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Issue 39, 2019
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A light-responsive, self-immolative linker for controlled drug delivery via peptide- and protein-drug conjugates

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Abstract

When designing prodrugs, choosing an appropriate linker is the key to achieving efficient, controlled drug delivery. Herein, we report the use of a photocaged C4′-oxidized abasic site (PC4AP) as a light-responsive, self-immolative linker. Any amine- or hydroxyl-bearing drug can be loaded onto the linker via a carbamate or carbonate bond, and the linker is then conjugated to a carrier peptide or protein via an alkyl chain. The PC4AP linker is stable under physiologically relevant conditions. However, photodecaging of the linker generates an active intermediate that reacts intramolecularly with a primary amine (the ε-amine of a lysine residue and the N-terminal amine) on the carrier, leading to rapid and efficient release of the drug via an addition–elimination cascade, without generating any toxic side products. We demonstrated that the use of this self-immolative linker to conjugate the anticancer drug doxorubicin to a cell-penetrating peptide or an antibody enabled targeted, controlled delivery of the drug to cells. Our results suggest that the linker can be used with a broad range of carriers, such as cell-penetrating peptides, proteins, antibodies, and amine-functionalized polymers, and thus will find a wide range of practical applications.

Graphical abstract: A light-responsive, self-immolative linker for controlled drug delivery via peptide- and protein-drug conjugates

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Supplementary files

Article information


Submitted
19 Jun 2019
Accepted
08 Aug 2019
First published
19 Aug 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2019,10, 8973-8980
Article type
Edge Article

A light-responsive, self-immolative linker for controlled drug delivery via peptide- and protein-drug conjugates

C. Zang, H. Wang, T. Li, Y. Zhang, J. Li, M. Shang, J. Du, Z. Xi and C. Zhou, Chem. Sci., 2019, 10, 8973
DOI: 10.1039/C9SC03016F

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