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When selecting the optimal degradable release system for a specific application, the most significant criteria is for the material to decompose within a suitable and tuneable time period that is compatible with the desired drug release rate. Within nature, the most important, fundamental substances are macromolecules that can adapt their structure or behaviour depending on their surrounding environment.139 Inspired by the dynamic versatility and efficiency observed within living systems, research into the synthesis and development of stimuli-responsive (also known as ‘smart’ or ‘intelligent’) polymers has been intensively researched.140-142 _{Synthetic smart} polymers have been designed to undergo either chemical or physical changes within response to small environmental variations.142 _{A wide variety of stimuli parameters}

have previously been investigated, such as, pH, temperature, light and carbon dioxide.143-149 Furthermore, as a consequence of the high efficiency offered by stimuli- responsive polymers, they have been applied for a broad array of applications with a multitude of controlled release devices (e.g., hydrogels, nano/micro-particles, films, etc.).50, 150-152

Stimulus-Responsive Particles

Incorporating a stimulus-responsive polymer within a particle system enables modulated control over the site-specific AI release. Furthermore, this can be advantageous in both controlling the concentration of AI released and for tailoring the AI release rate. For this reason, multiple approaches have been investigated to develop stimulus-responsive particles; development of novel responsive polymers, copolymerisation of one or more smart polymers with a conventional polymer, blending smart polymers with conventional polymers, etc.153-155

33 In general, pH-responsive polymers consist of an ionisable acidic or basic residue, whose ionisation depends on the pH of the surrounding solution.156 pH-Responsive particles have received a lot of attention especially for drug delivery applications.60, 157, 158 _{Indeed, within the medical field, numerous particle systems have been} developed specifically targeting delivery to the low pH of the stomach (pH 1.5-3.5) or higher pH observed within the intestine (pH 6.0-7.4).159, 160 Lin et al., discovered that particles synthesised from differing ratios of chitosan and heparin could encapsulate antibiotics for the prevention and treatment of peptic ulcers.161 In more detail, the degradable particles controlled the localised release of the encapsulated drug whilst acting to protect the incorporated AI from destructive gastric acids. On a similar note, numerous pH-sensitive drug-delivery systems have also taken advantage of the difference in pH observed with healthy tissues (7.4) and the extracellular environment of solid tumours (6.5-7.2), thus enabling site-specific release of anti-cancer drugs to cancerous cells.162, 163

Stimuli parameters can often require forcing conditions to trigger an environmental change. However, the excellent exogeneous and non-invasive control attainable using a photo-responsive system has enabled the engineering of light-responsive polymers whose structural modification can be induced under mild conditions for a variety of wavelengths (ultraviolet, visible or near-infrared regions).164 Consequently, a wide range of photo-responsive systems have been designed and investigated for a broad array of applications.51, 139 Azobenzene derived materials have received particular attention as a consequence of their easily irradiation-induced switchable isomerisation.165 Moreover, cis-azobenzene is relatively polar with a dipole moment, conversely, trans-azobenzene is a stable macromolecule with no dipole moment. The

34 observed change from cis-trans azobenzene can result in a complete change in

electronic structure, geometric shape and polarity.139

In recent years, to further improve the versatility of drug delivery systems, increasing research into the synthesis and design of multi-responsive polymers has been observed.155, 166, 167 In certain pathological systems, pH-gradients and oxidative environments co-exist, therefore, the combination of pH and redox responsive particles has been shown to be highly advantageous for the design of drug delivery vehicles.168 Indeed, Sokolovskaya et al. synthesised novel dual responsive Janus

microparticles based on a novel poly(ethylene glycol) based polymer.169 The polymer contained both a redox responsive thioether and a light sensitive nitrobenzyl group, thus enabling selective degradation via the application of either oxidative stress or UV light, thus demonstrating their high potential for controlled release.

Smart Release in Agriculture

With the increasing population and imminent strain on the agricultural industry, controlled release technology has emerged as a promising alternative to conventional agrochemical delivery with the promise to solve the problems accompanying the use of some agrochemicals, while avoiding possible side effects with others. The agrochemical can be contained within a material, which allows for the controlled release of the AI to the desired target. Therefore, the substance can be slowly and continuously released for up to several years. This can be highly advantageous, leading to fewer repeat applications, reduced agrochemical toxicity levels and increased efficiency of the agrochemical. This can be demonstrated by the recent work by Meyer et al., who investigated the controlled release of the pesticide imidacloprid from PLGA

microparticles.170 On its own, imidacloprid is known to cause undesirable toxicity towards and has been found to be especially detrimental to colonies of honey bees.

35 However, Meyer et al., discovered by encapsulating the imidacloprid into PLGA

microparticles using a solvent evaporation technique, approximately 200 times less pesticide was required to achieve the same mortality of psyllids as the pesticide on its own.

Currently, several micro-encapsulated products are commercially available that aim to achieve slow release effects within the crop market, in particular Stomp Aqua (BASF), Samurai II CS Insecticide (J. Oliver Products) and Force (Syngenta).171-174 Syngenta owns a patent that uses base-triggered microparticles which are designed to open in the alkaline environment of insect guts.174 As a consequence of the high levels of localised control offered by ‘smart’ release systems, increasing research is being performed to enable stimulus-responsive release of agrochemicals. Indeed, Hill et al. investigated the synthesis of biodegradable pH-responsive nanoparticles for site- specific agrochemical delivery.175 Moreover, the synthesised amphiphilic functionalised polysuccinimide particles displayed controlled release under alkaline conditions, thus enabling the localised release of an AI to the plant phloem (pH 7.3- 8.5). Similar work by Chen et al., also detailed the localised release of an encapsulated AI to the plant phloem through the novel synthesis and encapsulation into pH- responsive amphiphilic polysuccinimide star copolymers.176 The next fifty years are predicted to be the most challenging yet with regards to the strain applied on the agricultural industry. Therefore, the exciting opportunities attainable through the application of innovative ‘smart’ release technologies have the potential to shape and define the successful future for more efficient, enhanced agricultural practices.

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