title: Augmenting the Efficacy of Immunotoxins and Other Targeted Protein Toxins by Endosomal Escape Enhancers.
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.
authors.affiliation: Institut f&#252;r Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charit&#233; - Universit&#228;tsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany. hendrik.fuchs@charite.de.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: Institut f&#252;r Pharmazie, Freie Universit&#228;t Berlin, 14195 Berlin, Germany. weng@zedat.fu-berlin.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Weng
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada. rgilabertoriol@bccrc.ca.
authors.forename: Roger
authors.initials: R
authors.lastname: Gilabert-Oriol
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding; D016503:Drug Delivery Systems; D004355:Drug Stability; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D000922:Immunotoxins
keywords: cancer treatment; controlled drug release; cytosolic drug delivery; efficacy enhancers; endocytosis; endosomal escape; immunotoxins; targeted toxins