ a carbon nitride‑based nanocomposite that drives light‑induced water splitting to alleviate tumor hypoxia and enhance PDT. Carbon dots are doped into C3N4 to extend red‑light absorption, and a polymer bearing a protoporphyrin photosensitizer, PEG, and an RGD targeting motif is incorporated onto the nanoparticles to enable in vivo water splitting and oxygen generation. The resulting PCCN nanoparticles raise intracellular oxygen, boost reactive‑oxygen‑species production under both hypoxic and normoxic conditions, fully reverse hypoxia‑induced PDT resistance, achieve significant cancer‑cell growth inhibition at 1 % O₂, and demonstrate superior in vivo capacity to overcome tumor hypoxia, indicating promise for improving intratumoral oxygenation and reducing metastasis.

Abstract

Hypoxia, a typical feature of solid tumors, remarkably restricts the efficiency of photodynamic therapy (PDT). Here, a carbon nitride (C3N4)-based multifunctional nanocomposite (PCCN) for light-driven water splitting was used to solve this problem. Carbon dots were first doped with C3N4 to enhance its red region absorption because red light could be used to trigger the in vivo water splitting process. Then, a polymer containing a protoporphyrin photosensitizer, a polyethylene glycol segment, and a targeting Arg-Gly-Asp motif was synthesized and introduced to carbon-dot-doped C3N4 nanoparticles. In vitro study showed that PCCN, thus obtained, could increase the intracellular O2 concentration and improve the reactive oxygen species generation in both hypoxic and normoxic environments upon light irradiation. Cell viability assay demonstrated that PCCN fully reversed the hypoxia-triggered PDT resistance, presenting a satisfactory growth inhibition of cancer cells in an O2 concentration of 1%. In vivo experiments also indicated that PCCN had superior ability to overcome tumor hypoxia. The use of water splitting materials exhibited great potential to improve the intratumoral oxygen level and ultimately reverse the hypoxia-triggered PDT resistance and tumor metastasis.