Yingli An

Glucose-Responsive Micelles from Self-Assembly of Poly(ethylene glycol)-b-Poly(acrylic acid-co-acrylamidophenylboronic acid) and the Controlled Release of Insulin

Poly(ethylene glycol)-block-poly(acrylic acid-co-acrylamidophenylboronic acid) [PEG(114)-b-(PAA(63)-co-PAAPBA(107))] was synthesized by the modification of poly(ethylene glycol)-block-poly(acrylic acid) (PEG(114)-b-PAA(170)) with 3-aminophenylboronic acid (APBA). Glucose-responsive PEG(114)-b-(PAA(63)-co-PAAPBA(107)) self-assembled into core-shell micelles with the hydrophobic core composed of PAAPBA and hydrophilic shell composed of PEG in aqueous solution. The swelling and disaggregating behaviors of micelles responding to glucose were investigated by using light scattering in aqueous solution at pH 7.4. Characterization of insulin-loaded micelles and their drug release in solutions with various glucose concentrations were further studied. The results demonstrated that the drug release rate can be controlled by variation of glucose concentration.

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

Polymeric nanoparticles with glucose-responsiveness under physiological conditions are of great interests in developing drug delivery system for the treatment of diabetes. Herein, glucose-responsive complex micelles were prepared by self-assembly of a phenylboronic acid-contained block copolymer PEG-b-P(AA-co-APBA) and a glycopolymer P(AA-co-AGA) based on the covalent complexation between phenylboronic acid and glycosyl. The formation of the complex micelles with a P(AA-co-APBA)/P(AA-co-AGA) core and a PEG shell was confirmed by HNMR analysis. The glucose-responsiveness of the complex micelles was investigated by monitoring the light scattering intensity and the fluorescence (ARS) of the micelle solutions. The complex micelles displayed an enhanced glucose-responsiveness compared to the simple PEG-b-P(AA-co-APBA) micelles and the sensitivity of the complex micelles to glucose increased with the decrease of the amount of P(AA-co-AGA) in the compositions. The cytotoxicity of the polymers and the complex micelles was also evaluated by MTT assay. This kind of complex micelles may be an excellent candidate for insulin delivery and may find application in the treatment of diabetes.

Formation and catalytic activity of spherical composites with surfaces coated with gold nanoparticles

Micelle-supported gold composites with a polystyrene core and a poly(4-vinyl pyridine)/Au shell are synthesized using NaBH(4) to reduce a mixture of micelle and HAuCl(4) in acidic aqueous solution (pH approximately 2). The template micelle with a polystyrene core and a poly(4-vinyl pyridine) shell is formed by self-assembly of block copolymer polystyrene-block-poly(4-vinyl pyridine). The gold nanoparticles coated onto the surfaces of the composites possess an average diameter of about 15 nm. The composites are applied to catalyze the reduction of p-nitrophenol in the presence of NaBH(4), and the results indicate that the kinetic constant of the reaction increases when the composite concentration and the reaction temperature increase. In addition, research results also indicate that composites with high content of gold show higher catalytic activity and higher catalytic efficiency.

A glucose-responsive complex polymeric micelle enabling repeated on–off release and insulin protection

We developed a glucose-responsive complex polymeric micelle (CPM) through the self-assembly of two types of diblock copolymers, poly(ethylene glycol)-b-poly(aspartic acid-co-aspartamidophenylboronic acid) (PEG-b-P(Asp-co-AspPBA)) and poly(N-isopropylacrylamide)-b-poly(aspartic acid-co-aspartamidophenylboronic acid) (PNIPAM-b-P(Asp-co-AspPBA)). By controlling the weight ratio between PNIPAM and PEG (WPNIPAM/WPEG = 6/4), the block copolymers form complex micelles with a novel core–shell–corona structure. By following this structure, the continuous PNIPAM shell collapsed on the glucose-responsive P(Asp-co-AspPBA) core. As a result, the CPM exhibits a reversible swelling in response to changes in the glucose concentration, enabling the repeated on–off release of insulin regulated by glucose level. Furthermore, the CPM could effectively protect the encapsulated insulin against protease degradation. Therefore, this glucose-responsive CPM provides a simple and powerful strategy to construct a self-regulated insulin delivery system for diabetes treatment.

Fabrication of Complex Micelles with Tunable Shell for Application in Controlled Drug Release

At room temperature, diblock copolymers of PLA-b-PNIPAM and PEG-b-PLA self-assembled into complex micelles with a PLA core and a mixed PEG/PNIPAM shell. By increasing the temperature, these complex micelles could be converted into a core-shell-corona structure composed of a PLA core, a collapsed PNIPAM shell and a soluble PEG corona, and the PEG chains stretched from the inner core to outside, leading to the formation of PEG channels. The PEG channels could be used for the exchange of substance between the core and the external environment. Compared with core-shell micelles, complex micelles with a core-shell-corona structure could avoid the burst diffusion in the release of ibuprofen and inhibit the degradation of PLA by lipase to a certain extent.

