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

Abstract

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/HMnO₂, to achieve synergistic chemotherapy and amplified oxidative stress for melanoma-specific treatment. The APAP@PEG/HMnO₂ nanosystem was constructed by encapsulating non-toxic prodrug acetaminophen (APAP) into hollow PEG/HMnO₂ nanostructures. After tumor accumulation of APAP@PEG/HMnO₂ amplifier, substantial amounts of oxygen (O₂) was generated through reaction between HMnO₂ and excessive H₂O₂ present in tumor environment. Meanwhile, APAP was released at acidic tumor environment and subsequently activated by overexpressed tyrosinase in the presence of O₂ 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 HMnO₂ and AOBQ, the APAP@PEG/HMnO₂ 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.

Keywords: Acetaminophen; Melanoma treatment; Nano-prodrug; Oxidative stress; Tyrosinase activation.