Designed glucose-responsive microgels with selective shrinking behavior.

We report on the synthesis of various glucose-responsive microgels based on N-alkylacrylamide derivatives and phenylboronic acid (PBA) as a glucose sensing moiety. Depending on their chemical composition, the microgels exhibit opposite behaviors in response to glucose concentration increase: they can either swell or shrink, using two different mechanisms for glucose recognition. Both behaviors may be suitable for glucose sensing and insulin delivery. When glucose binds a single boronate receptor, the microgel swells as glucose concentration increases. This mechanism can be used to deliver a drug by diffusion through the network. In other cases, glucose binds specifically to two boronates, which creates additional cross-links within the network and provokes shrinkage. Such systems are promising for the development of sensors with improved selectivity and also as potential "intelligent" valves in microfabricated delivery systems. By a rational choice of the constituting units of the network structure, we show how to favor one or the other type of response to glucose variation. Therefore, glucose-swelling microgels operating under physiological conditions have been obtained by copolymerization with an appropriate choice of alkylacrylamide monomer and boronate derivative. At a pH above the pK(a) of the boronic acid derivative, the same structures shrink in response to glucose concentration. The nature of the cross-linker is a key parameter to enable this dual behavior. In other microgels, an amine group is introduced in the vicinity of the boronic acid, which lowers its pK(a) and favors microgel contraction at physiological pH. This work has allowed us to give some general rules to control the swelling/shrinking behavior of glucose-responsive microgels.

Glucose-responsive microgels with a core-shell structure.

New multiresponsive core-shell microgels have been synthesized, with a thermoresponsive core and a glucose-responsive shell, made respectively of poly(N-isopropylacrylamide) (pNIPAM) and pNIPAM-co-acrylamidophenylboronic acid (pNIPAM-co-APBA). The structure of the particles was elucidated by means of dynamic light scattering. Their thermal properties were investigated and compared to those of the core alone. Without glucose, the hydrophobic shell prevented the core from swelling in a certain temperature range where the shell was shown to be collapsed. This core compression vanished upon glucose addition, when the shell became hydrophilic and swelled. Therefore, the extent of core swelling was regulated by two processes: its own internal stimulus, i.e. temperature, and shell compression, which is proportional to glucose concentration, even at physiological salinity. The concept was applied to a selected chemical composition. Core-shell microgels with a response to glucose at physiological pH were obtained and used to encapsulate insulin. Insulin release was shown to be regulated by the presence of glucose.

Chemically controlled closed-loop insulin delivery.

Alternative treatments for diabetes are currently being investigated to improve both patient comfort and avoid complications due to hyperglycaemia episodes. In the absence of a cure like pancreas or beta-islets transplants, the ideal method would be an artificial "closed-loop" system able to mimic pancreas activity. This would operate continuously and automatically, causing appropriate response to losses and gains in glucose levels. Chemically controlled closed-loop insulin delivery has been explored by two main strategies. The first one consists in delivering insulin with a glucose-responsive matrix. Polymeric hydrogels that swell or shrink according to the glucose concentration allow delivering insulin doses adapted to the glucose concentration. The second strategy consists in modifying insulin itself with glucose-sensitive functional groups that trigger its activity. Recent developments made in these areas represent significant progress in terms of biocompatibility, selectivity, pharmacokinetics, and easiness of administration, as required for in vivo applications. Although some issues still have to be overcome, this field of research is promising as a possible alternative to other approaches for diabetes treatment.