In cancer treatment, radiotherapy is an important approach for more than 70% of solid tumors, and it is of great significance, especially for glioblastoma multiforme. However, the radioresistance of tumor cells and the toxicity of radiation to normal tissues severely limit the efficacy of radiotherapy. Radiosensitizers also have difficulty functioning efficiently due to physiological barriers within the body. The nanodrug delivery system holds promise. for breaking through this bottleneck.
This study has developed an innovative peptide–radiosensitizer composite system, aiming to enhance the radiosensitivity of glioblastoma multiforme during radiotherapy. The core of this system is the peptide–metronidazole conjugate molecule, which integrates four functional modules: a targeting peptide segment capable of penetrating the blood–brain barrier, a cathepsin B cleavage sequence, a pH-sensitive self-assembling fragment, and metronidazole, a nitroimidazole radiosensitizer. In vivo, the radiosensitizer exhibits a multi-stage dynamic transformation; it forms a complex with heparin during systemic circulation to avoid immune clearance. After reaching the tumor site, heparinase causes the complex to depolymerize into small particles, thereby increasing the uptake by tumor cells. After entering the lysosome, it self-assembles into nanofibers, which damage the lysosomal membrane, block the AKT signaling pathway, inhibit autophagy, disintegrate the cytoskeleton, and synergize with radiotherapy to induce apoptosis of tumor cells. Experiments show that under a low-dose radiation of 6 Gy, the inhibition rate of this system against orthotopic glioma reaches 80%, and there is no intracranial metastasis. This research brings a new paradigm and a breakthrough direction for cancer radiotherapy.