葡萄糖敏感苯硼酸基高分子纳米药物传输体系

近年来,智能葡萄糖敏感自调式药物传递系统备受关注。这种智能药物释放系统能够模拟胰腺分泌胰岛素的生理模式而精准调控药物释放并控制血糖水平,在糖尿病治疗中具有良好的应用前景。其中,苯硼酸(PBA)功能化的葡萄糖敏感高分子纳米载体成为近年来的研究热点之一。该类材料具有体系稳定、可长期储存、可逆的葡萄糖敏感性能等优势。根据响应因素不同,葡萄糖敏感药物传递系统可分为pH响应、温度响应和光响应等类型。本文重点介绍了基于PBA的葡萄糖敏感高分子纳米药物载体的发展过程、性能和应用,并对该领域的发展前景进行了展望。     

Permeability and conductivity of red blood cell templated polyelectrolyte capsules coated with supplementary layers

The permeability of ions and small polar molecules through polyelectrolyte multilayer capsules templated on red blood cells was studied by means of confocal microscopy and electrorotation. Capsules were obtained by removing the cell after polyelectrolyte multilayer formation by means of NaOCl treatment. This procedure results in cross-linking of poly(allylamine hydrochloride) (PAH) molecules and destroying poly(styrene sulfonate) (PSS) within the multilayer. Capsules are obtained being remarkably different from layer-by-layer (LbL) capsules. These capsules are rather permeable for low as well as for high molecular weight species. However, upon adsorption of extra polyelectrolyte layers the permeability decreased remarkably. The assembly of six supplementary layers of PAH and PSS rendered the capsule almost impermeable for fluorescein. Resealing by supplementary layers is a potential means for filling and release control. By means of electrorotation measurements, it was shown that the capsule walls obtained isolating properties in electrolyte solutions. Conclusions are drawn concerning the mechanism of permeability through cell templated polyelectrolyte multilayer capsules.     

Chemosensors and biosensors based on polyelectrolyte microcapsules containing fluorescent dyes and enzymes

The concept of enzyme-assisted substrate sensing based on use of fluorescent markers to detect the products of enzymatic reaction has been investigated by fabrication of micron-scale polyelectrolyte capsules containing enzymes and dyes in one entity. Microcapsules approximately 5 μm in size entrap glucose oxidase or lactate oxidase, with peroxidase, together with the corresponding markers Tris(4,7-diphenyl-1,10-phenanthroline)ruthenium(II) dichloride (Ru(dpp)) complex and dihydrorhodamine 123 (DHR123), which are sensitive to oxygen and hydrogen peroxide, respectively. These capsules are produced by co-precipitation of calcium carbonate particles with the enzyme followed by layer-by-layer assembly of polyelectrolytes over the surface of the particles and incorporation of the dye in the capsule interior or in the multilayer shell. After dissolution of the calcium carbonate the enzymes and dyes remain in the multilayer capsules. In this study we produced enzyme-containing microcapsules sensitive to glucose and lactate. Calibration curves based on fluorescence intensity of Ru(dpp) and DHR123 were linearly dependent on substrate concentration, enabling reliable sensing in the millimolar range. The main advantages of using these capsules with optical recording is the possibility of building single capsule-based sensors. The response from individual capsules was observed by confocal microscopy as increasing fluorescence intensity of the capsule on addition of lactate at millimolar concentrations. Because internalization of the micron-sized multi-component capsules was feasible, they could be further optimized for in-situ intracellular sensing and metabolite monitoring on the basis of fluorescence reporting.     

Effect of shear stress on adhering polyelectrolyte capsules

A parallel plate flow chamber was implemented to study the deformation and adhesion of individual spherical hollow polyelectrolyte multilayered shells adhering to a coated surface. The device provides a well-defined laminar flow allowing the determination of the shear stress to which the capsules are being exposed up to 15 N/m(2). The results of the investigations indicate a strong dependence of the adhesion and mechanical resistance on the capsule size and wall thickness. Thin walled capsules, constituted of 8 polyelectrolyte layers (thickness congruent with 12 nm), are immediately deformed when exposed to flow while thick capsules, constituted of 16 layers (thickness congruent with 24 nm), of equal dimensions are detached from the surface for drag forces below 50 nN. It was observed that adhering capsules exposed to flow undergo an increase in their adhesion area in the direction of flow, resulting in rolling of the capsules. It was also found that the resistance of the capsules decreases after acetone treatment, indicating a weakening of the polyelectrolyte multilayer structure in the presence of this solvent.     

