International Journal of Nanomedicine (Aug 2019)
Targeting breast cancer stem cells by a self-assembled, aptamer-conjugated DNA nanotrain with preloading doxorubicin
Abstract
Zhiyuan Xu,1 Ronghua Ni,1 Yun Chen1,21School of Pharmacy, Nanjing Medical University, Nanjing 211166, People’s Republic of China; 2State Key Laboratory of Reproductive Medicine, Nanjing 210029, People’s Republic of ChinaCorrespondence: Yun ChenSchool of Pharmacy, Nanjing Medical University, 818 Tian Yuan East Road, Nanjing 211166, People’s Republic of ChinaTel +86 258 686 8326Fax +86 258 686 8467Email [email protected]: Cancer relapse and metastasis is an obstacle to the treatment of breast cancer. Breast cancer stem cells (BCSCs), which can evade the killing effect of traditional chemotherapies, such as doxorubicin (DOX), may contribute to cancer development. Therefore, it is necessary to develop novel drugs that can target and eliminate BCSCs. While multiple strategies have been conceived, they are normally limited by the low drug loading capacity.Purpose: An aptamer-conjugated DNA nanotrain TA6NT-AKTin-DOX, which consists of a CD44 aptamer TA6, DNA building blocks M1 and M2 conjugated with an AKT inhibitor peptide AKTin individually and DOX, was designed.Methods: This DNA nanotrain was prepared through hybridization chain reactionand this highly ordered DNA duplex has plenty of sites where DOX and AKTin can be intercalated or anchored. By performing on MCF-7 BCSCs and tumors by xenografting BCSCs into nude mice, efficacy of the newly prepared drug was evaluated and compared with that of free DOX and various DNA nanotrains.Results: TA6NT-AKTin-DOX showed better efficacy both in vitro and in vivo. To some extent, the enhanced efficacy could be attributed to the targeting effect of TA6 and the high drug loading capacity of the nanotrain (∼20 DOX molecules). Besides, a synergistic response was demonstrated by combining DOX with AKTin, probably due to that the anchored AKTin can reverse the drug resistance of BCSCs including apoptosis resistance and ABC transporters overexpression via the AKT signaling pathway.Conclusion: The aptamer-conjugated DNA nanotrain TA6NT-AKTin-DOX demonstrated its targeting capability to BCSCs.Keywords: breast cancer stem cells (BCSCs), aptamer-conjugated DNA nanotrain, CD44 aptamer TA6, doxorubicin (DOX), AKT peptide inhibitor, hybridization chain reaction
