Tyrosinase-activated prodrug nanomedicine as oxidative stress amplifier for melanoma-specific treatment.

Malignant melanoma is one of the most aggressive skin cancers, posing severe threat to human health. Tyrosinase, overexpressed in melanoma cells, is a specific in-situ weapon to augment the therapeutic efficacy of melanoma-specific treatment by in-situ accelerating the activation of anti-melanoma prodrugs. Herein, we developed a tyrosinase-triggered oxidative stress amplifier, denoted as APAP@PEG/HMnO, to achieve synergistic chemotherapy and amplified oxidative stress for melanoma-specific treatment. The APAP@PEG/HMnO nanosystem was constructed by encapsulating non-toxic prodrug acetaminophen (APAP) into hollow PEG/HMnO nanostructures. After tumor accumulation of APAP@PEG/HMnO amplifier, substantial amounts of oxygen (O) was generated through reaction between HMnO and excessive HO present in tumor environment. Meanwhile, APAP was released at acidic tumor environment and subsequently activated by overexpressed tyrosinase in the presence of O to produce cytotoxic benzoquinone metabolites (AOBQ). On the basis of the combinational effect of AOBQ-triggered reactive oxygen species (ROS) generation and synergistic glutathione (GSH) depletion as promoted by HMnO and AOBQ, the APAP@PEG/HMnO administration augmented the therapeutic efficacy of chemotherapy by amplifying the intratumoral oxidative stress, thus inducing remarkable cell apoptosis in vitro and tumor suppression in vivo. Therefore, the constructed prodrug nanomedicine represents a prospective tumor-specific therapeutic nanoagent for melanoma treatment.