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

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.

STAT3 pathway in cancers: Past, present, and future

“…designed a calcium phosphate‐cored low‐density lipoprotein nanovehicle as a Trojan horse to load STAT3 decoy ODNs to overcome tumor necrosis factor‐related apoptosis‐inducing ligand resistance. 330 Wu et al. introduced PEGylated liposomal FLLL32, a specific STAT3 inhibitor that binds to the SH2 domain.…”

Crosstalk of low density lipoprotein and liposome as a paradigm for targeting of 5-fluorouracil into hepatic cells: cytotoxicity and liver deposition

“…LDL-loaded drug conjugates could traffic into the cell through LDL-r mediated endocytosis similar to native LDL. Particularly, LDL-r is abundant in hepatic cells as well as they are upregulated on tumor cell membranes [ 4 , 6 , 26 , 27 ]. Additionally, nanostructure features, biodegradability, and biocompatibility of LDL particulates inhibit their clearance by the mononuclear phagocyte system [ 26 , 27 ].…”

“…Particularly, LDL-r is abundant in hepatic cells as well as they are upregulated on tumor cell membranes [ 4 , 6 , 26 , 27 ]. Additionally, nanostructure features, biodegradability, and biocompatibility of LDL particulates inhibit their clearance by the mononuclear phagocyte system [ 26 , 27 ]. In this study, 5-FUC was encapsulated into liposomes and LDL as a promising approach to target 5- FU into liver tissues in a selective manner.…”

Effect of STAT3 decoy oligodeoxynucleotides mediated by ultrasound-targeted microbubbles combined with ultrasound on the growth of squamous cell carcinoma of the esophagus

“…Multiple studies have indicated that the sustained activation of STAT3 has a close relationship with the occurrence and development of various tumors such as gastric, esophageal, breast, and liver cancer (8). Blocking the continuous activation of STAT3 has been considered to be an effective treatment, and STAT3 decoy ODN is a continuously mature blocking method that can weaken downstream biochemical reactions by downregulating the hyperphosphorylation of intracellular STAT3 protein to inhibit the proliferation activity of tumor cells (9,10). Therefore, the competitive blocking method of inhibiting tumor proliferation through the transfection of STAT3 decoy ODN has been highly valued.…”