Thermo‐ and glucose‐sensitive microgels with improved salt tolerance for controlled insulin release in a physiological environment

Abstract

The response to temperature and glucose, high salt tolerance and self-regulated drug delivery are simultaneously probable by applying a multifunctional microgel in a rational design by a colloid chemistry method. Such smart microgels were fabricated with thermoresponsive N-isopropylacrylamide, glucose-sensitive (2-phenylboronic esters-1,3-dioxane-5-ethyl)methyl acrylate (PBDEMA) and water-soluble crosslinker poly(ethylene glycol) diacrylate through a precipitation emulsion method. These colloidal nanoparticles exhibited PBDEMA-composition-dependent responsive behavior with changing temperature and ionic strength. Amongst them, the microgel with 20.7 mol% PBDEMA with a narrow size distribution is suitable for diabetes treatment because it can adapt to the surrounding medium of different glucose concentrations over a clinically relevant range (0-2.0 mg mL −1 ), control the release of preloaded insulin and is highly stable under normal physiological conditions. Preliminary experiments suggest these highly stable microgels have the potential to be used for self-regulated therapy and monitoring the response to treatment.

Hydrogels as Potential Nano-, Micro- and Macro-Scale Systems for Controlled Drug Delivery

“…Suitable controlled-release mechanisms include (Figure 8): diffusion [17], swelling [68], chemical and environmental stimuli (degradation or deformation) [67]. Drug release from HGs in response to environmental stimuli may occur due to changes in pH [110,204], temperature [110,[205][206][207], electric field [109,111,208] or ionic strength [209,210]. Some ideas are schematically presented in Figure 8 [17].…”

Lyophilisation Improves Bioactivity and Stability of Insulin-Loaded Polymeric-Oligonucleotide Nanoparticles for Diabetes Treatment

“…Apart from investigating the effect of pH, dissolution studies were performed to investigate the effect of glucose concentration (2 mg/mL and 5 mg/mL glucose in pH 7.4 PBS) on amount of insulin release from lyophilised nanoparticles. The normal range of blood sugar level is 0.6 and 1.2 mg/mL in individuals with normoglycemia (38). It was previously suggested that the under fasting blood glucose concentrations of healthy individuals (5 mM) and diabetes patients (10 mM) can vary (39).…”

“…Therefore, a few studies used 5 mg/ mL as the reference blood sugar concentration for patients with diabetes (40). The glucose-responsive behaviour of nanoparticles can be assessed by incubation in medium with various glucose concentration ranging from 0 to 5 mg/mL at pH 7.4 (38)(39)(40)(41). The glucose-responsive drug delivery systems, such as amino-phenylboronic acid nanoparticles (39), phenyl-boronic acid-grafted chitosan nanoparticles (41) and 2-formyl-3thienylboronic acid nanoparticles (32), were reported to reduce the risk of hypoglycaemia and manage the blood glucose level better.…”

Insulin Delivery Using Dynamic Covalent Boronic Acid/Ester‐Controlled Release

“…Recent work by Zhang and co-workers showed an example of a multifunctional glucose and thermally responsive microgel with high salt tolerance. [90] The authors synthesised a random copolymer using 7 and (2-phenylboronic esters-1,3dioxane-5-ethyl)methyl acrylate (16) as monomers, endowing thermo-responsiveness and the other in glucose-responsiveness respectively, with PEG diacrylate used as a crosslinker (17) (Scheme 3). Three microgels varying in monomer ratio were prepared via radical initiated polymerisation.…”

“…A pictographic representation of the glucose responsive microgel as developed by Zhang and co‐workers. [ 90 ] i) Radical initiated polymerisation of acrylamide monomers. ii) Schematic of the materials response to temperature and the presence of glucose.…”