Glucose-responsive microgels integrated with enzyme nanocapsules for closed-loop insulin delivery.

A glucose-responsive closed-loop insulin delivery system represents the ideal treatment of type 1 diabetes mellitus. In this study, we develop uniform injectable microgels for controlled glucose-responsive release of insulin. Monodisperse microgels (256 ± 18 μm), consisting of a pH-responsive chitosan matrix, enzyme nanocapsules, and recombinant human insulin, were fabricated through a one-step electrospray procedure. Glucose-specific enzymes were covalently encapsulated into the nanocapsules to improve enzymatic stability by protecting from denaturation and immunogenicity as well as to minimize loss due to diffusion from the matrix. The microgel system swelled when subjected to hyperglycemic conditions, as a result of the enzymatic conversion of glucose into gluconic acid and protonation of the chitosan network. Acting as a self-regulating valve system, microgels were adjusted to release insulin at basal release rates under normoglycemic conditions and at higher rates under hyperglycemic conditions. Finally, we demonstrated that these microgels with enzyme nanocapsules facilitate insulin release and result in a reduction of blood glucose levels in a mouse model of type 1 diabetes.

[1]  Kyoung Taek Kim,et al.  Monosaccharide-responsive release of insulin from polymersomes of polyboroxole block copolymers at neutral pH. , 2012, Journal of the American Chemical Society.

[2]  Jun Ge,et al.  Encapsulation of single enzyme in nanogel with enhanced biocatalytic activity and stability. , 2006, Journal of the American Chemical Society.

[3]  S. Genuth,et al.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. , 1993, The New England journal of medicine.

[4]  Bogdan Catargi,et al.  Chemically controlled closed-loop insulin delivery. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[5]  Daniel G Anderson,et al.  Injectable nano-network for glucose-mediated insulin delivery. , 2013, ACS nano.

[6]  K. Leong,et al.  Electrohydrodynamics: A facile technique to fabricate drug delivery systems. , 2009, Advanced drug delivery reviews.

[7]  David R. Owens,et al.  New horizons — alternative routes for insulin therapy , 2002, Nature Reviews Drug Discovery.

[8]  Francis J. Doyle,et al.  Preparation and dynamic response of cationic copolymer hydrogels containing glucose oxidase , 2000 .

[9]  R. Langer,et al.  Enzymatically controlled drug delivery. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Isao Shinohara,et al.  Glucose Induced Permeation Control of Insulin through a Complex Membrane Consisting of Immobilized Glucose Oxidase and a Poly(amine) , 1984 .

[11]  David J S Birch,et al.  Nanomedicine and its potential in diabetes research and practice , 2008, Diabetes/metabolism research and reviews.

[12]  T. Okano,et al.  A microcapsule self-regulating delivery system for insulin , 1990 .

[13]  Ming Yan,et al.  Protein nanocapsule weaved with enzymatically degradable polymeric network. , 2009, Nano letters.

[14]  Weitai Wu,et al.  Multifunctional hybrid nanogel for integration of optical glucose sensing and self-regulated insulin release at physiological pH. , 2010, ACS nano.

[15]  N A Peppas,et al.  Glucose-sensitivity of glucose oxidase-containing cationic copolymer hydrogels having poly(ethylene glycol) grafts. , 2000, Journal of Controlled Release.

[16]  Robert Langer,et al.  Materials for Diabetes Therapeutics , 2012, Advanced healthcare materials.

[17]  Zhen Gu,et al.  A novel intracellular protein delivery platform based on single-protein nanocapsules. , 2010, Nature nanotechnology.

[18]  C. R. Kahn,et al.  Insulin Action, Diabetogenes, and the Cause of Type II Diabetes , 1994, Diabetes.

[19]  Y. Miyahara,et al.  Innentitelbild: A Synthetic Approach Toward a Self‐Regulated Insulin Delivery System (Angew. Chem. 9/2012) , 2012 .

[20]  Y. Cohen,et al.  Characterization of glucose-sensitive insulin release systems in simulated in vivo conditions. , 2000, Biomaterials.

[21]  Jeandidier,et al.  Current status and future prospects of parenteral insulin regimens, strategies and delivery systems for diabetes treatment. , 1999, Advanced drug delivery reviews.

[22]  Zhefu Chen,et al.  Organization of glucose-responsive systems and their properties. , 2011, Chemical reviews.

[23]  Teruo Okano,et al.  Sensitive glucose-induced change of the lower critical solution temperature of poly [N,N-dimethylacrylamide-co-3-(acrylamido) phenyl-boronic acid] in physiological saline , 1994 .

[24]  Michael Stumvoll,et al.  Type 2 diabetes: principles of pathogenesis and therapy , 2005, The Lancet.

[25]  Simon Chiang,et al.  Nanotechnology‐Enabled Closed Loop Insulin Delivery Device: In Vitro and In Vivo Evaluation of Glucose‐Regulated Insulin Release for Diabetes Control , 2011 .

[26]  Roman Hovorka,et al.  Artificial pancreas: an emerging approach to treat Type 1 diabetes , 2009, Expert review of medical devices.

[27]  A. Domb,et al.  Chitosan chemistry and pharmaceutical perspectives. , 2004, Chemical reviews.

[28]  T. Okano,et al.  Totally Synthetic Polymer Gels Responding to External Glucose Concentration: Their Preparation and Application to On−Off Regulation of Insulin Release , 1998 .

[29]  B. Zinman,et al.  Insulins today and beyond , 2001, The Lancet.