Review Perspectives About Self-Immolative Drug Delivery Systems Rodrigo Vieira Gonzaga, Lucas Adriano do Nascimento, Soraya Silva Santos, Bruna Araujo Machado Sanches, Jeanine Giarolla, Elizabeth Igne Ferreira * Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 580 e Bl 13 e ZC 05580-000, S~ ao Paulo, Brazil article info Article history: Received 1 April 2020 Revised 27 July 2020 Accepted 17 August 2020 Available online 27 August 2020 Keywords: Drug delivery systems Prodrug design Trigger classes Self-immolative linkers abstract Self-immolative drug delivery system is one of the delivery systems, which have drawn attention, in recent research, highlighting the improvement they generate in drug selectivity and efficacy. Self- immolative linkers, or spacers, are covalent groups, which have the role of cleavaging two bonds be- tween a protector group and a drug, in the case of drug delivery systems, after a stimuli.The cascade of reactions allows to control the release of the drug. The choice of the adequate self-immolative linker is essential and depend on many variables and goals as well. Many approaches can be explored when designing a system adequate for achieving these goals, especially prodrugs. Some of the most used stimuli-responses for self-immolative drugs e enzyme triggers, chemical triggers, as pH, redox system, 1,4-, 1,6-, 1,8-eliminations, photodegradable triggers, multiple triggers, among others e are described in this ten-year review, along with their application as theranostic agents. We intend that the examples presented in this review inspire researchers working on drug delivery systems to further explore their application. © 2020 American Pharmacists Association ® . Published by Elsevier Inc. All rights reserved. Introduction Self-immolative systems (SIS), including polymer systems, have been employed in diverse fields, such as drug delivery, supramo- lecular chemistry, signal amplification, chemical materials, and diagnostic probe design. When activated by a specific stimulus, these molecules undergo spontaneous intramolecular disassem- bling, in which they are broken down to their building blocks, and the compound of interest attached to them is released. Self- immolative linker displays an important role in the cascade mechanism of release of the compound linked. 1 It is defined as a covalent groups, which have the role of cleavaging two bonds be- tween a protector group and a drug, in the case of drug delivery systems, after a stimuli.Then, this allows to control the release of the drug and the adequate choice of its nature is very important for the success of the system. SIS draw attention as potential drug delivery systems (SIDD) as they can be tailored to provide programmable drug release by exploiting particular features found in diseased tissues, such as a different pH, reductive conditions, or even enzyme expression. 2e5 These SIS are considered stimuli-responsive polymeric bioma- terial, also known as smart polymers, 6,7 which are defined as compounds that respond to many changes in the environment such as pH, temperature, light, electrical or magnetic changes and me- chanical forces. Both internal and external stimuli can be used to trigger the self-immolation. 8,9 Fig. 1 shows a general structure of SIDD and itys mechanism of drug release. Increasing research of SIS in the last few decades highlights their potential in the drug delivery field, especially in noncommunicable chronic diseases. Their features, such as changed chemical envi- ronment and modified metabolism, pose an interesting means for drug delivery as they can potentially be exploited to achieve higher drug activity and lower systemic toxicity by preferential accumu- lation at the drug's active site. 2e5 As stated, SIS are compounds which undergo cascade reactions for disintegrating via end-to-end decomposition or cyclization mechanisms by a stimulus that is able to trigger the sequential release of their small constituent molecules. These cascade re- actions are based on carbamate fragments, elimination reaction, cyclization of an amine-terminated spacer to a five membered urea ring, or cyclization of a trimethyl lock linker to the lactone portion. 10 In the presence of a specific stimulus, the trigger is broken, creating an unstable intermediate that self-immolates to release the output derivative. 2e5 Upon stimulation, these systems suffer head-to-tail disassembly, triggered by a single cleavage at a focal point, which initiates a sequential fragmentation into the substance's building blocks, releasing multiple end-groups from * Corresponding author. E-mail address: hajudan@usp.br (E.I. Ferreira). Contents lists available at ScienceDirect Journal of Pharmaceutical Sciences journal homepage: www.jpharmsci.org https://doi.org/10.1016/j.xphs.2020.08.014 0022-3549/© 2020 American Pharmacists Association ® . Published by Elsevier Inc. All rights reserved. Journal of Pharmaceutical Sciences 109 (2020) 3262-3281