Singlet oxygen-responsive micelles for enhanced photodynamic therapy

Photodynamic therapy (PDT) efficacy is limited by the very short half-life and limited diffusion radius of singlet oxygen (O-1(2)). We report a O-1(2)-responsive micellar nanoplatform subject to considerable size-expansion upon light triggering to facilitate on-demand release of photosensitizers. Imidazole, a well-known O-1(2) scavenger, was incorporated in the hydrophobic core of amphiphilic copolymer micelles, and was used to coordinate with biocompatible Zn2+ and encapsulate the photosensitizer chlorin e6 (Ce6). The micelles are highly sensitive to light irradiation: O-1(2) triggering induced dramatic particle size expansion due to the conversion of imidazole to hydrophilic urea, resulting in instantaneous release of Ce6 and rapid intracellular distribution. This O-1(2)-responsive, size-expandable nanosystem delivered substantially more Ce6 to tumor sites as compared to free Ce6, and exhibited improved anti-tumor efficacy in vivo in 4T1 tumor-bearing mice. This work opens new avenues of particle expansion-induced PDT enhancement by controlled imidazole chemistry.