Customizing a tri-domain TRAIL variant to achieve active tumor homing and endogenous albumin-controlled release of the molecular machine in vivo.

Customizing a tri-domain TRAIL variant to achieve active tumor homing and endogenous albumin-controlled release of the molecular machine in vivo. Biomacromolecules. 2020 Aug 17;: Authors: Tao Z, Liu Y, Yang H, Feng Y, Li H, Shi Q, Li S, Cheng J, Lu X Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive antitumor drug candidate for precision cancer therapy due to its superior selective cytotoxicity in a variety of tumor cells. However, the clinical application of TRAIL in cancer therapy has been limited by its poor tumor-homing capacities and short half-life. Herein, we designed a tri-domain TRAIL variant, Z-ABD-TRAIL, by sequentially fusing the platelet-derived growth factor receptor beta (PDGFRβ)-specific affibody ZPDGFRβ and an albumin-binding domain (ABD) to the N-terminus of TRAIL. The fusion protein Z-ABD-TRAIL was produced as a soluble protein with high yield in Escherichia coli (E. coli). The ZPDGFRβ domain provided Z-ABD-TRAIL with PDGFRβ-binding properties and thus promoted its tumor homing via the engagement of PDGFRβ-expressing pericytes on tumor microvessels. ABD-mediated binding of Z-ABD-TRAIL to albumin in the blood endowed TRAIL with long-lasting (>72 h for Z-ABD-TRAIL versus <0.5 h for TRAIL) abilities to kill tumor cells. Although the in vitro cytotoxicity of Z-ABD-TRAIL in tumor cells was similar to that of the parent TRAIL, the in vivo tumor uptake, apoptosis-inducing...
Source: Biomacromolecules - Category: Biochemistry Authors: Tags: Biomacromolecules Source Type: research