Platinum(IV) Prodrug-grafted Phosphorothioate DNA and Its Self-assembled Nanostructure for Targeted Drug Delivery

cis-Platin drugs play a vital role in the clinical treatment of various cancers. However, its poor water solubility, non-targeting capability and severe side effects result in limited antitumor efficacy and greatly impede its clinic practices. To address these challenges, we successfully graft a multitude of Pt (IV) prodrugs on a diblock DNA that consists of a regular phosphodiester DNA segment with MUC-1 aptamer sequence and a phosphorothioate (PS) ploy T segment. After being modified with iodoacetate moiety, the prodrug can efficiently react with PS groups and grafted onto the backbone of PS segment, resulting in the formation of an MUC-1/(PO)DNA-b-((PS)DNA-g-Pt) conjugate. Owing to its amphiphilic feature, the obtained DNA-drug conjugate (DDC) could further self-assembled into spherical nucleic acid like nanostructure(MUC-1/Pt-SNAs) to serve as a new drug delivery system. With the presence of MUC-1 aptamer on particle surface, MUC-1/Pt-SNAs can actively target the tumor cells overexpressed MUC-1 proteins and internalize into cells with high efficiency. Together with a high drug loading ratio (39.6%) achieved by simple and convenient conjugation method, the obtained DNA-based targeted delivery system shows substantial antitumor effect and low side effects both in vitro and in vivo.