Affiliation:
1. School of Pharmacy, University of Otago, Dunedin 9054,New Zealand
Abstract
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.
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmacology (medical),Cancer Research,Drug Discovery,Oncology,General Medicine
Cited by
10 articles.
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