Development of Photoremovable Linkers as a Novel Strategy to Improve the Pharmacokinetics of Drug Conjugates and Their Potential Application in Antibody–Drug Conjugates for Cancer Therapy

Audrey Nathania Johan, Yi Li*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

Although there have been extensive research and progress on the discovery of anticancer drug over the years, the application of these drugs as stand-alone therapy has been limited by their off-target toxicities, poor pharmacokinetic properties, and low therapeutic index. Targeted drug delivery, especially drug conjugate, has been recognized as a technology that can bring forth a new generation of therapeutics with improved efficacy and reduced side effects for cancer treatment. The linker in a drug conjugate is of essential importance because it impacts the circulation time of the conjugate and the release of the drug for full activity at the target site. Recently, the light-triggered linker has attracted a lot of attention due to its spatiotemporal controllability and attractive prospects of improving the overall pharmacokinetics of the conjugate. In this paper, the latest developments of UV-and IR-triggered linkers and their application and potential in drug conjugate development are reviewed. Some of the most-well-researched photoresponsive structural moieties, such as UVtriggered coumarin, ortho-nitrobenzyl group (ONB), thioacetal ortho-nitrobenzaldehyde (TNB), photocaged C40-oxidized abasic site (PC4AP), and IR-triggered cyanine and BODIPY, are included for discussion. These photoremovable linkers show better physical and chemical stabilities and can undergo rapid cleavage upon irradiation. Very importantly, the drug conjugates containing these linkers exhibit reduced off-target toxicity and overall better pharmacokinetic properties. The progress on photoactive antibody–drug conjugates, such as antibody–drug conjugates (ADC) and antibody– photoabsorber conjugate (APC), as precision medicine in clinical cancer treatment is highlighted.

Original languageEnglish
Article number655
JournalPharmaceuticals
Volume15
Issue number6
DOIs
Publication statusPublished - Jun 2022

Keywords

  • antibody–drug conjugates
  • drug conjugates
  • photoremovable linker

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