Cancer Drug Delivery Systems Using Bacterial Toxin Translocation Mechanisms

Abstract

Recent advances in targeted cancer therapy hold great promise for both research and clinical applications and push the boundaries in finding new treatments for various currently incurable cancers. However, these therapies require specific cell-targeting mechanisms for the efficient delivery of drug cargo across the cell membrane to reach intracellular targets and avoid diffusion to unwanted tissues. Traditional drug delivery systems suffer from a limited ability to travel across the barriers posed by cell membranes and, therefore, there is a need for high doses, which are associated with adverse reactions and safety concerns. Bacterial toxins have evolved naturally to specifically target cell subtypes via their receptor binding module, penetrating the cell membrane efficiently through the membrane translocation process and then successfully delivering the toxic cargo into the host cytosol. They have, thus, been harnessed for the delivery of various drugs. In this review, we focus on bacterial toxin translocation mechanisms and recent progress in the targeted delivery systems of cancer therapy drugs that have been inspired by the receptor binding and membrane translocation processes of the anthrax toxin protective antigen, diphtheria toxin, and Pseudomonas exotoxin A. We also discuss the challenges and limitations of these studies that should be addressed before bacterial toxin-based drug delivery systems can become a viable new generation of drug delivery approaches in clinical translation.

Keywords: bacterial toxin; cancer therapy; drug delivery; immunotoxins; translocation mechanism.

Figure 1

Anthrax toxin translocation mechanism. The anthrax toxin protective antigen (PA) first binds to the host cell membrane protein receptor anthrax toxin receptor ANTXR1/2 and then is cleaved by the host cell surface furin family protease to oligomerize. Then, the lethal factor (LF) and edema factor (EF) are recruited by PA oligomers, and the toxin complex is internalized by the host receptor-mediated endocytosis pathway. Acidic conditions within the endosome trigger the structural rearrangement and channel formation of PA for LF/EF translocation into the cytosol. Refolded LF cleaves cytosol target protein MAPKKs from the N-terminal, and refolded EF catalyzes the cAMP formation, thus inducing cell necrosis and edema, respectively. This image was adapted from “Mechanism of Action-Diphtheria Toxin” by BioRender.com (2023), accessed on 9 May 2023. Retrieved from https://app.biorender.com/biorender-templates, accessed on 9 May 2023.

Figure 2

Cryo-EM structure models of Anthrax PA prechannel-LF and PA channel–LF complexes. (a) Ribbon representation of Anthrax PA₈ prechannel–LF₄ complex viewed from the side and colored by subunits. (b) Ribbon representation of Anthrax PA₇ channel–LF complex viewed from the side (left) and top (right) and colored by subunits. All the protein structural models were generated using the program PyMOL (https://pymol.org/2/ (accessed on 13 March 2023).).

Figure 3

Diphtheria toxin translocation mechanisms. Diphtheria toxin (DT) binds to the cell surface receptor HB-EGF receptor and then becomes internalized via clathrin-mediated endocytosis. Within the endosome, the proteases partially cleave the bond between the DT domains. Endosome acidification triggers the translocation of the A subunit of DT into the cytosol. A subunit of DT catalyzes the ribosylation of the eukaryotic EF-2 (eEF-2) protein, which inhibits the host cell protein synthesis and thus induces cell death. This image was adapted from “Mechanism of Action-Diphtheria Toxin” by BioRender.com (2023), accessed on 1 May 2023. Retrieved from https://app.biorender.com/biorender-templates, accessed on 1 May 2023.