PEGylation prolongs the blood circulation time of drugs; however, it simultaneously reduces the
tumor penetration of drugs due to the nonfouling function and bulky hydrodynamic volume of PEG, leading to unsatisfactory outcomes in the treatment of solid
tumors. Herein, we report the in situ growth of a bioreducible
polymer of poly(N-
oxide) from an important
protein drug of
interferon alpha (IFN) to generate site-specific IFN-poly(N-
oxide) conjugates with higher bioactivity than a clinically used PEGylated IFN of
PEGASYS. An IFN-poly(N-
oxide) conjugate is screened out to have a circulating half-life as long as 51 h, which is similar to that of
PEGASYS but 96-fold greater than that of IFN. However, the conjugate greatly outperforms
PEGASYS and IFN in
tumor penetration and antitumor efficacy in mice bearing
melanoma. This enhanced
tumor penetration is ascribed to the adsorption-mediated transcytosis of the conjugate whose poly(N-
oxide) is biologically reduced into poly(tertiary
amine), under
hypoxia, which can be further protonated in the acidic tumor microenvironment. These novel findings demonstrate that poly(N-
oxide)s are not only long-circulating but also bioreducible under
hypoxia and are of great promise as next-generation carriers to deliver drugs into the interior of solid
tumors to enhance their antitumor efficacy.