Organic disulfide crosslinked nucleic acid-based nanocarriers for anticancer drug applications

To improve the delivery efficiency of chemotherapeutic agents, selective drug carriers have been developed to encapsulate chemotherapeutic drugs. Green biomaterials, highly biocompatible with and non-toxic to organisms, have been attracting attention in the biomedical field. Kiwifruit-derived nucleic acids were treated with HCl to expose the aldehyde groups in their deoxyriboses. The product, DNA-HCl, was then crosslinked with two disulfides, cystamine (CTM) or cystine (CYS) under an emulsification process. As the aldehyde groups react with the primary amine in the disulfides, stable imine bonds form. When DNA-HCl-CTM and DNA-HCl-CYS enter cancerous microenvironments, the disulfide bonds will be catalyzed by overexpressed GSH and release the chemotherapeutic agent, DOX. We also found that when both solutions contain GSH, the above NGs release more DOX in the one with weak acidity than the one with a neutral pH. Therefore, when compared to cancer cells treated with free DOX and DOX/DNA-HCl NGs, those dosed with DOX/DNA-HCl-CTM and DOX/DNA-HCl-CYS NGs showed a higher uptake. The enhanced uptake of DOX induced apoptosis in cancer cells and cancer organoids, evidenced by DAPI-stained condensed DNA as well as caspase-3 and PARP expression. The results of this study verify a new approach to encapsulating chemotherapeutic drugs with modified nucleic acid while selectively triggering the cytotoxic effects in cancer cells.