Microenvironment-responsive DNA-conjugated albumin nanocarriers for targeted therapy

Abstract

Drug delivery with accurate targeting and efficient treatment has become an essential strategy for cancer therapy. Two nanocarriers based on bovine serum albumin (BSA) and DNA were synthesized via click chemistry and DNA hybridization reactions (DNA–BSA1 and DNA–BSA2). One of the hybridized oligonucleotides, Linker1, in DNA–BSA1 included a pH-sensitive i-motif sequence and a cancer cell-targeted guanine-quadruplex-structured AS1411 aptamer sequence, and the other, Linker2, in DNA–BSA2 had only the same pH-sensitive i-motif sequence. Doxorubicin (DOX) molecules could be quickly and preferentially intercalated into double-stranded DNA via non-covalent interactions, and the encapsulation efficiency of DNA–BSA1 and DNA–BSA2 was almost 100% and 87.5%, respectively. As a mimic of the cancer cell microenvironment, a pH-trigger and a deoxyribonuclease I (DNase I)-trigger release mechanism was individually proposed to explain the dynamic release of the DNA–BSA@DOX under acidic conditions and the presence of DNase I in vitro. Intracellular uptake and cytotoxicity experiments confirmed that the nanocarrier DNA–BSA1@DOX had accurate targeting and efficient treatment towards cancer cells due to the high affinity and specificity of AS1411 to nucleolin, which is overexpressed in cancer cells. Furthermore, in vivo studies showed that the nanocarrier system could efficiently inhibit tumor growth. Therefore, the entire bio-based nanocarrier DNA–BSA is a promising candidate for the loading and release of anti-cancer drugs for accurate delivery and efficient treatment.