Nanomedicine-Leveraged Intratumoral Coordination and Redox Reactions of Dopamine for Tumor-Specific Chemotherapy

Great efforts have been made in investigating the neurotoxicity of dopamine (DA) in the presence of manganous ions. In contrast, here, we probe the possibility of DA-based cancer chemotherapy by leveraging intratumoral redox reactions of DA for producing cytotoxic species in situ. For this purpose, we have constructed a Mn-engineered, DA-loaded nanomedicine. Based on the unique size effect of the nanocarrier, this nanomedicine will not enter the central nervous system but can effectively accumulate in the tumor region, after which the nanocarrier can degrade to release Mn2+ and DA in response to the mild acidic intracelluar microenvironment of cancer cells. DA can chelate Mn2+ to form a binary coordination complex, where the strong metal-ligand interaction significantly promotes electron delocalization and elevates the reducibility of Mn center, favoring two sequential one-electron oxygen reduction reactions forming H2O2, which can be further converted into highly oxidizing OH under the cocatalysis by Mn2+ and intracellular Fe2+. Additionally, as a twoelectron oxidation product of DA ligand, DA-oquinone is potent in exhausting cellular sulfhydryl and depleting reduced glutathione, inhibiting the intrinsic antioxidative mechanism of cancer cells, finally triggering severe oxidative damages in a synergistic manner. It is expected that such a strategy of nanotechnology-mediated metal-ligand coordination and subsequent nontoxicity-to-toxicity transition of DA in tumor may provide a promising prospect for future chemotherapy design.