Triggered insulin release studies of triply responsive supramolecular micelles† Xian Jun Loh,‡ Mei-Hsuan Tsai,‡ Jes us del Barrio, Eric A. Appel, Tung-Chun Lee and Oren A. Scherman * Received 31st May 2012, Accepted 12th July 2012 DOI: 10.1039/c2py20380d The synthesis of a supramolecular double hydrophilic glucose responsive block copolymer (DHBC) held together by cucurbit[8]uril (CB[8]) ternary complexation and its subsequent self-assembly into micelles is described. The supramolecular block copolymer assembly consists of poly(N- isopropylacrylamide) (PNIPAAm) and poly(acrylamidophenyl boronic acid) (PAAPBA) as temperature and glucose responsive blocks, respectively, and poly(dimethylacrylamide) (PDMAAm) as a hydrophilic block. Drug release studies of insulin-loaded micelles using three external triggers were studied with release of insulin achieved by changing temperature, glucose concentration or by adding a competitive guest for CB[8]. This system offers good control over the release of insulin under physiological conditions (pH 7.4, 37  C). These exciting results suggest that this system could be a model for a clinically relevant drug delivery vehicle for diabetic treatment. 1 Introduction Diabetes mellitus (DM) is a metabolic disease whereby a person does not produce sufficient insulin or does not respond well to insulin produced in the body on the account of elevated blood glucose levels 1–3 leading to conditions, such as polyuria, poly- dipsia and polyphagia. Type I DM results from the body’s failure to produce insulin as a result patients require frequent injections of the hormone. It remains a challenge to develop systems that are able to release insulin in a triggered manner, in order to allay patient discomfort and the inconvenience of multiple injections every day. Glucose responsive polymers are highly attractive candidates for use in insulin delivery to patients as these poly- mers are able to release insulin in response to the blood glucose concentrations. Phenylboronic acid derivatives have been widely used as a sensing moiety for glucose. 4 Hydrophobic phenyl- boronic acid derivatives (A) produce water-soluble species (B) when complexed with hydroxyl ions below their pK a as illus- trated in Fig. 1. 5 The addition of glucose favours the formation of the stable water-soluble phenyl borate (C) between the phenyl boronic acid derivatives and glucose. When phenylboronic acid moieties are included in the main polymer chain, the polymer is endowed with glucose sensitivity which has potential applications in drug delivery. Recently, a variety of glucose-responsive hydrogels have been reported. 6–8 Kataoka et al. have embarked on a series of experiments to utilise phenylboronic acid derivatives at the physiological pH of 7.4, for potential glucose triggered release of insulin. 9–11 Several systems relying on micron or sub-micron particulate matter have been reported. For example, glucose and temperature sensitive microgels have been utilised for the development of self-regulated insulin delivery systems. 12,13 These systems release insulin when they are induced to swell under the application of either a glucose or temperature stimuli. Insulin can also be loaded into meso- porous silica particles for controlled delivery. These silica parti- cles serve as an insulin reservoir, and enzyme multilayers cross- linked with glutaraldehyde act as a valve to control the release of insulin in response to the external glucose level. 14 Insulin loaded nanoparticles derived from a copolymer of phenylboronic acid and sugar-based side chains were shown to be non-toxic and useful for glucose sensitive delivery. These nanoparticles self- assemble by forming cross-links between the pendant boronic acid groups and the free hydroxyl groups of the sugar, with insulin incorporated between the chains. When free glucose is added, it competitively binds with the boronic acid moieties, breaking the cross-links and swelling the nanoparticle, thus releasing an insulin payload. 15 Micelles are a highly desirable system for the encap- sulation and delivery of hydrophobic compounds. 16–18 Tempera- ture sensitive micelles can be fabricated by chemically conjugating Fig. 1 Formation of the boronic acid–glucose complex. Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. E-mail: oas23@cam.ac.uk; Tel: +44 (0)1223 331508 † Electronic supplementary information (ESI) available. See DOI: 10.1039/c2py20380d ‡ These authors contributed equally to this work. 3180 | Polym. Chem., 2012, 3, 3180–3188 This journal is ª The Royal Society of Chemistry 2012 Dynamic Article Links C < Polymer Chemistry Cite this: Polym. Chem., 2012, 3, 3180 www.rsc.org/polymers PAPER Published on 17 August 2012. Downloaded on 02/11/2015 18:38:27. View Article Online / Journal Homepage / Table of Contents for this issue