A New Bio-Inorganic Nanocomposite Membrane for Glucose-Modulated Release of Insulin
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A New Bio-Inorganic Nanocomposite Membrane for Glucose-Modulated Release of Insulin Claudia R. Gordijo, Adam J. Shuhendler and Xiao Yu Wu* Leslie L. Dan Faculty of Pharmacy, University of Toronto 144 College Street, Toronto, ON, M5S 3M2, Canada. E-mail: [email protected]
ABSTRACT This work focuses on the development of a new bio-inorganic nanocomposite glucoseresponsive membrane to be applied as a single self-regulated platform for insulin delivery. Crosslinked bovine serum albumin (BSA)-based membranes were prepared containing impregnated pH-responsive poly(N-isopropyl acrylamide-co-methacrylic acid) nanoparticles (hydrogel NPs), glucose oxidase (GOx), catalase (CAT), with or without MnO2 NPs. The membrane acts as a glucose sensor and insulin release attenuator. In this system glucose is oxidized by GOx to produce gluconic acid, which regulates the permeability of the membrane to insulin. CAT and/or MnO2 NPs are introduced into the membrane in order to quench unwanted H2O2 produced by GOx turnover cycles, which can cause inactivation of GOx and toxicity. The glucose-modulated insulin release through the membrane is determined by alternating glucose concentration between 100 – 400 mg/dL (normal and hyperglycemic levels, respectively). The results show that the combination of CAT and MnO2 NPs in the membrane formulation leads to better efficiency in quenching the H2O2 and better long-term stability of GOx than using either alone. Very small amounts of insulin permeate though the membrane at the normal blood glucose level while a four-fold increase in the release rate is observed when glucose concentration is raised to a hyperglycemic level. The release rate of insulin drops when the glucose level is reduced to a normal value. These results demonstrate the self-regulated capability of the system.
INTRODUCTION Diabetes mellitus is a major public health problem that affects more 246 million people worldwide. It is a disorder in glucose regulation, characterized by the accumulation of glucose in the blood due to the inability of the pancreas to secrete insulin or the body incapability to respond to insulin. The conventional way of controlling glycemia in insulin-dependent diabetic patients is the frequent self-administration of insulin injections, which often results in hypoglycemia along with bad patient compliance [1, 2]. A more effective approach to delivering insulin in direct response to blood glucose levels mimicking a healthy human pancreas is thus highly desirable [3]. For this propose, smart nanomaterials have been investigated for glucosemodulated insulin delivery [3, 4]. Glucose-responsive nanocomposite membranes, for example, are able to control the permeation of insulin as a direct response to glucose concentration [8-7]. Our approach to producing glucose-responsive membranes involves the incorporation of pH-
sensitive hydrogel NPs and the enzyme GOx into a polymeric matrix [5 - 7]. The membrane acts as a glucose sensor by the action of GOx, which catalyzes the oxidation of glucose to gl
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