Glucose and H₂O₂ Dual-Responsive Nanocomplex Grafted with Insulin Prodrug for Blood Glucose Regulation

Abstract

Although "closed-loop" smart insulin delivery systems have been extensively investigated, the majority of them suffer from low insulin loading efficiency and slow glucose response. Here, we constructed a novel nanocomplex (NC), which was prepared by electrostatic interaction between negatively charged insulin prodrug nanoparticles (NPs) and positively charged polycaprolactone− polyethylenimine (PCL−PEI) micelles. The insulin prodrug was linked to acetalated dextran (AD) via borate ester bonds to form IAD NPs, and glucose oxidase (GOx) was encapsulated in PCL−PEI micelles. The NC was negatively charged with a high insulin grafting rate (0.473 mg/mg), and in vitro experiments revealed that IAD was sensitive to hyperglycemia and H 2 O 2 , whereas GOx significantly improved the response to glucose by altering the microenvironment to promote sustained insulin release. Furthermore, compared with free insulin and IAD NPs, subcutaneously injected NCs in diabetic rats had long-term hypoglycemic effects, showing excellent biocompatibility in vitro and in vivo, which had good potential in insulin self-regulation delivery.

Electrostatic-Interaction-Aided Microneedle Patch for Enhanced Glucose-Responsive Insulin Delivery and Three-Meal-Per-Day Blood-Glucose Regulation

“…to that of the native INS. 16,49,50 With the help of the circular dichroism spectroscope (J-1500-150ST), the typical α-helix pattern (bands at 208 and 223 nm) was found in the native INS as well as the released INS from GR-MNP (Figure S11a). The BGL-lowering abilities of INS were also tested on extracted INS from GR-MNP (Figure S11b).…”

“…Circular dichroism (CD) spectroscopy was widely adopted to study the secondary structures of INS, in which the bioactive INS sample usually exhibited a similar CD spectrum to that of the native INS. ,, With the help of the circular dichroism spectroscope (J-1500-150ST), the typical α-helix pattern (bands at 208 and 223 nm) was found in the native INS as well as the released INS from GR-MNP (Figure S11a). The BGL-lowering abilities of INS were also tested on extracted INS from GR-MNP (Figure S11b).…”

PVA-based bulk microneedles capable of high insulin loading and pH-triggered degradation for multi-responsive and sustained hypoglycemic therapy

“…To investigate the effect of different H 2 O 2 concentrations on insulin release, microneedles loaded with INS (MNs@INS) were dissolved in 1 mL of 10 mM PBS ( pH 7.4) with varying concentrations of H 2 O 2 (0.1 mM and 0.5 mM). 27 At predetermined time intervals, 50 μL of the sample solution was removed and stained with Coomassie blue (250 μL) and measured at an absorbance of 595 nm using a microplate reader. To assess the association between H 2 O 2 and the phenyl borate ester, MNs@GOx was scattered into 3.0 mL of PBS with diverse glucose concentrations (1 mg mL −1 and 4 mg mL −1 ), and MNs containing 4 units of APBA were labeled as MNs@GOx I, while those containing 8 units of APBA were denominated as MNs@GOx II.…”

“…It has been reported that hydrogen peroxide (H 2 O 2 ) produced by GOx during glucose oxidation can bind to phenylboronic acid esters, leading to further degradation of the phenylboronic acid ester structure, which increases the sensitivity of the glucose response and promotes rapid insulin release. [26][27][28] Therefore, phenyl borate and its derivatives (PBE) in combination with GOx have been extensively utilized for diabetes treatment. [29][30][31] It is noteworthy that the solubility of microneedles and "closed-loop" systems is independent of conventional microneedles.…”

ICAM-1 targeted and ROS-responsive nanoparticles for the treatment of acute lung injury

“…36–38 Moreover, PBA/PBAE could be used as linkers or directly coupled to drugs to prepare prodrugs. 39–42 Branch polyethyleneimine (PEI) is a cationic polymer, extensively employed in drug delivery field due to abundant amino groups. 43…”