Synthesis, Biophysical Properties, and Antitumor Activity of Antisense Oligonucleotides Conjugated with Anisamide
Zhe Zhang,
Zuyi Chen,
Cheng Li,
Zhenyu Xiao,
Yuan Luo,
Xiaochen Pan,
Liang Xu,
Xuesong Feng
Affiliations
Zhe Zhang
School of Pharmacy, China Medical University, Shenyang 110122, China
Zuyi Chen
School of Pharmacy, China Medical University, Shenyang 110122, China
Cheng Li
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China
Zhenyu Xiao
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China
Yuan Luo
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China
Xiaochen Pan
Beijing Easyresearch Technology Limited, Beijing 100850, China
Liang Xu
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China
Xuesong Feng
School of Pharmacy, China Medical University, Shenyang 110122, China
Antisense oligonucleotides (ASONs) have proven potential for the treatment of various diseases. However, their limited bioavailability restricts their clinical application. New structures with improved enzyme resistance stability and efficient drug delivery are needed. In this work, we propose a novel category of ASONs bearing anisamide conjugation at phosphorothioate sites for oncotherapy. ASONs can be conjugated with the ligand anisamide very efficiently and flexibly in a solution. The conjugation sites and the ligand amount both influence anti-enzymatic stability and cellular uptake, resulting in changes in antitumor activity that are detectable by cytotoxicity assay. The conjugate with double anisamide (T6) was identified as the optimal conjugate, and its antitumor activity and the underlying mechanism were examined further in vitro and in vivo. This paper presents a new strategy for the design of nucleic acid-based therapeutics with improved drug delivery and biophysical and biological efficacy.
