Investigation On Nano Mesoporous Silica Based Glucose-responsive Insulin Delivery System

Glucose-responsive insulin delivery systems,which can adjust the amount of insulin according to the change of blood glucose level and maintain blood glucose at a stable level,have been proposed as a promising method to treat diabetes.They can reduce potential toxicity and enhance patient compliance compared to traditional therapies.Accordingly,we established an insulin delivery system with glucose-responsive and self-regulated drug release properties.In this system,mesoporous silica nanoparticles(MSN)was served as drug repository and glucose-responsive switch carboxyphenylboronic acid(CPBA)was modified on the surface of MSN to form CPBA-MSN nanoparticles.After that,insulin(INS)was loaded in the channels of MSN(CPBA-MSN/INS)through physical adsorption,and biocompatible polyanionic polysaccharide sodium alginate(SA),which served as the gatekeeper,was introduced onto the surface of CPBA-MSN/INS nanoparticles(SA/CPBA-MSN/INS)via amidation reaction to obtain glucose–responsive drug delivery system.SA/CPBA-MSN/INS was characterized by particle size,zeta potential,ultraviolet spectrum,transmission electron microscope,thermogravimetric analysis and x-ray diffraction to determine the best prescription.The size distribution of the drug delivery system was 209 nm and the zeta potential was-32.3 nm.The best conjugation ratio(w/w)of SA and CPBA on MSN was measured as 2:1,and the best mass proportion of drug-carries was 3:1.In addition,the drug loading ratio of SA/CPBA-MSN/INS was 261 mg/g.According to the results of in vitro release,the cumulative release amount was up to 75.35 % within 12 h when the glucose concentration was 5 mg/mL.By contrast,a moderate release(36.81%)was achieved in glucose solution at the critical concentration of 2 mg/mL glucose.These results suggested that release behavior of INS was glucose-triggered and relied on the concentration of glucose.In addition,SA/CPBA-MSN/INS had “on-off” regulated INS release property with the fluctuant glucose concentration.The cytotoxicity of SA/CPBA-MSN and SA/CPBA-MSN/INS wasinvestigated with Hela cells in the SRB assay.The results clearly manifested that the cell viability up to 96 % even at highest concentration of 500 μg/mL,which indicating the drug delivery system was low toxicity.Hemolysis results showed that SA/CPBA-MSN and SA/CPBA-MSN/INS nanoparticles were hemocompatibility.Finally,the safety studies in vivo showed that SA/CPBA-MSN/INS had no significant effect on blood glucose in healthy mice,which could effectively avoid hypoglycemia and laying a foundation for in vivo study.In vivo activity study,streptozotocin(STZ)was used as the inducer of diabetic animal model and we constructed type I diabetes rats and mice models successfully.In vivo experiments on diabetic rats displayed that SA/CPBA-MSN/INS sustained normal blood glucose level up to 12 h with a single dose.Moreover,the pharmacokinetics results showed that,area under the curve(AUC)of SA/CPBA-MSN/INS group was almost 4-and 1.7-folders higher than Novolin R and Novolin 30 R,respectively.The mean retention time(MRT)was nearly 11 h,which was almost 3.7-and 1.6-folders longer than Novolin R and Novolin 30 R,respectively.The above results indicating that SA/CPBA-MSN/INS with a controlled-release manner and high bioavailability.The biodistribution result indicated that SA/CPBA-MSN could achieve protection and long circulation in the blood for INS.In addition,pharmacodynamics results showed that the lipid metabolism disorder and organ damage of diabetics rats were alleviated after treatment with SA/CPBA-MSN/INSIn summary,SA/CPBA-MSN/INS characterized by “on-off” regulated drug release property and high biocompatibility should be promising for applications in diabetes treatment.