Maintenance of Amyloid β Peptide Homeostasis by Artificial Chaperones Based on Mixed‐Shell Polymeric Micelles

The disruption of Aβ homeostasis, which results in the accumulation of neurotoxic amyloids, is the fundamental cause of Alzheimers disease (AD). Molecular chaperones play a critical role in controlling undesired protein misfolding and maintaining intricate proteostasis in vivo. Inspired by a natural molecular chaperone, an artificial chaperone consisting of mixed-shell polymeric micelles (MSPMs) has been devised with tunable surface properties, serving as a suppressor of AD. Taking advantage of biocompatibility, selectivity toward aberrant proteins, and long blood circulation, these MSPM-based chaperones can maintain Aβ homeostasis by a combination of inhibiting Aβ fibrillation and facilitating Aβ aggregate clearance and simultaneously reducing Aβ-mediated neurotoxicity. The balance of hydrophilic/hydrophobic moieties on the surface of MSPMs is important for their enhanced therapeutic effect.

pH/Sugar Dual Responsive Core-Cross-Linked PIC Micelles for Enhanced Intracellular Protein Delivery

Herein, a series of biocompatible, robust, pH/sugar-sensitive, core-cross-linked, polyion complex (PIC) micelles based on phenylboronic acid-catechol interaction were developed for protein intracellular delivery. The rationally designed poly(ethylene glycol)-b-poly(glutamic acid-co-glutamicamidophenylboronic acid) (PEG-b-P(Glu-co-GluPBA)) and poly(ethylene glycol)-b-poly(l-lysine-co-ε-3,4-dihydroxyphenylcarboxyl-L-lysine) (PEG-b-P(Lys-co-LysCA)) copolymers were successfully synthesized and self-assembled under neutral aqueous condition to form uniform micelles. These micelles possessed a distinct core-cross-linked core-shell structure comprised of the PEG outer shell and the PGlu/PLys polyion complex core bearing boronate ester cross-linking bonds. The cross-linked micelles displayed superior physiological stabilities compared with their non-cross-linked counterparts while swelling and disassembling in the presence of excess fructose or at endosomal pH. Notably, either negatively or positively charged proteins can be encapsulated into the micelles efficiently under mild conditions. The in vitro release studies showed that the release of protein cargoes under physiological conditions was minimized, while a burst release occurred in response to excess fructose or endosomal pH. The cytotoxicity of micelles was determined by cck-8 assay in HepG2 cells. The cytochrome C loaded micelles could efficiently delivery proteins into HepG2 cells and exhibited enhanced apoptosis ability. Hence, this type of core-cross-linked PIC micelles has opened a new avenue to intracellular protein delivery.

Effect of Coordination on the Glucose-Responsiveness of PEG-b-(PAA-co-PAAPBA) Micelles.

Poly(ethylene glycol)-block-poly(acrylic acid) (PEG-PAA) is modified by 3-aminophenylboronic acid (APBA) with different modification degrees, such as PEG(114) -b-(PAA(0.37) -co-PAAPBA(0.63) )(170) , PEG(114) -b-(PAA(0.23) -co-PAAPBA(0.77) )(170) and PEG(114) -b-(PAA(0.02) -co-PAAPBA(0.98) )(170) . Micelles self-assembled from these three copolymers possess glucose-responsiveness at varying pH values. Micelles self-assembled from PEG(114) -b-(PAA(0.37) -co-PAAPBA(0.63) )(170) have glucose-responsiveness at the physiological pH (7.4), endowing them with potential applications in the treatment of diabetes. (11) B magic-angle spinning nuclear magnetic resonance ((11) B MAS NMR) analysis indicates that interactions between PAAPBA segments and PAA segments induce boron changes from the trigonal planar form to the tetrahedral form, resulting in glucose-responsiveness of PEG(114) -b-(PAA(0.37) -co-PAAPBA(0.63) )(170) micelles at pH 7.4.

Core-shell-corona au-micelle composites with a tunable smart hybrid shell.

Micelles having a core of polystyrene and a mixed shell of poly(ethylene glycol) and poly(4-vinylpyridine) were formed through self-assembly of a triblock copolymer poly(ethylene glycol)- block-polystyrene- block-poly(4-vinylpyridine) in acidic water (pH 2). Reducing the HAuCl(4)-treated micelle solution leads to the formation of the Au-micelle composites with a core of polystyrene, a hybrid shell of poly(4-vinylpyridine)/Au/poly(ethylene glycol), and a corona of poly(ethylene glycol). The gold nanoparticles with controlled sizes were anchored to poly(4-vinylpyridine) to form the physically cross-linked hybrid shell. In aqueous solution, the hybrid shell is swollen and the swollen degree is sensitive to the pH condition. Under basic conditions, the channel in the hybrid shells of the composite is produced, which renders the composites a good catalytic activity. In addition, the composites also show good stability, unchanged hydrodynamic diameter, and surface plasmon absorption under different pH conditions.

Thermosensitive and pH-sensitive Au-Pd bimetallic nanocomposites.

The bimetallic nanoparticles were protected by a double stimuli-sensitive diblock copolymer, poly(N-isopropylacrylamide)-block-poly(4-vinylpyridine) (PNIPAM-b-P4VP), which was synthesized via the reversible addition-fragmentation chain transfer (RAFT) polymerization. The obtained nanocomposites were made up of bimetallic nanoparticles cross-linked P4VP core and PNIPAM shell. Energy-dispersive X-ray (EDX) spectra and UV-vis transmittance revealed the formed nanoparticles was truly bimetallic particles with incomplete core-shell structures, Au as core and Pd as shell, rather than the physical mixture of monometallic nanoparticles. Laser light scattering (LLS) demonstrated the nanocomposites exhibit both thermo and pH sensitivity. X-ray diffraction (XRD) clearly showed Au formed a high-ordered crystal while Pd fashioned amorphous aggregates. In addition, the bimetallic nanocomposites show special responsiveness for temperature and better catalytic activity than corresponding monometallic nanocomposites.