Glucose-responsive Insulin Nanoparticles Based On 3D-dendritic Mesoporous Silica As Drug Delivery System For Diabetes

Diabetes is a metabolic disorder with hyperglycemia caused by insufficient insulin secretion or insulin resistance.The traditional treatment for diabetes mellitus is frequent subcutaneous injection of insulin,which is painful and difficult to control blood glucose.Therefore,it is necessary to develop a smart drug delivery system that can improve drug delivery compliance and self-regulate release.In this paper,we developed two glucose-responsive delivery systems based on mesoporous silica:(1)Oral polyelectrolyte complexes for type Ⅱ diabetes;(2)CD/FPB A-MSN for type I diabetes.The research contents as follows:(1)Briefly,alginate-g-3-aminophenylboronic acid(ALG-g-APBA)and chitosan-g-3-fluoro-4carboxyphenylboronic acid(CS-g-FPBA)were wrapped on MSN to form the negative charged ALGg-APB A@MSN and the positive charged CS-g-FPB A@MSN,with optimum insulin loading capacity of 124 mg/g and 295 mg/g respectively.ALG-g-APBA@MSN was further cross-linked with CS-gFPBA@MSN to form PECs through electrostatic interaction and borate esters.The dense network on MSN was capable of protecting insulin from diffusion and regulating release.The in vitro insulin release of PECs demonstrated an obvious glucose response in different glucose concentrations(0 mg/mL,2 mg/mL,5 mg/mL)and presented an "switch-on" and“off" release regulation at hyperglycemic or normal state.The CCK-8 assay showed that both ALG-g-APBA@MSN and CS-gFPBA@MSN nanoparticles possessed no cytotoxicity to Caco-2 cells.For in vivo tests,the PECs exhibited a significant hypoglycemic effect on diabetic rats after oral administration and the euglycemic level was observed for approximately 8 h.In summary,the glucose-responsive PECs have a good potential to be applied for oral insulin delivery.(2)Briefly,β-cyclodextrin was modified with carboxyl group,and its structure was characterized by 1H-NMR spectroscopy.MSN was modified with 3-fluoro-4-carboxyphenylboronic acid(FPB A)on the surface as insulin carrier.The synthesized carboxylated β-cyclodextrin is grafted on the surface of MSN-FPBA through amide reaction.Cyclodextrin formed a reversible ester bond with FPBA in order to prevent insulin leakage and regulate release.The CD/FPBA-MSN was characterized by transmission electron microscopy,particle size,nitrogen adsorption and desorption.The in vitro insulin release of CD/FPBA-MSN demonstrated an obvious glucose response profile in different glucose concentrations(0 mg/mL,2 mg/mL,5 mg/mL)and presented an "switch-on" and "off" release regulation at hyperglycemic or normal state.The CCK-8 assay showed that CD/FPBA-MSN possessed no cytotoxicity to Caco-2 cells.For in vivo tests,the nanoparticles exhibited a significant hypoglycemic effect on diabetic rats after subcutaneous injection and the euglycemic level was observed for approximately 12 h.In summary,the glucose-responsive CD/FPBA-MSN have a good potential to be applied for insulin delivery.