A Synthetic Approach Toward a Self‐Regulated Insulin Delivery System

Abstract

Stimuli-responsive “smart gels” that undergo physicochemical property changes in response to external stimuli can provide both a functional and structural basis for selfregulated materials and systems. Of particular interest are those materials sensitive to chemical stimuli, that is, the fluctuation in the concentration of specific biomolecules, that can mimic biofeedback systems, thus providing many attractive platforms for biomedical applications. Glucose has been a molecule of interest for decades owing to its relevance to the treatment of diabetes. Diabetes is not an infectious disease, but its rapidly increasing worldwide prevalence has been recognized as a pandemic, and thus diabetes poses a serious global health threat much like epidemics of truly infectious diseases, such as HIV/AIDS. Despite the necessity for the continuous and accurate glycemic control in the management of insulin-dependent diabetes mellitus (IDDM), the current palliative treatment relies almost solely on the patients self injection of insulin; this self injection not only impinges on the quality of life of the patient but also fails to precisely control the dose of insulin, where an overdose must be strictly avoided as it causes serious hypoglycemia. For the preparation of self-regulated insulin delivery systems, the following two approaches have historically prevailed. One is based on enzymatic reactions between glucose oxidase (GOD) and glucose, a similar rationale to those exploited in commercial glucose sensors. The other type utilizes carbohydrate-binding lectin proteins, such as concanavalin A (Con A), as a complementary binder to glucose. These protein-based materials eventually denature and lose activity, and thus are not practical for long-term use and storage. Another problem is the strong cytotoxicity of Con A; this cytotoxicity has, thus far, prevented any clinical applications of these materials. Herein we describe a totally synthetic alternative to these materials. Phenylboronic acid (PBA), a synthetic molecule capable of reversibly binding with 1,2or 1,3-cis-diols including glucose, is utilized as the molecular basis. Our previous studies have shown that the glucose-dependent shift in the equilibrium of PBA between the uncharged and anionically charged forms, when coupled with a properly amphiphilic three-dimensional backbone (or gel), could induce a reversible change in the volume of the gel. The resultant abrupt and rapid change in the hydration, under certain conditions, could cause a localized dehydration of the gel surface, that is, a so-called skin layer, thus offering a method to instantly control the permeation of gel-loaded insulin. This goal is a great challenge and relies on achieving sufficient glucose sensitivity under physiological pH and temperature, that is, pH 7.4 and 37 8C, while also fine tuning the system so it shows a gated response to the change in glucose concentration critically at the level of normoglycemia, i.e., ca. 1 gl . To achieve this goal, we have systemically explored the structure–property correlation by focusing on (meth)acrylamide-based hydrogels. The major efforts have been directed to controlling the apparent pKa of PBA; the pKa depends not only on chemical structure of PBA, but also on the state of hydration. To make the situation more complicated, in a hydrogel environment the degree of hydration is a function of (as well as temperature, ionic strength, pH, and sugar concentration) the hydrophilicity, rigidity, and density of the main chain components and the amount of PBA. Herein we describe a gel that meets all the above criteria; the chemical structure of this gel turned out to be a remarkably simple copolymer system. A smart gel has been shown to act as an artificial pancreas under conditions closely related to human glucose homeostasis. As illustrated in Figure 1a, PBA derivatives in water exist in equilibrium between uncharged (i) and anionically charged (ii) forms. Upon addition of glucose, only the charged PBA (ii) can form a stable complex with glucose (iii), and the formation of this complex results in an apparent decrease in the amount of anionically charged PBA (ii). On consumption of the phenylboronate (ii), the equilibrium between (i) and (ii) shifts toward the latter (ii). Since the complexed PBA (iii) is also anionically charged, further addition of glucose leads to a shift in the equilibrium (i + ii + iii) toward the phenylboronate anions (ii + iii), and a decrease in the amount of [*] Dr. A. Matsumoto, J. Nishida, Dr. H. Matsumoto, Dr. Y. Miyahara Institute of Biomaterials and Bioengineering Tokyo Medical and Dental University Kanda-surugadai 2-3-10, Chiyoda-ku, Tokyo 101-0062 (Japan) E-mail: miyahara.bsr@tmd.co.jp Dr. T. Ishii Department of Bioengineering, The University of Tokyo Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8656 (Japan)