A pH-responsive Pt-based nanoradiosensitizer for enhanced radiotherapy via oxidative stress amplification

Abstract

Tumor radioresistance is a major issue in radiotherapy. To address it, a pH-responsive nanoradiosensitizer was synthesized employing a simple method. Initially, chloroplatinic acid was reduced by human serum albumin (HSA) to form HSA-wrapped Pt@HSA nanoparticles (NPs). Subsequently, cinnamicaldehyde (CA) was grafted on Pt@HSA via aldimine condensation to obtain nanoradiosensitizer Pt@HSA/CA NPs. CA would be released in tumor cells (pH = 5.5) to induce the production of reactive oxygen species, including H₂O₂, ˙OH, etc. The increased decomposition of H₂O₂ catalyzed by the NPs resulted in enhanced production of oxygen, leading to hypoxia relief of the tumor cells, which is beneficial for radiotherapy. Due to the high X-ray attenuation coefficient of Pt, Pt@HSA/CA NPs enhance the energy deposition of radiation. Cytotoxicity assay revealed that Pt@HSA/CA NPs resulted in a cell death rate of 77%, which was 24.4% higher than that of Pt@HSA NPs even under low-dose X-ray irradiation of 4 Gy. Colony formation assay demonstrated that the sensitization enhancement ratio was 1.37, indicating that Pt@HSA/CA NPs displayed remarkable radiosensitizing ability. Notably, in vivo results indicated that the NPs could increase the tumor inhibition rate to 91.2% with negligible side effects to normal tissues. These results demonstrate that Pt@HSA/CA NPs had outstanding tumor curative efficacy and hypotoxicity.