In Situ Growth of a Cationic Polymer from the N-Terminus of Glucose Oxidase To Regulate HO Generation for Cancer Starvation and HO Therapy.

Hydrogen peroxide (HO)-generating enzymes (HGEs) are potentially useful for tumor therapy, but the potential is limited by the challenge in regulating HO production. Herein, we present site-specific in situ growth of a cationic polymer poly( N, N'-dimethylamino-2-ethyl methacrylate) (PDMA) from the N-terminus of glucose oxidase (GOX) to generate a site-specific and cationic GOX-PDMA conjugate with well-retained activity and enhanced stability to regulate HO generation for cancer starvation and HO therapy. Notably, the efficiency of endocytosis of the conjugate was 4-fold higher than that of free GOX. As a result, relative to free GOX, the conjugate showed 1.5-fold increased cytotoxicity, 2-fold enhanced tumor retention, and 5-fold increased tolerability after intratumoral injection. Importantly, a single intratumoral injection of the conjugate completely abolished colon tumors without detectable side effects, whereas free GOX was ineffective and systemically toxic. This chemistry may provide a new, simple, general, and efficient solution to regulate HO production and thereby to dramatically improve the antitumor efficacy of HGEs while reducing side effects.