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      Polymer-Based Nanoparticle Strategies for Insulin Delivery

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          Diabetes mellitus (DM) is a chronic metabolic illness estimated to have affected 451 million individuals to date, with this number expected to significantly rise in the coming years. There are two main classes of this disease, namely type 1 diabetes (T1D) and type 2 diabetes (T2D). Insulin therapy is pivotal in the management of diabetes, with diabetic individuals taking multiple daily insulin injections. However, the mode of administration has numerous drawbacks, resulting in poor patient compliance. In order to optimize insulin therapy, novel drug delivery systems (DDSes) have been suggested, and alternative routes of administration have been investigated. A novel aspect in the field of drug delivery was brought about by the coalescence of polymeric science and nanotechnology. In addition to polymeric nanoparticles (PNPs), insulin DDSes can incorporate the use of nanoplatforms/carriers. A combination of these systems can bring about novel formulations and lead to significant improvements in the drug delivery system (DDS) with regard to therapeutic efficacy, bioavailability, increased half-life, improved transport through physical and chemical barriers, and controlled drug delivery. This review will discuss how recent developments in polymer chemistry and nanotechnology have been employed in a multitude of platforms as well as in administration routes for the safe and efficient delivery of insulin for the treatment of DM.

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          Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery.

          A glucose-responsive "closed-loop" insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch ("smart insulin patch") containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GOx) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.
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            Nanoparticles in cancer therapy and diagnosis

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              Chitosan reduced gold nanoparticles as novel carriers for transmucosal delivery of insulin.

              Colloidal metallic systems have been recently investigated in the area of nanomedicine. Gold nanoparticles have found themselves useful for diagnostic and drug delivery applications. Herein we have reported a novel method for synthesis of gold nanoparticles using a natural, biocompatible and biodegradable polymer; chitosan. Use of chitosan serves dual purpose by acting as a reducing agent in the synthesis of gold nanoparticles and also promotes the penetration and uptake of peptide hormone insulin across the mucosa. To demonstrate the use of chitosan reduced gold nanoparticles as carriers for drug delivery, we report herein the transmucosal delivery of insulin loaded gold nanoparticles. Gold nanoparticles were prepared using different concentrations of chitosan (from 0.01% w/v up to 1% w/v). The gold nanoparticles were characterized for surface plasmon band, zeta potential, surface morphology, in vitro diffusion studies and fluorescence spectroscopy. The in vivo studies in diabetic male Wistar rats were carried out using insulin loaded chitosan reduced gold nanoparticles. Varying concentrations of chitosan used for the synthesis of gold nanoparticles demonstrated that the nanoparticles obtained at higher chitosan concentrations (>0.1% w/v) were stable showing no signs of aggregation. The nanoparticles also showed long term stability in terms of aggregation for about 6 months. Insulin loading of 53% was obtained and found to be stable after loading. Blood glucose lowering at the end of 2 h following administration of insulin loaded gold nanoparticles to diabetic rats was found to be 30.41 and 20.27% for oral (50 IU/kg) and nasal (10 IU/kg), respectively. Serum gold level studies have demonstrated significant improvement in the uptake of chitosan reduced gold nanoparticles. The synthesis of gold nanoparticles using a biocompatible polymer, chitosan would improve its surface properties for binding of biomolecules. Our studies indicate that oral and nasal administration of insulin loaded chitosan reduced gold nanoparticles has led to improved pharmacodynamic activity. Thus, chitosan reduced gold nanoparticles loaded with insulin prove to be promising in controlling the postprandial hyperglycemia.

                Author and article information

                Polymers (Basel)
                Polymers (Basel)
                22 August 2019
                September 2019
                : 11
                : 9
                Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa
                Author notes
                [* ]Correspondence: viness.pillay@ 123456wits.ac.za ; Tel.: +27-11-717-2274
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).



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