Targeted Cytolysins Synergistically Potentiate Cytoplasmic Delivery of Gelonin Immunotoxin
Author(s)Wittrup, K. D.; Pirie, Christopher M.; Liu, David V.; Wittrup, Karl Dane
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Targeted endocytic uptake is a first step toward tissue-specific cytoplasmic macromolecular delivery; however, inefficient escape from the endolysosomal compartment makes this generally impractical at present. We report here a targeted cytolysin approach that dramatically potentiates endosomal release of an independently targeted potent gelonin immunotoxin. Fibronectin domains engineered for affinity to EGF receptor or carcinoembryonic antigen were fused to the plant toxin gelonin or bacterial pore-forming cytolysins. These fusion proteins display synergistic activity in both antigen-specific cytotoxicity in vitro, enhancing potency by several orders of magnitude, and in tumor growth inhibition in vivo. In addition, the number of internalized gelonin molecules required to induce apoptosis is reduced from approximately 5 × 106 to less than 103. Targeted potentiation shows promise for enhancing cytoplasmic delivery of other macromolecular payloads such as DNA, siRNA, and miRNA.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Chemical Engineering
Molecular Cancer Therapeutics
American Association for Cancer Research
Pirie, C. M., D. V. Liu, and K. D. Wittrup. “Targeted Cytolysins Synergistically Potentiate Cytoplasmic Delivery of Gelonin Immunotoxin.” Molecular Cancer Therapeutics 12, no. 9 (July 5, 2013): 1774–1782.
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