Hydrolytically Degradable Polyethylene Glycol Bottlebrush Polymers Address the Stability-Clearance Trade-Off for Drug...

Long-circulating polyethylene glycol bottlebrush polymers (Brush_PEG) are attractive drug carriers, but their nondegradable backbones cause persistent tissue retention, raising concerns about long-term safety and clinical translation. Here, we report a hydrolytically degradable PEG bottlebrush polymer (D-Brush_PEG) created by incorporating 7-oxa-2,3-diazanorbornene (ODAN) units into the backbone. D-Brush_PEG retains prolonged circulation (elimination half-life ≈24.7 h, compared with ≈0.78 h for a small-molecule dye) while undergoing controlled hydrolysis that greatly improves systemic and tissue clearance. More than 99% of the circulating signal is removed within 13 days, accompanied by a near-complete loss of liver and skin fluorescence. In contrast, a nondegradable Brush_PEG analog exhibits slower plasma elimination (∼5% remaining at day 13) and persistent accumulation in the liver and skin for over one month. When conjugated with gemcitabine (GEM) through a reduction-responsive self-immolative linker, D-Brush_PEG demonstrated comparable antitumor efficacy to the nondegradable Brush_PEG-GEM formulation. Systemic evaluation indicates comparable hepatic and renal safety profiles for both polymers, with only mild renal changes observed, while skin irritation is reduced for D-Brush_PEG relative to Brush_PEG. These results demonstrate that controlled backbone hydrolysis allows PEG bottlebrush polymers to balance long circulation with efficient clearance, reducing tissue persistence and the risk of side effects.