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Liu, Xiaowen; Zhang, Peng; Rodl, Wolfgang; Maier, Kevin; Lächelt, Ulrich; Wagner, Ernst (2017): Toward Artificial Immunotoxins: Traceless Reversible Conjugation of RNase A with Receptor Targeting and Endosomal Escape Domains. In: Molecular Pharmaceutics, Vol. 14, No. 5: pp. 1439-1449
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Abstract

The specific transport of bioactive proteins into designated target cells is an interesting: and challenging perspective fot the generation, innovative biopharmaceuticals. Natural protein cytotoxins perform this task with outstanding efficacy. They,enter cells with receptor-targeted RNA degradation specificity,.: respond to changing intracellular microenvironments, and by various mechanisms translocate their,cytotoxic protein subunit into the cytosol. Here we imitate this toxin based delivery strategy in an artificial Setting, by bioreversible conjugation of a cytotoxic cargo protein (RNase with receptor-targeting PEG-folate and the pH-specific endosomolytic peptide INF7 as synthetic delivery domains. Covalent modification of the cargo, protein was achieved using the pH-labile AzMMMan linker and copper-free click chemistry with DBCO-modified delivery modules. This linkage is supposed to enable traceless intracellular release of the RNase A after exposure to the endo somal Weakly acidic environment. Delivery of RNase A via this polycation-free delivery strategy resulted in high-cytotoxicity against receptor-positive KB tumor cells only when both PEG: folate and INF7 were attached.