Phenylboronic Acid-Based Complex Micelles with Enhanced Glucose-Responsiveness at Physiological pH by Complexation with Glycopolymer

Ma, Rujiang; Yang, Hao; Li, Zhong; Gan, Liangbing; Sun, Xiuzhu; Liu, Xiaojun; An, Yingli; Shi, Linqi

doi:10.1021/bm3012715

Cited by 123 publications

(139 citation statements)

References 41 publications

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“…Polymers based on PBA retain this glucose sensitivity; further, they generally possess high stability and can be structurally very versatile, and thus can be used to develop a broad range of systems. 17,18 Unfortunately, glucose-sensitive PBA polymers face a number of challenges, including having shown some cytotoxicity. The pKa of PBA (~9.0) is much higher than the physiological pH, and thus, in the body, a PBA homopolymer is largely unionized.…”

Section: Introductionmentioning

confidence: 99%

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Glucose- and temperature-sensitive nanoparticles for insulin delivery

Wu¹,

Williams²,

Li³

et al. 2017

IJN

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Glucose- and temperature-sensitive polymers of a phenylboronic acid derivative and diethylene glycol dimethacrylate (poly(3-acrylamidophenyl boronic acid- b -diethylene glycol methyl ether methacrylate); p(AAPBA- b -DEGMA)) were prepared by reversible addition–fragmentation chain transfer polymerization. Successful polymerization was evidenced by 1 H nuclear magnetic resonance and infrared spectroscopy, and the polymers were further explored in terms of their glass transition temperatures and by gel permeation chromatography (GPC). The materials were found to be temperature sensitive, with lower critical solution temperatures in the region of 12°C–47°C depending on the monomer ratio used for reaction. The polymers could be self-assembled into nanoparticles (NPs), and the zeta potential and size of these particles were determined as a function of temperature and glucose concentration. Subsequently, the optimum NP formulation was loaded with insulin, and the drug release was studied. We found that insulin was easily encapsulated into the p(AAPBA- b -DEGMA) NPs, with a loading capacity of ~15% and encapsulation efficiency of ~70%. Insulin release could be regulated by changes in temperature and glucose concentration. Furthermore, the NPs were non-toxic both in vitro and in vivo. Finally, the efficacy of the formulations at managing blood glucose levels in a murine hyperglycemic diabetes model was studied. The insulin-loaded NPs could reduce blood glucose levels over an extended period of 48 h. Since they are both temperature and glucose sensitive and offer a sustained-release profile, these systems may comprise potent new formulations for insulin delivery.

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Section: Introductionmentioning

confidence: 99%

“…The pKa of PBA (~9.0) is much higher than the physiological pH, and thus, in the body, a PBA homopolymer is largely unionized. 18 This renders it insoluble, and therefore it has only a minimal interaction with glucose in solution, limiting its ability to respond to changes in the concentration of the latter.…”

Section: Introductionmentioning

confidence: 99%

Glucose- and temperature-sensitive nanoparticles for insulin delivery

Wu¹,

Williams²,

Li³

et al. 2017

IJN

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“…34 This demonstrated that the introduction of nitrogen atom adjacent the boronic acid via formation of imine bond by aldehyde and amino group induced most of the neutral R-B(OH) 2 being transformed into the anionic R-B(OH) 3 À which had a stronger tendency to combine 1,2-diols. 23 When CAPE was further added into the 1-BA/2-FPBA system, the peak of the N-B coordinated tetrahedral boron moved from 8.9 ppm to 14.4 ppm, indicating the formation of cyclic boronate. 34 The N-B coordination was favourable for the formation of boronate, and in return the boronate also could promote the N-B coordination by raising the electrophilicity, or the Lewis acidity, of the boron atom.…”

Section: Characterizationsmentioning

confidence: 98%

“…[23][24][25][26][27][28] Based on these properties, pH and GSHresponsive releases of CAPE were studied. The pH and GSHsensitive dissociation of the micelles can also be applied in a general manner to other 1,2-diol containing drugs, presenting a promising utility in biomedical eld.…”

Section: 12mentioning

confidence: 99%

Iminoboronate-based dual-responsive micelles via subcomponent self-assembly for hydrophilic 1,2-diol-containing drug delivery

Zhang

Liu

et al. 2017

RSC Adv.

