X-ray-responsive polypeptide nanogel for concurrent chemoradiotherapy

Concurrent chemoradiotherapy (CCRT) is a standard treatment regimen for medically inoperable stage III non-small-cell lung carcinoma (NSCLC) owing to its superior prognostics compared with the sequential modality. Nevertheless, the current pattern of CCRT still fails to provide satisfactory survival outcome. Furthermore, CCRT is always accompanied by a higher risk of severe side effects, limiting the dose escalation. Herein, an X-ray-responsive polypeptide nanogel (PNG) was developed for on-demand delivery of chemotherapeutic agent triggered by radiotherapy to synergistically improve the efficacy of CCRT with reduced side effects. The smart PNG was formed by crosslinking methoxy poly(ethylene glycol)-block-poly(L-glutamic acid-co-γ-2-chloroethyl-L-glutamate) (mPEG-b-P(LG-co-CELG)) with a diselenide (Se−Se) bond. The doxorubicin (DOX)-loaded polypeptide nanogel (PNG/DOX) exhibited accelerated drug release when exposed to X-ray irradiation as a result of Se−Se bond degradation. With prolonged circulation and enhanced intratumoral accumulation in vivo, PNG/DOX combined with X-ray irradiation exhibited better synergistic antitumor efficacy and fewer side effects toward human A549 lung carcinoma-bearing nude mice. The smart X-ray-responsive nanogel provides a promising bridge between chemotherapy and radiotherapy and enhances the potential application of CCRT in clinic.