Targeting breast cancer stem cells by a self-assembled, aptamer-conjugated DNA nanotrain with preloading doxorubicin

Abstract

Background

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

Acknowledgments

The National Natural Science Fund (21722504, 21675089), the SEU-NJMU-CPU cooperation project (2242019K3DNZ2), the SEU-NJMU cooperation project (2242017K3DN12), the Primary Research & Development Plan of Jiangsu Province (BE2018725) and the Open Foundation of State Key Laboratory of Reproductive Medicine [SKLRM-GA201804] awarded to Dr Chen are gratefully acknowledged.

Copyright/ethics

The use of the gifted cells was approved by the Institutional Review Board of Nanjing Medical University, Nanjing, People's Republic of China. This study was approved by our institutional ethics committee.

Disclosure

The authors report no conflicts of interest in this work.