A facile route to synthesize silver nanoparticles in polyelectrolyte capsules

We are reporting a novel green approach to incorporate silver nanoparticles (NPs) selectively in the polyelectrolyte capsule shell for remote opening of polyelectrolyte capsules. This approach involves in situ reduction of silver nitrate to silver NPs using PEG as a reducing agent (polyol reduction method). These nanostructured capsules were prepared via layer by layer (LbL) assembly of poly(allylamine hydrochloride) (PAH) and dextran sulfate (DS) on silica template followed by the synthesis of silver NPs and subsequently the dissolution of the silica core. The size of silver nanoparticles synthesized was 60±20 nm which increased to 100±20 nm when the concentration of AgNO(3) increased from 25 mM to 50 mM. The incorporated silver NPs induced rupture and deformation of the capsules under laser irradiation. This method has advantages over other conventional methods involving chemical agents that are associated with cytotoxicity in biological applications such as drug delivery and catalysis.     

Motion‐Based,High‐Yielding,and Fast Separation of Different Charged Organics in Water

We report a self‐propelled Janus silica micromotor as a motion‐based analytical method for achieving fast target separation of polyelectrolyte microcapsules, enriching different charged organics with low molecular weights in water. The self‐propelled Janus silica micromotor catalytically decomposes a hydrogen peroxide fuel and moves along the direction of the catalyst face at a speed of 126.3 μm s^?1. Biotin‐functionalized Janus micromotors can specifically capture and rapidly transport streptavidin‐modified polyelectrolyte multilayer capsules, which could effectively enrich and separate different charged organics in water. The interior of the polyelectrolyte multilayer microcapsules were filled with a strong charged polyelectrolyte, and thus a Donnan equilibrium is favorable between the inner solution within the capsules and the bulk solution to entrap oppositely charged organics in water. The integration of these self‐propelled Janus silica micromotors and polyelectrolyte multilayer capsules into a lab‐on‐chip device that enables the separation and analysis of charged organics could be attractive for a diverse range of applications.     

Protein Templated Au-CuO Bimetallic Nanoclusters toward Neutral Glucose Sensing

In this study, the application of bovine serum albumin (BSA) as a carrier to glucose-sensitive materials for the detection of glucose was proposed. Au-CuO bimetallic nanoclusters (Au-CuO/BSA) were prepared using BSA as a template, the new sensing material (Au-CuO/BSA/MWCNTs) was synthesized by mixing with multi-walled carbon nanotubes (MWCNT) and applied to non-enzymatic electrochemical sensors to detect glucose stably and effectively under neutral condition. The scanning electron microscopy was used to investigate the morphology of the synthesized nanocomposite. The electrochemical properties of the sensor were studied by cyclic voltammetry. Glucose detection experiments show that Au-CuO/BSA/MWCNTs/Au electrode has good glucose detection ability, stability, accuracy, repeatability, and high selectivity in neutral environment. Unlike existing glucose-sensitive materials, due to the use of BSA, the composite material is firmly fixed to the electrode surface without a Nafion solution, which reduces the current blocking effect on the modified electrode. The composite materials can be effectively preserved for extremely long periods, higher than 80% activity is maintained at room temperature in a closed environment for 3 to 4 months, due to the special effects of BSA. In addition, the feasibility of using BSA in glucose-sensitive materials is confirmed.     

