1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 A Glucose-Responsive Polymer Nanocarrier Based on Sulfonated Resorcinarene for Controlled Insulin Delivery Tatiana Yu. Sergeeva, [a] Rezeda K. Mukhitova, [a] Irek R. Nizameev, [b] Marsil K. Kadirov, [a] Anastasia S. Sapunova, [a] Alexandra D. Voloshina, [a] Timur A. Mukhametzyanov, [c] Albina Y. Ziganshina,* [a] and Igor S. Antipin [c] A nanocarrier (p(6SRA-5B)) for glucose-controlled insulin deliv- ery consists of sulfonated resorcinarenes (SRA) that are assembled into a spherical shell and are attached to each other with phenylboronate linkers. p(6SRA-5B) is stable in water and blood plasma at normal glucose concentrations. At high glucose levels (> 5 mM), p(6SRA-5B) dissociates into SRA and phenylboronates through competitive interaction with excess glucose. Insulin was successfully encapsulated into the cavity of p(6SRA-5B) and its release was investigated in water and blood plasma by NMR, UV, CD, and fluorescence spectroscopy. The results show that the dissociation of the nanocarrier and the insulin release occurs with an increase in glucose concentration. At 5 mM glucose, the nanocarrier is stable, and the insulin release does not exceed 10%. Increasing the glucose concen- tration to 7.5–10 mM results in a 40–100% insulin release. p (6SRA-5B) is thus a promising insulin nanocarrier for the treatment of type 1 diabetes. Introduction Insulin is one of the most important hormones, affecting metabolism in almost all tissues. [1] The main purpose of insulin is to keep glucose levels under control. Insulin secretion disorders, and consequently, increase in blood glucose results in the pathogenesis of type 1 diabetes. [2] The treatment of diabetes consists of a daily injection of insulin. However, the difficulty in controlling glucose surges and calculating the required dose of insulin causes many side effects. Nano- technology and nanomedicine provide an alternative way for diabetes therapy. [3–7] One of the most promising approaches is the creation of nanocarriers that release insulin at high glucose concentrations. [8–18] The structure of many carriers obtained consists of phenylboronic acid, [19–27] and their action is based on the interaction of boronates with glucose. [28–33] Boronic acid and their esters are sensitive to many carbohydrates containing cis- 1,2- and cis-1,3-diol fragments. However, only glucose exists in the blood, other carbohydrates undergo chemical transforma- tions to glucose and triglycerides in the liver. [34] Therefore, it is important to develop a carrier that is sensitive to glucose. Despite the many promising results, problems in the creation of effective insulin carriers still exist. They include low efficiency and loading capacity, biocompatibility, poor circula- tion in the blood and uncontrolled insulin release. Our group has developed the micro- and nanoemulsion synthesis of nanocarriers. [35,36] The principle consists in the self- assembly of amphiphilic resorcinarenes at the oil-water inter- face of the microemulsion. The polar or charged groups of resorcinarenes are direct to water while the hydrophobic tails are into the oil phase. The binding of the tails with responsive linkers gives the polymer nanocarrier sensitive to the stimuli. The stimuli act on the linkers, destroying the nanocarrier, which can be used for controlled drug release. Recently we developed a pH-driven molecular nanocarrier based on sulfonated resorcinarene and phenylboronic acid. [37] The nanocarrier is stable in water and releases substrates at low pH and in the presence of glucose. Unfortunately, the carrier obtained is unsuitable for the controlled delivery of insulin due to high sensitivity to glucose. Even a small concentration of glucose leads to its dissociation. Continue this research, we have created a new nanocarrier for insulin using similar reagents. We have varied the ration of reagents as well as reaction conditions, and we chose those for which the nano- carrier is stable at normal glucose level but it dissociates at high glucose concentration. The sulfonated resorcinarene used in the nanocarrier synthesis is non-toxic, [38] its synthesis consists of two simple steps with inexpensive reagents. [39] In this article, we report on the synthesis and properties of a glucose-sensitive nanocarrier and its application in insulin delivery. Results and Discussion The “oil-in-water” microemulsion method has been applied for the creation of nanocarrier for insulin (Ins) (Scheme 1). Triolein [a] T. Y. Sergeeva, R. K. Mukhitova, Prof. M. K. Kadirov, A. S. Sapunova, Dr. A. D. Voloshina, Dr. A. Y. Ziganshina Arbuzov Institute of Organic and Physical Chemistry FRC Kazan Scientific Center of RAS Arbuzov str. 8, Kazan 420088 (Russia) E-mail: az@iopc.ru [b] Dr. I. R. Nizameev Kazan National Research Technical University named after A.N. Tupolev – KAI K. Marx str. 10, Kazan 420111 (Russia) [c] Dr. T. A. Mukhametzyanov, Prof. I. S. Antipin A. M. Butlerov Institute of Chemistry Kazan Federal University Kremlevskaya str. 18, Kazan 420008 (Russia) Supporting information for this article is available on the WWW under https://doi.org/10.1002/cplu.201900428 Full Papers DOI: 10.1002/cplu.201900428 1560 ChemPlusChem 2019, 84,1560–1566 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim