4-(Hydroxymethyl)phenylboronic acid

Disruption of intestinal homeostasis is an important event in the development of inflammatory bowel disease (IBD), and genistein (GEN) is a candidate medicine to prevent IBD. However, the clinical application of GEN is restricted owing to its low oral bioavailability. Herein, a reactive oxygen species (ROS)-responsive nanomaterial (defined as GEN-NP2) containing superoxidase dismutase-mimetic temporally conjugated β-cyclodextrin and 4-(hydroxymethyl)phenylboronic acid pinacol ester-modified GEN was prepared. GEN-NP2 effectively delivered GEN to the inflammation site and protected GEN from rapid metabolism and elimination in the gastrointestinal tract. In response to high ROS levels, GEN was site-specifically released and accumulated at inflammatory sites. Mechanistically, GEN-NP2 effectively increased the expression of estrogen receptor β (ERβ), simultaneously reduced the expression of proinflammatory mediators (apoptosis-associated speck-like protein containing a CARD (ASC) and Caspase1-p20), attenuated the infiltration of inflammatory cells, promoted autophagy of intestinal epithelial cells, inhibited the secretion of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), modulated the gut microbiota, and ultimately alleviated colitis. In addition, the oral administration of these nanoparticles showed excellent safety, thereby providing confidence in the further development of precise treatments for IBD.

Background: It has been reported that boron induces changes in the immune response, including in inflammatory processes. Recently, the effect of boric acid has been documented on the differentiation of lymphocyte clusters in mice and rats. However, the differences among boron-containing compounds (BCC) have been poorly explored. Methods: In this study, we analyzed the effects after oral administration of boric acid (BOR), methylboronic (MET), 3-thyenylboronic (3TB), 4-hydroxymethyl-phenylboronic (4MP) and 4-methanesulfonyl-phenylboronic (4SP) acids on the populations of lymphocytes from spleen and Peyer's patch (PP) as well as on antibodies. Groups of six male BALB/c were orally treated with 4.6 mg/kg of body weight with BOR, MET, 3TB, 4MP, and 4SP/daily for 10 days or vehicle (VEH) as a control group. After euthanasia, the spleen and small intestine were dissected. We conducted flow cytometry assays to assess B, CD3+ T, CD4+ T, and CD8+ T cells. Levels of IgG and IgM in serum, and IgA in intestinal fluid samples were analyzed by enzyme immunoassay. Results: In particular, we observed the effects of the administration of boronic acids on the number of lymphocytes; these changes were more notable in spleen than in PP. We found different profiles for each boron-containing compound, that is BOR induced an increase in the percentage of CD8+ T and CD19+/IgA+ cells in spleen, but a decrease in CD8+ T and B220+/CD19+ cells in PP. Meanwhile MET induced a decrease of CD4+ T in spleen, but induced an increase of CD4+ T cells and a decrease in the number of CD8+ T cells in PP. Boronic acids with an aromatic ring moiety induced changes in serum immunoglobulins levels, while 3TB acid induced a notable increase in S-IgA. Conclusions: Effects in lymphocyte populations and antibodies are different for each tested compound. These results highlight the establishment of the necessary structure-activity relationship for BCC as immunomodulatory drugs. This is relevant in the biomedical field due to their attractiveness for selecting compounds to develop therapeutic tools.

The present study describes the synthesis, self-assembly and responsiveness to glucose and lactic acid of biocompatible and biodegradable block copolymer micelles using phenylboronic ester as the linkage between hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic poly(ethylene oxide) (PEO). The PCL block with pendant phenylboronic acid (PCLBA) was synthesized by combining ε-caprolactone (ε-CL) ring-opening polymerisation (ROP), using 4-hydroxymethyl(phenylboronic) acid pinacolate as the initiator, and pinacol deprotection. The glucose-terminated PEO (PEOGlc) was prepared by 1,3-dipolar, Cu(i)-catalysed, alkyne-azide cycloaddition of α-methoxy-ω-propargyl poly(ethylene oxide) and 1-azido-1-deoxy-d-glucopyranose. All new compounds were evaluated by 1H NMR spectroscopy and by SEC analysis. PCLBA and PEOGlc blocks were linked in NaOH acetone solution, which was indirectly confirmed by Alizarin Red S fluorescence and directly by 1H NMR spectroscopy. Dialysis against Milli-Q water induced the self-assembly of PCLBA-b-PEOGlc nanoparticles, which were characterised by static (SLS) and dynamic (DLS) light scattering and by cryogenic transmission electron microscopy (cryo-TEM). Furthermore, the microscopic properties of the charged interface between the hydrophobic PCLBA core and the hydrophilic PEOGlc shell were examined by electrophoretic light scattering (zeta potential) and by fluorescence spectroscopy using the fluorescent probe 5-(N-dodecanoyl)aminofluorescein (DAF) as a pH indicator. Subsequently, the nanoparticles were transferred to a phosphate buffer saline (PBS) solution supplemented with different concentrations of glucose to simulate the physiological conditions in blood or lactic acid to simulate acidic cytosolic or endosomal conditions in tumour cells. Adding a surplus of glucose or lactic acid, which competitively binds to PBA, removes the stabilising hydrophilic PEOGlc blocks, thereby triggering marked nanoparticle aggregation. However, the rate of aggregation induced by lactic acid is considerably faster than that induced by glucose, as confirmed by light scattering. Thus, this novel block copolymer may contribute to the field of selective, lactic acid- and/or glucose-responsive drug delivery vehicle design under both pathological and physiological conditions.