Improved Antitumor Activity and Tumor Targeting of NH2-Terminal–Specific PEGylated Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand

Abstract

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is considered an attractive anticancer agent due to its tumor cell–specific cytotoxicity. However, its low stability, solubility, unexpected side effects, and weak pharmacokinetic profiles restrict its successful clinical application. To develop efficient TRAIL-based anticancer biotherapeutics, a new version of trimeric TRAIL was constructed by incorporating trimer-forming zipper sequences (HZ-TRAIL), and then NH2-terminal–specific PEGylation was done to produce PEGylated TRAIL (PEG-HZ-TRAIL). The biological, physicochemical, and pharmaceutical characteristics of PEG-HZ-TRAIL were then investigated using various in vitro and in vivo experiments, including a cell-based cytotoxicity test, a solubility test, pharmacokinetic analysis, and antitumor efficacy evaluations. Although slight activity loss occurred after PEGylation, PEG-HZ-TRAIL showed excellent tumor cell–specific cytotoxic effects via apoptotic pathways with negligible normal cell toxicity. The stability and pharmacokinetic problems of HZ-TRAIL were successfully overcome by PEGylation. Furthermore, in vivo antitumor tests revealed that PEG-HZ-TRAIL treatment enhanced therapeutic potentials compared with HZ-TRAIL in tumor xenograft animal models, and these enhancements were attributed to its better pharmacokinetic properties and tumor-targeting performance. These findings show that PEG-HZ-TRAIL administration provides an effective antitumor treatment, which exhibits superior tumor targeting and better inhibits tumor growth, and suggest that PEG-HZ-TRAIL should be considered a potential candidate for antitumor biotherapy.

TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer

“…It should also be noted that TRAIL liposomes tethered to the surface of circulating leukocytes exhibited a circulation half-life (Fig. 1) significantly longer than any previously described nanoparticle formulations of TRAIL [31-33]. Nanomedicine-based therapeutic approaches such as the one demonstrated here may hold the key to exploiting the potency of TRAIL within the circulation.…”

A novel capsid-modified oncolytic recombinant adenovirus type 5 for tumor-targeting gene therapy by intravenous route

“…In the current study, we adopted the Gene-Viro-Therapy (CTGVT) approach of cancer targeting, as it has demonstrated much higher anti-tumor effects [42, 43]. Many reports have shown that TRAIL could induce the selective death in a wide range of human cancer cells [44–46]. Therefore, researchers have used TRAIL as a foreign gene for cancer treatment in CTGVT research [47–49].…”

Delivery of tumor-homing TRAIL sensitizer with long-acting TRAIL as a therapy for TRAIL-resistant tumors

“…A stable isoleucine zipper (iLZ)-TRAIL is known to be more potent in vitro and in vivo compared to that of rhTRAIL because of the improved trimeric protein stability induced by the iLZ motif [39]. Additionally, TRAIL PEG offers improved stability and solubility over rhTRAIL and iLZ fusion TRAIL as well as reduced aggregation at high concentrations, which enables easy handling of the protein in solution [21]. Trimeric TRAIL PEG also has advantages over TRAIL agonistic antibodies in terms of safety and activity induced by clustering of DRs to induce DISC formation efficiently.…”

“…PEGylation is considered the gold standard for half-life extension and a highly efficient commercial strategy as proven by PEGylated interferons and other FDA-approved biologics [20]. TRAIL PEG has increased stability over rhTRAIL with a significantly longer circulation half-life in rats [21, 22]. As a result, TRAIL PEG demonstrated superior in vivo anticancer potencies in xenografts bearing TRAIL-sensitive HCT116 colon cancer tumors over iLZ-TRAIL.…”