Mechanistic insights into the novel glucose-sensitive behavior of P(NIPAM-co-2-AAPBA)

A glucose-sensitive polymer,poly(N-isopropylacrylamide-co-2-acrylamidophenylboronic acid)(P(NIPAM-co-2-AAPBA)),was synthesized by reversible addition fragmentation chain transfer(RAFT) copolymerization.Addition of glucose results in reduced solubility and hence increased turbidity,rather than the normal increase in solubility(decreased turbidity) observed for other PBA-based glucose-sensitive polymers.The novel glucose-sensitive behavior is explained by a new mechanism,in which glucose acts as an additive and depresses the lower critical solution temperature(LCST) of the polymer,instead of increasing solubility by increasing the degree of ionization of the PBA groups.Experimental and theoretic analysis for the influence of glucose on the thermal behavior of P(NIPAM-co-2-AAPBA) reveals that glucose depresses the LCST of P(NIPAM-co-2-AAPBA) copolymers in a two-stage manner,a fast decrease at low glucose concentrations followed by a slow decrease at high glucose concentrations.For low glucose concentrations,the binding of glucose with PBA groups on the polymer chain increases the number of glucose molecules proximal to the polymer which influences the thermal behavior of the polymer,causing a rapid decrease in LCST.Importantly,the transition occurs at a glucose concentration equal to the reciprocal of the binding constant between PBA and glucose,thus providing a novel method to determine the binding constant.Other saccharides,including mannose,galactose and fructose,also depress the LCST of P(NIPAM-co-2-AAPBA) copolymer in the same way.     

Hydrothermal-induced structure transformation of polyelectrolyte multilayers: from nanotubes to capsules

The assembled polyelectrolyte nanotubes composed of poly(styrenesulfonate) and poly(allylamine hydrochloride) multilayers by using the layer-by-layer assembly combined with the porous template method can be transformed into capsules by a high-temperature treatment. Scanning electron microscopy and confocal laser scanning microscopy images revealed the whole transition process. The structure transformation of polyelectrolyte multilayers after annealing can be initiated by the input of thermal energy which leads to a breakage of ion pairs between oppositely charged polyelectrolyte groups. The transition process from tubes to capsules is supposed to be driven by the Raleigh instability and leads to the generated polyelectrolyte capsules with different sizes.     

From the 2-dimensional unstable polyelectrolyte multilayer to the 3-dimensional stable dry polyelectrolyte capsules

Polystyrene-poly(acrylic acid)/poly(allylamine hydrochloride) polyelectrolyte multilayer was found to be instable and apt to reconstruct in the pure water. By depositing polystyrene-poly(acrylic acid)/poly(allylamine hydrochloride) multilayer on the polystyrene-poly(acrylic acid) hybrid CaCO(3) templates, novel polyelectrolyte capsules could be prepared after the removal of the templates. The resultant capsules could keep their three-dimensional (3D) spherical shape after being dried at room temperature, dramatically different from the conventional polyelectrolyte capsules based on nonhybrid templates by layer-by-layer procedure. The instable polyelectrolyte multilayer, hybrid templates, and assembly cycles were demonstrated to be three indispensable factors responsible for the formation of this type of 3D stable capsules. The formation mechanism was also discussed in this study.     

Incorporation of Naphthalocyanine into Shells of Polyelectrolyte Capsules and Their Disruption under Laser Radiation

Different methods have been proposed for the incorporation of a dye, vanadyl tetra-5,14,23,32-phenyl-2,3-naphthalocyanine, into the shells of polyelectrolyte capsules. Capsule preparation conditions have been selected to provide efficient incorporation of the dye and stability of capsules to aggregation. A suspension of the capsules has been irradiated with lasers operating at wavelengths belonging to the near-infrared spectral region. It has been found that the capsules can be disrupted under the irradiation. Continuous and pulsed laser radiations have been shown to have different effects on the capsules.     

