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A multifunctional self-immolative hydrogel for accelerating the healing of chronic wounds

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A smart molecule delivery system that switches between active and dormant states, depending on environment

Controlled release is a desired property for biomedical and agrochemical delivery technologies: both for maximum efficacy and to avoid non-specific side effects. European scientists developed an innovative controlled release platform that can dynamically become activated and deactivated in response to pH changes.


In chemistry, self-immolation refers to the chemical breakdown of compounds into their components in a head-to-tail cascade fashion like the burning of fuse. The process has spurred great research interest in controlled release systems for drug delivery, biological imaging and nutrient or pesticide release in agriculture. Additional applications include the development of degradable polymeric materials such as plastics, coatings and nanoparticles.

Controlling self-immolation in response to pH

Compounds capable of undergoing self-immolation contain a chemical linker that connects a stimulus-cleavable protecting group – the ‘trigger’ – to a ‘payload’ molecule such as a drug. The linker serves to accelerate removal of the trigger upon exposure to a suitable stimulus such as pH, temperature, or enzymes. The steric and chemical properties of the linker predetermine the kinetics of self-immolation, which when activated, results in uninterrupted release of the payload, regardless of the environment. Undertaken with the support of the Marie Skłodowska-Curie (MSC) programme, one aim of the Multi-SIP Hydrogel project was to dynamically control the kinetics of self-immolation using external stimuli. “We wanted to control the degradation reaction of the linker, and hence the release of the payload, in response to a specific transient or changing stimulus,” explains MSC research fellow, Derrick Roberts. The project was a collaboration between the Karolinska Institute and Professor Molly Stevens’ group at Imperial College London. Researchers exploited the fact that self-immolative linkers contain residues which are sensitive to changes in acidity. They synthesised linkers whose self-immolation cascade – and hence payload release – can be paused and restarted, based on the acidity of the environment.

Linker optimisation for future applications

The degradable linker design allows the self-immolation cascade to be readily switched on and off, thereby ensuring that payload delivery proceeds only under specific environmental conditions. This is a significant innovation in the field – this level of dynamic pH control over payload release has not been explicitly demonstrated before. Importantly, this work has potential biological applications in situations where pH changes drive the release of drugs. In wound healing, for example, a pH-responsive self-immolative linker could ensure rapid initial payload release, while attenuation and reactivation would proceed according to the changing needs of the wound, averting the risk of overdosing. Self-immolative linkers can also be conjoined to form special types of rapidly degradable polymers. By contrast, conventional degradable polymers break down into smaller fragments over much longer time periods because there is no cascade mechanism for their degradation. “To efficiently exploit our linker in biological applications, further optimisation is required in terms of water solubility, the pH response range, and the cytotoxicity of the self-immolation products,” emphasises Roberts. This is the focus of his newly established group at the University of Sydney, where he is also investigating the application of self-immolative linkers in fields such as agriculture and stimuli-responsive coatings. His current Australian Research Council Early Career grant is to use self-immolative linkers and polymers to trigger controlled morphological transformations of self-assembled polymer nanoparticles. He envisages, “control of nanoparticle morphology – and thus function – to fuel the development of new stimuli-responsive nanotechnologies.”


Multi-SIP Hydrogel, linker, self-immolation, drug, controlled release, nanoparticles

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Scientific advances

9 October 2020