Glucose-responsive microgels with a core–shell structure
Graphical abstract
The extent of core swelling is regulated either by its own internal stimulus or by shell compression, which is proportional to glucose concentration.
Introduction
Environmentally responsive polymers have attracted much interest over the past few years, due to their promising applications in various fields such as sensors [1], [2], [3], drug delivery systems [4], [5], [6], [7], or optical devices [8]. Microgels are colloidally stable particles of chemically cross-linked polymer, swollen by a solvent. When the constituting polymer is stimuli-responsive, the microgels undergo volume changes upon stimulus application. For example, microgels obtained from poly-N-isopropylacrylamide (pNIPAM) as constituting polymer, which exhibits a lower critical solution temperature (LCST) at 32 °C, shrink upon heating above the LCST [9]. Structural changes can also be obtained upon application of various stimuli like pH, ionic strength, and even molecular recognition [10]. Microgels with multiresponsive behavior can be synthesized, generally by the copolymerization of at least two different functional monomers. A more advanced architecture is the core–shell morphology, which offers the possibility to accurately control the spatial distribution of the monomer units within the particles, with the core and the corona being responsive to a different single stimulus.
A few years ago, multiresponsive microgels with core–shell morphology were synthesized by Jones and Lyon [11], [12], [13]. These systems were composed with the well-known temperature-responsive pNIPAM, associated to pNIPAM-co-acrylic acid, which is also sensitive to pH. Other combinations of polymers were further investigated: polymers with different LCST such as poly-N-isopropylmethacrylamide (pNIPMAM) [14] or pNIPAM modified with a hydrophobic monomer, butylmethacrylate [15], and other pH-sensitive polymers based on 4-vinylpyridine [16]. These fundamental studies helped elucidating the fine structure of such objects [17], [18], as well as understanding the mutual influence of core and shell on thermodynamic and mechanical properties [19], [20].
A step further toward applications, especially in biomedical science, requires the need for functionalized nanomaterials, which have the ability to bind to a target molecule. More interestingly, some functionalized microgels display the ability to respond to a concentration change of this target molecule in the environment, exactly like biofeedback systems. Such systems appear as promising candidates for sensing, drug or gene delivery, and possibly new biomaterials or microreactors. Glucose is one of the actual challenging target molecules, owing to the widely spread disease of diabetes mellitus and the great demand for elaborating noninvasive glucose monitoring, as well as finding new ways for insulin administration. A pioneering work reported by Kataoka et al., showed the delivery of insulin amounts according to the presence of glucose from glucose-responsive hydrogels bearing phenylboronic acid (PBA) groups [21]. These hydrogels were further improved to operate at physiological pH [22], [23]. Glucose-responsive hydrogels were recently scaled down to microgels, as reported by our group [24] and others [25], [26], [27], [28]. Microgels with different composition and structure were thus achieved. A response to glucose was obtained at physiological salinity conditions [24] and more recently at temperature and pH physiological conditions [28]. The elaboration of glucose-responsive capsules was also reported although not active at physiological pH [26]. The principle of swelling relies on the change in the ionization state between the PBA receptor and the PBA–glucose complex. Indeed, PBA groups are known for their ability to complex glucose [29], [30]. When complexation occurs at a pH close to the p of the PBA derivative, the equilibrium between charged and neutral species is shifted towards an increase of the fraction of charged entities (Fig. 1), which also increases the overall hydrophilic character of the polymer chain [21]. This phenomenon induces swelling of the PBA modified microgel, proportional to glucose concentration in the surrounding medium. Such materials are perceived as potential candidates for insulin self-delivery according to glucose concentration.
The control of the receptor location within the microgel is a key parameter to build up particles with a fine response to glucose concentration, as well as the good properties for future insulin encapsulation. Hoare and Pelton have made a step in that direction by grafting PBA groups on microgels having a controlled internal distribution of the carboxylic acid functions [27]. However, a limitation of this latter procedure is the only partial control of PBA conjugation due to steric and diffusive barriers. The provided particles may therefore have a complex chemical composition with an undefined amount of unreacted carboxylic sites. The copolymerization method presents the advantage to better control the chemical nature of the microgels. Keeping our initial strategy of copolymerization, we chose to control receptor location through core–shell morphology, with receptors being located in the shell. The core will be conceived as a hydrophilic interior aimed at loading hydrophilic guest molecules such as insulin. Conceptually, such particles have a structure closed to that of a capsule but can benefit from the own responsiveness of the core.
In this paper, we report on the synthesis and characterization of core–shell microgels having a thermoresponsive core and a thermo/glucose-responsive shell. PBA receptors were introduced in the shell by copolymerization. The thermal phase transition properties of the obtained particles were studied by photon correlation spectroscopy (PCS), as well as their response to glucose. The first part of the work was dedicated to a detailed characterization of the core–shell structure of model microgels, i.e. which did not respond to glucose at physiological conditions. The separate swelling states of the core and the shell were estimated in order to understand their mutual influence. In a second time, the concept was transposed to another chemical composition, selected to obtain a glucose response at pH physiological conditions. These particles were finally applied to deliver insulin.
Section snippets
Materials
All the reagents were purchased from Sigma–Aldrich unless otherwise noted. N-isopropylacrylamide (NIPAM) and N-isopropylmethacrylamide (NIPMAM) were recrystallized from hexane (ICS) and dried under vacuum prior to use. d-Glucose, -methylenebis(acrylamide) (BIS), sodium dodecyl sulfate (SDS) and ammonium persulfate (APS) were used as received. 3-Aminophenylboronic acid hemisulfate and N-(3-dimethylaminopropyl)--ethylcarbodiimide hydrochloride (EDCI) were purchased from Acros Organics and
Particles synthesis and characterization of the core–shell structure
A two-step precipitation polymerization was performed at 70 °C in an aqueous medium to obtain a series of core–shell microgels bearing a pNIPAM core and a pNIPAM-co-APBA shell. Simple microgels from these two polymers can be obtained by this method at this temperature [24], [32]: their corresponding monomers are soluble but the polymer phase separate into dense polymer globule. After a first polymerization step, monodispersed pNIPAM particles were obtained (PDI below 0.1). They were added to a
Conclusion
In this paper, we have synthesized new multiresponsive microgels with one of the stimuli being the response to a target molecule, just like biofeed-back systems. Their core–shell morphology offers original properties in term of swelling. This work has developed the concept of a temperature-responsive/hydrophilic core combined with a glucose-responsive shell. The versatile affinity of the shell for water—hydrophobic without any glucose in the medium, which turns out to be hydrophilic upon
Acknowledgments
The authors acknowledge the Region Aquitaine for financial support. We also thank Claude Roux from the Laboratoire Interrégional de la Direction Générale de la Concurrence, Consommation et Répression des Fraudes for carrying out the elemental analysis experiments.
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