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Theranostics 2017; 7(18):4480-4497. doi:10.7150/thno.21707 This issue Cite

Research Paper

Inorganic Kernel-Reconstituted Lipoprotein Biomimetic Nanovehicles Enable Efficient Targeting “Trojan Horse” Delivery of STAT3-Decoy Oligonucleotide for Overcoming TRAIL Resistance

Kai Shi^1✉, Jianxiu Xue¹, Yan Fang¹, Hongshu Bi², Shan Gao¹, Dongjuan Yang¹, Anqi Lu¹, Yuai Li¹, Yao Chen¹, Liyuan Ke³

1. Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 117004, P. R. China;
2. Liaoning Yaolian Pharmaceutical Co., Ltd., Benxi, Liaoning 117004, P. R. China;
3. Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, P. R. China.

✉ Corresponding author: Dr. Kai Shi, Department of Pharmaceutics, School of Pharmaceutical Science, Shenyang Pharmaceutical University, Shenyang 117004, China. Tel: +86-24-43520557. Email address: shikaiedu.cn.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in a variety of tumor cells, but not most normal cells. Nevertheless, its therapeutic potential is limited due to the frequent occurrence of resistance in tumor cells, especially hepatocellular carcinoma cell lines. Therefore, we investigated the reversal effect of STAT3-decoy oligonucleotides (ODNs) on TRAIL resistance. Methods. Considering that the drawback of poor cellular permeability and rapid degradation in vivo limited ODNs' further clinical applications, we developed a biomimetic calcium phosphate-reconstituted low density lipoprotein nanovehicle (CaP@LDL) that would serve as a “Trojan horse” to carry STAT3-decoy ODNs into tumor cells and then regulate TRAIL-induced apoptosis. Results. In comparison with native ODNs, the reconstituted CaP@LDL packaged ODNs showed significantly increased serum stability, cellular transfection, in vitro synergistic cytotoxicity and apoptosis in hepatoma cells, while there was no cytotoxicity to normal cells. The improved TRAIL sensitization is attributed to blocking of STAT3 signaling and consequent expression of the downstream target antiapoptotic gene. Following systemic administration, CaP@LDL displayed LDL-mimicking pharmacokinetic behavior such as attenuated blood clearance as well as enhanced accumulation in tumor and hepatorenal sites. With the synergistic combination of decoyODN/CaP@LDL, TRAIL dramatically inhibited hepatic tumor growth in a xenograft model and induced significant tumor apoptosis in vivo. Conclusion. These results suggested that CaP@LDL-mediated STAT3-decoy ODN delivery might be a promising new strategy for reversing TRAIL resistance in hepatocellular carcinoma therapy.

Keywords: calcium phosphate, low-density lipoprotein, STAT3, decoy oligonucleotide, TRAIL.

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