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Amphiphilic block copolymer micelles in aqueous solution have been used extensively in delivery of hydrophobic drugs with the hydrophobic core serving as the reservoir. However, encapsulation of hydrophilic drugs by polymeric micelles with hydrophobic core is relatively difficult because of the poor interaction between them. Herein, we report a novel kind of pH/GSH dual-responsive complex micelles with a hydrophilic drug loaded, via direct subcomponent self-assembly of block copolymer poly(ethyleneglycol)-block-poly(L-lysine) (PEG-b-PLys), 2-formylbenzeneboronic acid (2-FPBA) and hydrophilic 1,2-diol-containing drugs (e.g. capecitabine (CAPE)) under physiological pH 7.4 based on the synergistic formation of an iminoboronate structure. The PEG-b-PLys/2-FPBA micelles without CAPE are well-characterized in terms of micellization mechanism, size, morphology, pH-and GSHresponsiveness. Encapsulation of CAPE by forming PEG-b-PLys/2-FPBA/CAPE complex micelles via synergistic formation of the iminoboronate structure is discussed and pH-and GSH-responsive drugrelease studies are carried out. The complex micelles are stable under physiological neutral conditions but could be destroyed in response to the stimuli of physiological acidic condition (pH 5.0) and/or glutathione (GSH) at pH 7.4. pH-and GSH-responsive drug-releases are successfully achieved. The drug-loaded complex micelles could be endocytosed by HepG2 cells and efficiently deliver hydrophilic drugs into them. This type of complex micelles could be used as a promising platform for the delivery of hydrophilic 1,2-diol-containing drugs.

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“…This delivery is also more resistant to enzymatic degradation, denaturation and immune recognition, which are major problems faced by insulin delivered through non-invasive administration. To design closedloop smart insulin delivery, insulin is embedded in a polymeric matrix that contains glucose-sensitive molecules, such as phenylboronic acid [56], glucose oxidase [55], and glucose binding proteins, mainly lectins [57] such as concanavalin A that possesses four glucose binding sites.…”

Section: Nascent Nanotechnology-based Approaches For Controlled Delivmentioning

confidence: 99%

Harnessing Structural Data of Insulin and Insulin Receptor for Therapeutic Designs

et al. 2015

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To lower blood glucose concentration, insulin binds to insulin receptor (IR) that possesses two distinct insulin binding sites to trigger downstream signaling events leading to an increased uptake of glucose into muscle and fat cells. Comprehensive understandings of structural and dynamic mechanisms of insulin and its receptor are essential to design therapeutic agents for treating and delaying the onset of diabetes that affects over 347 million people worldwide. No full-length IR structure is available hitherto. Harnessing the currently available and state-of-the-art sequence and structural data, we have reviewed the insulin, IR, its extracellular domains and transmembrane domain, to derive structure-based clues to regulate aberrant insulin and its receptor. To propose testable hypotheses and future experiments, we have performed literature review, text mining, multiple structural clustering and normal mode analysis on insulin and its receptor. It appears that insulin-receptor interaction involves allostery and conformational changes (including rotation and tilting) to overcome steric clashes. To target a particular aberrant isoform of IRs, we need to identify the subtle yet distinct differences between IR isoforms. To improve the life quality of diabetics, better structure-based designs of insulin mimetics, formulation and nanotechnology-based delivery are required; efforts to bring them to patients necessitate thorough structural understandings of insulin and its receptor.

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Phenylboronic Acid-Based Complex Micelles with Enhanced Glucose-Responsiveness at Physiological pH by Complexation with Glycopolymer

Cited by 123 publications

References 41 publications

Glucose- and temperature-sensitive nanoparticles for insulin delivery

Glucose- and temperature-sensitive nanoparticles for insulin delivery

Iminoboronate-based dual-responsive micelles via subcomponent self-assembly for hydrophilic 1,2-diol-containing drug delivery

Harnessing Structural Data of Insulin and Insulin Receptor for Therapeutic Designs

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