An azo bond primary cleavage and C–C bond secondary cleavage-based polymeric β-lapachone prodrug for selective anti-cancer therapy

β-Lapachone (β-Lap) is a promising ortho-naphthoquinone drug for cancer treatment and has been in clinical trials. Its application is constrained by the low aqueous solubility, and severe side effects. Even prodrug designation is an effective approach to render it with tumor selectivity, it is limited by the lack of modifiable groups on β-Lap. Herein, a novel azo bond primary cleavage and carbon–carbon (C–C) bond secondary cleavage-based polymeric β-Lap prodrug (Azo-Lap NP) is designed, in which the self-immolated para-aminobenzyl linker is connected to poly(l-glutamic acid) (PGlu) via azo linkage and the responsive drug release of β-Lap against tumors can be achieved under high NAD(P)H:quinone oxidoreductase 1 (NQO1) expression and low pH environment in tumors. The effective covalent loading of β-Lap by Azo-Lap NPs permitted a high administration dose of β-Lap and enabled significant tumor retention time. Moreover, Azo-Lap NPs markedly reduced the side effects of β-Lap by avoiding hemolysis and the production of methemoglobin. The safety of Azo-Lap NPs administration is validated in the antitumor experiment of mice. In the 4T1 model, Azo-Lap NPs exhibited a markedly higher tumor suppression rate than β-Lap. This work provides an effective and safe polymeric prodrug for tumor selective delivery of β-Lap.