Terminal Deoxynucleotidyl Transferase-Catalyzed Preparation of pH-Responsive DNA Nanocarriers for Tumor-Targeted Drug Delivery and Therapy

• DOI: 10.1021/acsami.9b05358
• Publication Date: 2019-04-03T15:51:50Z
• Authors: Guo-Ying Sun; Yi-Chen Du; Yun-Xi Cui; Jing Wang; Xiao-Yu Li; An-Na Tang; De-Ming Kong
• Keywords: Mice, Inbred BALB C; Metal Nanoparticles; Mice, Nude; Neoplasms, Experimental; 02 engineering and technology; Aptamers, Nucleotide; Hydrogen-Ion Concentration; Xenograft Model Antitumor Assays; 3. Good health; DNA Adducts; Mice; Oligodeoxyribonucleotides; DNA Nucleotidylexotransferase; Doxorubicin; Delayed-Action Preparations; NIH 3T3 Cells; Animals; Humans; Female; Gold; 0210 nano-technology; HeLa Cells

Developing a highly efficient carrier for tumor-targeted delivery and site-specific release of anticancer drugs is a good way to overcome the side effects of traditional cancer chemotherapy. Benefiting from the nontoxic and biocompatible characteristics, DNA-based drug carriers have attracted increasing attention. Herein, we reported a novel and readily manipulated strategy to construct spherical DNA nanocarriers. In this strategy, terminal deoxynucleotidyl transferase (TdT)-catalyzed DNA extension reaction is used to prepare a thick DNA layer on a gold nanoparticle (AuNP) surface by extending long poly(C) sequences from DNA primers immobilized on AuNPs. The poly(C) extension products can then hybridize with G-rich oligonucleotides to give CG-rich DNA duplexes (for loading anticancer drug doxorubicin, Dox) and multiple AS1411 aptamers. Via synergic recognition of multiple aptamer units to nucleolin proteins, biomarker of malignant tumors, Dox-loaded DNA carrier can be efficiently internalized in cancer cells and achieve burst release of drugs in acidic organelles because of i-motif formation-induced DNA duplex destruction. An as-prepared pH-responsive drug carrier was demonstrated to be promising for highly efficient delivery of Dox and selective killing of cancer cells in both in vitro and in vivo experiments, thus showing a huge potential in anticancer therapy.