A novel glucose (Glc)-responsive gel formed by worm-like micelles (WLMs) has the potential to provide a self-regulating insulin delivery system. We have prepared a WLM gel system using 75 mM cetyltrimethylammonium bromide, 75 mM phenylboronic acid, and water. At pH 9.4, this gel-like system was highly viscous and supported its own weight, and dynamic viscoelasticity measurement indicated that it contained long and entangled WLMs. The visual observation of gels prepared to include >6 mM Glc revealed that these adopted a sol-like appearance, whereas those prepared to include a control compound (2-10 mM diethylene glycol) retained their gel-like appearance. The storage modulus ( G') of this system decreased as the Glc concentration increased (2-10 mM), indicating a gradual shortening of the WLMs. In vitro release was evaluated using a test compound (fluorescein isothiocyanate dextran) in a microsized flow system. By 120 min, the release of this compound from the WLM gel was around 27-fold greater in the presence of 100 mM Glc than without Glc or with 100 mM diethylene glycol. This demonstrated the successful preparation of a WLM gel that showed an altered drug release rate, depending on Glc concentration.

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Previous studies have shown that reversible chemical bond formation between phenylboronic acid (PBA) and 1,3-diol can be utilized as the driving force for the preparation of layer-by-layer (LbL) films. The LbL films composed of a PBA-appended polymer and poly(vinyl alcohol) (PVA) disintegrated in the presence of sugar. This type of LbL films has been recognized as a promising approach for sugar-responsive drug release systems, but an issue preventing the practical application of LbL films is combining them with insulin. In this report, we have proposed a solution for this issue by using PBA-appended insulin as a component of the LbL film. We prepared two kinds of PBA-appended insulin derivatives and confirmed that they retained their hypoglycemic activity. The LbL films composed of PBA-appended insulin and PVA were successfully prepared through reversible chemical bond formation between the boronic acid moiety and the 1,3-diol of PVA. The LbL film disintegrated upon treatment with sugars. Based on the results presented herein, we discuss the suitability of the PBA moiety with respect to hypoglycemic activity, binding ability, and selectivity for D-glucose.Key words layer-by-layer; phenylboronic acid; insulin; sugar response; smart materialThe layer-by-layer (LbL) deposition technique has attracted considerable interest for the preparation of nano-sized multilayer films on solid surfaces.1,2) The LbL deposition technique usually leverages the electrostatic interactions between oppositely charged molecules. This type of LbL films is stable on the solid support unless the pH of the surrounding solution is changed, which is advantageous for the construction of thin stable films. However, the good stability of the films, which need to be disintegrated for drug release, causes an issue for drug delivery applications.An LbL film that disintegrates upon exposure to specific stimuli is desirable for drug delivery systems, but requires a reversible driving force for LbL film.3) To meet this demand, the incorporation of phenylboronic acid (PBA) is a promising approach. [4][5][6][7][8][9][10] PBA derivatives show binding ability for the 1,2-diol, and 1,3-diol of sugars, which can result in the formation of a cyclic ester even in aqueous solution. 11,12) The cyclic ester formation is a reversible reaction, which is suitable for stimuli-responsive LbL films. For example, Anzai's group has prepared LbL films composed of a PBA-modified amine dendrimer and poly(vinyl alcohol) (PVA) through interaction between PBA and the 1,3-diol of PVA with great success. 7-9)This LbL film disintegrated when the film was immersed in sugar solutions, which is driven by the displacement of PVA by sugar on the PBA moiety.

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We previously found that indole-3-acetic acid (IAA) produced from tryptophan by gut microbiota decreases the expression of tumor necrosis factor alpha (TNFα), which is implicated in the pathogenesis of colorectal cancer (CRC). The present study aimed to determine IAA involvement in the proliferation of CRC-derived Caco-2 cells. Cell proliferation was suppressed by IAA, whereas IAA-induced aryl hydrocarbon receptor (AhR) activation had no impact. IAA activated extracellular signal-related (ERK) and c-Jun N-terminal (JNK) kinases, but not p38. Toll-like receptor 4 (TLR4) may be required to activate ERK and JNK, but only the TLR4-JNK pathway might elicit the anti-proliferative effects of IAA. Thus, IAA may be a ligand for TLR4 that contributes to inhibiting CRC cell proliferation by activating TLR4-mediated JNK. Because IAA did not induce cytotoxicity, inhibiting cell cycle progression might affect the anti-proliferative capacity of IAA. Therefore, colonic IAA accumulation might help to prevent CRC development and progression.