Synergistic Cancer Therapy: An NIR-Activated Methylene Blue-Nitrogen Mustard Prodrug for Combined Chemotherapy and Photodynamic Therapy

Nitrogen mustard, a widely used chemotherapeutic agent for more than 70 years, exhibits significant efficacy. However, its clinical applications are severely limited by poor tumor selectivity and severe side effects on normal tissues. To address these limitations, we developed a near-infrared (NIR)-activatable nitrogen mustard prodrug, MBNM. Upon NIR irradiation, the controlled cleavage of the urea bond within MBNM facilitates the simultaneous release of nitrogen mustard and methylene blue (MB), enabling a synergistic approach combining chemotherapy and photodynamic therapy (PDT) for effective tumor suppression. Moreover, the release of MB upon activation enables real-time monitoring of prodrug activation. Notably, MBNM demonstrated significantly improved biosafety compared to free nitrogen mustard. These findings suggest that the photocleavable prodrug MBNM offers a promising strategy for safe and effective combination cancer therapy.