Nuclease-resistant synthetic drug-DNA adducts: programmable drug-DNA conjugation for targeted anticancer drug delivery

Abstract

Targeted drug delivery is poised to improve cancer therapy, for which synthetic DNA can serve as targeting ligands (for example, aptamers) or drug nanocarriers. Inspired by natural DNA adducts, we report synthetic drug-DNA adducts (DDAs) for targeted anticancer drug delivery. Multiple copies of anthracycline drugs were site specifically (on deoxyguanosine) conjugated on each DNA, enabling programmable design of DNA and drugs for DDA preparation. DDAs were nuclease-resistant and stable for storage, yet gradually released drugs at physiological temperature. DDAs maintained DNA functionalities, including hybridization-mediated DNA nanoadduct formation and aptamer-mediated target recognition and targeted drug delivery into cancer cells. In a tumor xenograft mouse model, doxorubicin-aptamer adducts significantly inhibited target tumor growth while reducing the side effects. Using histopathological analysis and in situ immunohistochemical analysis of caspase-3 cleavage in mouse tumor and heart, DDAs were confirmed to have a potent antitumor efficacy while reducing tissue deformation and apoptosis in the heart, thus providing a new therapeutic avenue to prevent cardiomyopathy, the most dangerous side effect of doxorubicin leading to heart failure. Overall, DDAs are promising for scale-up production and clinical application in targeted anticancer drug delivery. Drug–DNA adducts have been developed for targeted drug delivery to inhibit tumor growth in mice while reducing side effects. Inspired by natural DNA adducts, researchers in China and USA have developed a simple but programmable way of producing synthetic drug-DNA adducts for targeted cancer therapy. They conjugated multiple copies of anthracycline drugs on each DNA base, using a one-step reaction in physiological buffer. The resultant DNA–drug adducts maintained the capability of DNA backbone to form specific aptamer conformations or to form DNA nanostructures by hybridization. Experiments on mice involving a commonly used chemotherapy drug revealed that the use of the adducts reduces toxicity in the heart, lowering the probability of cardiomyopathy, a frequently lethal side effect of chemotherapy. Drug–DNA adducts are promising for scale-up production and clinical applications of targeted drug delivery. We report nature-inspired drug-DNA adducts (DDAs) as a simple yet programmable platform for site-specific drug-DNA conjugation and application in targeted anticancer drug delivery. With multiple copies of drugs conjugated on one DNA, the DDAs were nuclease-resistant and stable for storage, yet gradually released drugs at physiological temperature. Designer DDAs were able to form nanoadducts by hybridization and fold into drug-aptamer adducts (DAAs) for specific recognition of cancer cells and targeted anticancer drug delivery. In a tumor xenograft mouse model, DAAs significantly inhibited tumor growth and reduced side effects, as verified by tissue analysis of tumors and hearts.