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Toxins 2016, 8(7), 200; doi:10.3390/toxins8070200

Augmenting the Efficacy of Immunotoxins and Other Targeted Protein Toxins by Endosomal Escape Enhancers

1
Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany
2
Institut für Pharmazie, Freie Universität Berlin, 14195 Berlin, Germany
3
Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada
*
Author to whom correspondence should be addressed.
Academic Editors: Tomas Girbes and David J. Fitzgerald
Received: 21 April 2016 / Revised: 14 June 2016 / Accepted: 17 June 2016 / Published: 1 July 2016
(This article belongs to the Collection Immunotoxins 2016)
View Full-Text   |   Download PDF [680 KB, uploaded 1 July 2016]   |  

Abstract

The toxic moiety of almost all protein-based targeted toxins must enter the cytosol of the target cell to mediate its fatal effect. Although more than 500 targeted toxins have been investigated in the past decades, no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date. Missing efficacy can be attributed in many cases to insufficient endosomal escape and therefore subsequent lysosomal degradation of the endocytosed toxins. To overcome this drawback, many strategies have been described to weaken the membrane integrity of endosomes. This comprises the use of lysosomotropic amines, carboxylic ionophores, calcium channel antagonists, various cell-penetrating peptides of viral, bacterial, plant, animal, human and synthetic origin, other organic molecules and light-induced techniques. Although the efficacy of the targeted toxins was typically augmented in cell culture hundred or thousand fold, in exceptional cases more than million fold, the combination of several substances harbors new problems including additional side effects, loss of target specificity, difficulties to determine the therapeutic window and cell type-dependent variations. This review critically scrutinizes the chances and challenges of endosomal escape enhancers and their potential role in future developments. View Full-Text
Keywords: endosomal escape; efficacy enhancers; targeted toxins; immunotoxins; cytosolic drug delivery; controlled drug release; cancer treatment; endocytosis endosomal escape; efficacy enhancers; targeted toxins; immunotoxins; cytosolic drug delivery; controlled drug release; cancer treatment; endocytosis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Fuchs, H.; Weng, A.; Gilabert-Oriol, R. Augmenting the Efficacy of Immunotoxins and Other Targeted Protein Toxins by Endosomal Escape Enhancers. Toxins 2016, 8, 200.

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