Injectable dual glucose-responsive hydrogel-micelle composite for mimicking physiological basal and prandial insulin delivery

For type 1 and advanced type 2 diabetic patients, insulin replacement therapy with simulating on-demand prandial and basal insulin secretion is the best option for optimal glycemic control. However, there is no insulin delivery system yet could mimic both controlled basal insulin release and rapid prandial insulin release in response to real-time blood glucose changes. Here we reported an artificial insulin delivery system, mimicking physiological basal and prandial insulin secretion, to achieve real-time glycemic control and reduce risk of hypoglycemia. A phenylboronic acid(PBA)/galactosyl-based glucose-responsive insulin delivery system was prepared with insulin-loaded micelles embedded in hydrogel matrix. At the hyperglycemic state, both the hydrogel and micelles could swell and achieve rapid glucose-responsive release of insulin, mimicking prandial insulin secretion.When the glucose level returned to the normal state, only the micelles partially responded to glucose and still released insulin gradually. The hydrogel with increased crosslinking density could slow down the diffusion speed of insulin inside, resulting in controlled release of insulin and simulating physiological basal insulin secretion. This hydrogel-micelle composite insulin delivery system could quickly reduce the blood glucose level in a mouse model of type 1 diabetes, and maintain normal blood glucose level without hypoglycemia for about 24 h. This kind of glucose-responsive hydrogel-micelle composite may be a promising candidate for delivery of insulin in the treatment of diabetes.

Complex micelles with the bioactive function of reversible oxygen transfer

A complex micelle as a hemoglobin functional model with the biaoactive function of reversible oxygen transfer has been constructed through the hierarchical assembly of the diblock copolymer poly（ethylene glycol）-block- poly（4-vinylpyridine-co-N-heptyl-4-vinylpyridine） （PEG-b-P（4VP-co-4VPHep））, tetrakis（4-sulfonatophenyl）porphinato iron（II） （Fe（II）TPPS） and β-cyclodextrin （β-CD）. The μ-oxo dimer of Fe（II）TPPS was successfully inhibited because the Fe（II）TPPS was included into the cavities of β-CDs through host-guest interaction. Fe（II）TPPS coordinated with pyridine groups functions as the active site to reversibly bind dioxygen. In adition, the host-guest inclusion （β-CD/Fe（II）TPPS） was encapsulated in the hydrophobic core of the complex micelle and tightly fixed by P4VP chains. The hydrophilic PEG blocks stretched in aqueous solution to constitute the shells which stabilize the structure of the complex micelle as well as endow the complex micelle with sufficient blood circulation time. Dioxygen can be bound to the Fe（II）TPPS located in the confined space and excellent reversibility of the binding-release process of dioxygen can be achieved. The quaternary amine N-heptyl-4-vinylpyridine can coerce abundant S2O4^2- ions into the core of the complex micelle to facilitate the self-reduction process. Dioxygen adducts （Fe（II）TPPS（O2）） were effectively protected by the double hydrophobic barriers constructed by the cavity of the cyclodextrin and the core of the complex micelle which enhances the ability to resist nucleophilic molecules. Therefore, the rationally designed amphiphilic structure can work as a promising artificial O2 carrier. Potentially, the complex micelle can be expected to improve the treatment of diseases linked with hypoxia.

In-biofilm generation of nitric oxide using a magnetically-targetable cascade-reaction container for eradication of infectious biofilms

Cascade-reaction chemistry can generate reactive-oxygen-species that can be used for the eradication of infectious biofilms.However,suitable and sufficient oxygen sources are not always available near an infection site,while the reactive-oxygen-species generated are short-lived.Therefore,we developed a magnetic cascade-reaction container composed of mesoporous Fe_(3)O_(4)@SiO_(2) nanoparticles containing glucose-oxidase and L-arginine for generation of reactive-oxygen-species.Glucose-oxidase was conjugated with APTES facilitating coupling to Fe_(3)O_(4)@SiO_(2) nanoparticles and generation of H_(2)O_(2) from glucose.L-arginine was loaded into the nanoparticles to generate NO from the H_(2)O_(2) generated.Using an externally-applied magnetic field,cascade-reaction containers could be homogeneously distributed across the depth of an infectious biofilm.Cascade-reaction containers with coupled glucose-oxidase were effective in killing planktonic,Gram-positive and Gram-negative bacteria.Additional efficacy of the L-arginine based second cascade-reaction was only observed when H_(2)O_(2) as well as NO were generated in-biofilm.In vivo accumulation of cascade-reaction containers inside abdominal Staphylococcus aureus biofilms upon magnetic targeting was observed real-time in living mice through an implanted,intra-vital window.Moreover,vancomycin-resistant,abdominal S.aureus biofilms could be eradicated consuming solely endogenous glucose,without any glucose addition.Herewith,a new,non-antibiotic-based infection-control strategy has been provided,constituting a welcome addendum to the shrinking clinical armamentarium to control antibiotic-resistant bacterial infections.