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Self-immolative Linkers in Prodrugs and Antibody Drug Conjugates in Cancer Treatment

[ Vol. 16 , Issue. 4 ]


Veera V. Shivaji R. Edupuganti, Joel D. A. Tyndall* and Allan B. Gamble*   Pages 479 - 497 ( 19 )


Background: The design of anti-cancer therapies with high anti-tumour efficacy and reduced toxicity continues to be challenging. Anti-cancer prodrug and antibody-drug-conjugate (ADC) strategies that can specifically and efficiently deliver cytotoxic compounds to cancer cells have been used to overcome some of the challenges. The key to the success of many of these strategies is a self-immolative linker, which after activation can release the drug payload. Various types of triggerable self-immolative linkers are used in prodrugs and ADCs to improve their efficacy and safety.

Objective: Numerous patents have reported the significance of self-immolative linkers in prodrugs and ADCs in cancer treatment. Based on the recent patent literature, we summarise methods for designing the site-specific activation of non-toxic prodrugs and ADCs in order to improve selectivity for killing cancer cells.

Methods: In this review, an integrated view of the potential use of prodrugs and ADCs in cancer treatment are provided. This review presents recent patents and related publications over the past ten years uptill 2020.

Results: The recent patent literature has been summarised for a wide variety of self-immolative PABC linkers, which are cleaved by factors including responding to the difference between the extracellular and intracellular environments (pH, ROS, glutathione) through over-expressed enzymes (cathepsin, plasmin, β-glucuronidase) or bioorthogonal activation. The mechanism for self-immolation involves the linker undergoing a 1,4- or 1,6-elimination (via electron cascade) or intramolecular cyclisation to release cytotoxic drug at the targeted site.

Conclusion: This review provides the commonly used strategies from recent patent literature in the development of prodrugs based on targeted cancer therapy and antibody-drug conjugates, which show promise in therapeutic applications.


Self-immolative linkers, cancer, prodrugs, antibody-drug-conjugate, 1, 4- elimination, 1, 6-elimination, Intramolecular cyclisation.


School of Pharmacy, University of Otago, Dunedin 9054, School of Pharmacy, University of Otago, Dunedin 9054, School of Pharmacy, University of Otago, Dunedin 9054

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