1. Immunoproteasome Inhibitor-Doxorubicin Conjugates Target Multiple Myeloma Cells and Release Doxorubicin upon Low-Dose Photon Irradiation.
- Author
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Maurits E, van de Graaff MJ, Maiorana S, Wander DPA, Dekker PM, van der Zanden SY, Florea BI, Neefjes JJC, Overkleeft HS, and van Kasteren SI
- Subjects
- Antibiotics, Antineoplastic pharmacology, Doxorubicin pharmacology, Humans, Models, Molecular, Proteasome Inhibitors pharmacology, Antibiotics, Antineoplastic therapeutic use, Doxorubicin therapeutic use, Multiple Myeloma drug therapy, Multiple Myeloma radiotherapy, Optics and Photonics methods, Proteasome Inhibitors therapeutic use
- Abstract
Proteasome inhibitors are established therapeutic agents for the treatment of hematological cancers, as are anthracyclines such as doxorubicin. We here present a new drug targeting approach that combines both drug classes into a single molecule. Doxorubicin was conjugated to an immunoproteasome-selective inhibitor via light-cleavable linkers, yielding peptide epoxyketone-doxorubicin prodrugs that remained selective and active toward immunoproteasomes. Upon cellular uptake and immunoproteasome inhibition, doxorubicin is released from the immunoproteasome inhibitor through photoirradiation. Multiple myeloma cells in this way take a double hit: immunoproteasome inhibition and doxorubicin-induced toxicity. Our strategy, which entails targeting of a cytotoxic agent, through a covalent enzyme inhibitor that is detrimental to tumor tissue in its own right, may find use in the search for improved anticancer drugs.
- Published
- 2020
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