Recent advances in self-immolative linkers and their applications in polymeric reporting systems

Gavriel, Alex; Sambrook, Mark R.; Russell, Andrew; Hayes, Wayne

doi:10.1039/d2py00414c

Cited by 52 publications

(58 citation statements)

References 372 publications

(696 reference statements)

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“…A wide range of self‐immolative linkers have been used in stimuli‐responsive drug delivery systems [44,50–52] . Whereas most known self‐immolative linkers are bound to functional groups such as the hydroxy or amine moiety, [53–56] functionalization of a triazole moiety is rare [57,58] and the strategic use of a triazolium group is elusive.…”

Section: Resultsmentioning

confidence: 99%

A Triazolium‐Anchored Self‐Immolative Linker Enables Self‐Assembly‐Driven siRNA Binding and Esterase‐Induced Release

Hollstein

Ali

Coste

et al. 2022

Chemistry A European J

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The increased importance of RNA-based therapeutics comes with a need to develop next-generation stimuliresponsive systems capable of binding, transporting and releasing RNA oligomers. In this work, we describe triazoliumbased amphiphiles capable of siRNA binding and enzymeresponsive release of the nucleic acid payload. In aqueous medium, the amphiphile self-assembles into nanocarriers that can disintegrate upon the addition of esterase. Key to the molecular design is a self-immolative linker that is anchored to the triazolium moiety and acts as a positively-charged polar head group. We demonstrate that addition of esterase leads to a degradation cascade of the linker, leaving the neutral triazole compound unable to form complexes and therefore releasing the negatively-charged siRNA. The reported molecular design and overall approach may have broad utility beyond this proof-of-principle study, because the underlying CuAAC "click" chemistry allows bringing together three groups very efficiently as well as cleaving off one of the three groups under the mild action of an esterase enzyme.

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Section: Resultsmentioning

confidence: 99%

A Triazolium‐Anchored Self‐Immolative Linker Enables Self‐Assembly‐Driven siRNA Binding and Esterase‐Induced Release

Hollstein

Ali

Coste

et al. 2022

Chemistry A European J

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“…In those instances when an intervening linker unit is used to connect CPP and cargo, additional issues may be considered. For example, a particular type of CPP–cargo junction, receiving significant attention over recent decades within the PDC field [ 119 ], is that of so-called self-immolative linkers (SILs), designed to degrade spontaneously in response to specific stimuli [ 120 ]. Unfortunately, to the best of our knowledge, no antiviral PDCs have been reported so far using this technology for selective and targeted drug delivery within the infected cells.…”

Section: Future Perspectivesmentioning

confidence: 99%

Antiviral Peptide-Based Conjugates: State of the Art and Future Perspectives

2023

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Infectious diseases caused by microbial pathogens (bacteria, virus, fungi, parasites) claim millions of deaths per year worldwide and have become a serious challenge to global human health in our century. Viral infections are particularly notable in this regard, not only because humankind is facing some of the deadliest viral pandemics in recent history, but also because the arsenal of drugs to combat the high levels of mutation, and hence the antigenic variability of (mostly RNA) viruses, is disturbingly scarce. Therefore, the search for new antivirals able to successfully fight infection with minimal or no adverse effects on the host is a pressing task. Traditionally, antiviral therapies have relied on relatively small-sized drugs acting as proteases, polymerases, integrase inhibitors, etc. In recent decades, novel approaches involving targeted delivery such as that achieved by peptide–drug conjugates (PDCs) have gained attention as alternative (pro)drugs for tackling viral diseases. Antiviral PDC therapeutics typically involve one or more small drug molecules conjugated to a cell-penetrating peptide (CPP) carrier either directly or through a linker. Such integration of two bioactive elements into a single molecular entity is primarily aimed at achieving improved bioavailability in conditions where conventional drugs are challenged, but may also turn up novel unexpected functionalities and applications. Advances in peptide medicinal chemistry have eased the way to antiviral PDCs, but challenges remain on the way to therapeutic success. In this paper, we review current antiviral CPP–drug conjugates (antiviral PDCs), with emphasis on the types of CPP and antiviral cargo. We integrate the conjugate and the chemical approaches most often applied to combine both entities. Additionally, we comment on various obstacles faced in the design of antiviral PDCs and on the future outlooks for this class of antiviral therapeutics.

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“…27 In the last few years the development of stimuli-responsive DDS has attracted increasing interest and a multitude of studies and reviews have been published dealing with this topic. [28][29][30] Numerous reviews discuss stimuli-responsive DDS under the aspect of a specific medical indication. [31][32][33][34] In contrast, in the present review, from the chemical point of view some emphasis is placed on the synthesis of the respective polymers used for the preparation of DDS and on their stimuli-dependent disintegration behavior.…”

Section: Introductionmentioning

confidence: 99%

“…In the last few years the development of stimuli‐responsive DDS has attracted increasing interest and a multitude of studies and reviews have been published dealing with this topic 28–30 . Numerous reviews discuss stimuli‐responsive DDS under the aspect of a specific medical indication 31–34 .…”

Section: Introductionmentioning

confidence: 99%

Stimuli‐accelerated polymeric drug delivery systems

Rust

Jung

Langer

et al. 2022

Polymer International

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The controlled delivery of active pharmaceutical ingredients to the site of disease represents a major challenge in drug therapy. Particularly when drugs have to be transported across biological barriers, suitable drug delivery systems are of importance. In recent years responsive delivery systems have been developed which enable a controlled drug release depending on internal or external stimuli such as changes in pH, redox environment or light and temperature. In some studies delivery systems with reactivity against two different stimuli were established either to enhance the response by synergies of the stimuli or to broaden the window of possible trigger events. In the present review numerous exciting developments of pH‐, light‐ and redox‐cleavable polymers suitable for the preparation of smart delivery systems are described. The review discusses the different stimuli that can be used for a controlled drug release of polymer‐based delivery systems. It puts a focus on the different polymers described for the preparation of stimuli‐sensitive systems, their preparation techniques as well as their stimuli‐responsive degradation. © 2022 The Authors. Polymer International published by John Wiley & Sons Ltd on behalf of Society of Industrial Chemistry.

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Recent advances in self-immolative linkers and their applications in polymeric reporting systems

Abstract: Interest in self-immolative chemistry has grown over the past decade with more research groups harnessing the versatility to control the release of a compound from a larger chemical entity, given...

Cited by 52 publications

References 372 publications

A Triazolium‐Anchored Self‐Immolative Linker Enables Self‐Assembly‐Driven siRNA Binding and Esterase‐Induced Release

A Triazolium‐Anchored Self‐Immolative Linker Enables Self‐Assembly‐Driven siRNA Binding and Esterase‐Induced Release

Antiviral Peptide-Based Conjugates: State of the Art and Future Perspectives

Stimuli‐accelerated polymeric drug delivery systems

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