Polyelectrolyte capsules made of two biocompatible natural polymers

In this study the influence of the experimental conditions on the obtention of polyelectrolyte multilayer capsules was investigated. Two ways of the simple coacervation method was used to obtain spherical capsules involving chitosan and hyaluronan, chitosan being inside the particle covered by a hyaluronan layer to increase the biocompatibility. The ¹H-NMR spectroscopy confirmed a polyelectrolyte complex formation and the optical microscopy shows that the complexed capsules have good sphericity with average diameters ranging from 590 at 1550 μm in the experimental conditions adopted. One can observe that in the acid medium the complexed capsules are much stable than the chitosan beads. The structures described provide a starting point for the design and fabrication of complexed capsules made of two biocompatible natural polymers with potential applicability in medical or pharmaceutical applications. Few diffusion experiments demonstrated that the complexed layer controls the diffusion of dextran included in the chitosan inner domain.     

Self-assembled polymer membrane capsules inflated by osmotic pressure

We fabricate and characterize capsules that are composite membranes, made of a polymer network stabilized by adsorption to colloids and inflated by osmotic pressure from internal free polyelectrolyte; here, poly-l-lysine forms the network and inflates the capsules. To assess these capsules' properties and structure, we deform capsules using microcantilevers and use finite element modeling to describe these deformations. Additional experimental tests confirm the model's validity. These capsules' resilient response to mechanical forces indicates that loading and shear should be good triggers for the release of contents via deformation. The osmotic pressure inflating these capsules has the potential to trigger release of contents via deflation in response to changes in the capsules' environment; we demonstrate addition of salt as a trigger for deflating capsules. Because these capsules have a variety of release triggers available and the technique used to fabricate them is very flexible and allows high encapsulation efficiency, these capsules have very high potential for application in many areas.     

胶束增强型聚电解质胶囊的结构研究

研究了胶束增强型聚电解质(PAH/PSS和PADA/PSS)胶囊在不同溶液环境中的形貌变化,发现这种新型的胶囊具有迥异于传统聚电解质胶囊的囊壁结构;研究了二维聚电解质复合膜与模板溶解液中嵌段共聚物PS-b-PAA胶束之间的相互作用,发现胶束层可以通过静电力与聚电解质胶囊囊壁相互作用.同时,模拟模板溶出后聚电解质胶囊内部的环境条件,研究了嵌段共聚物胶束在胶囊内部的存在状态及其在透析过程中的变化规律,认为共聚物可以通过疏水作用沉积于聚电解质复合膜的内壁,并通过Ca2+离子的桥联作用稳定,也就是在聚电解质复合膜层基础上又形成了一层胶束层.即这种胶束增强型聚电解质微胶囊的囊壁是由聚电解质层和胶束层所形成的双层结构.用这种双层结构模型,我们合理解释了胶囊在高盐离子浓度下的形貌变化.     

Preparation of glucose-sensitive microcapsules with a porous membrane and functional gates

A glucose-sensitive microcapsule with a porous membrane and with linear-grafted polyacrylic acid (PAAC) chains and covalently bound glucose oxidase (GOD) enzymes in the membrane pores acting as functional gates was successfully prepared. Polyamide microcapsules with a porous membrane were prepared by interfacial polymerization, PAAC chains were grafted into the pores of the microcapsule membrane by plasma-graft pore-filling polymerization, and GOD enzymes were immobilized onto the PAAC-grafted microcapsules by a carbodiimide method. The release rates of model drug solutes from the fabricated microcapsules were significantly sensitive to the existence of glucose in the environmental solution. In solution, the release rate of either sodium chloride or VB(12) molecules from the microcapsules was low but increased dramatically in the presence of 0.2mol/L glucose. The prepared PAAC-grafted and GOD-immobilized microcapsules showed a reversible glucose-sensitive release characteristic. The proposed microcapsules provide a new mode for injection-type self-regulated drug delivery systems having the capability of adapting the release rate of drugs such as insulin in response to changes in glucose concentration, which is highly attractive for diabetes therapy.     

Microcontainers with electrochemically reversible permeability

The present study demonstrates a novel application of polyelectrolyte microcapsules as microcontainers with electrochemically reversible flux of redox active materials into and out of the capsule volume. Incorporation of the capsules inside the conducting polymer (polypyrrole) film results in a new composite electrode combining electrocatalytic and conducting properties of the polypyrrole with the storage and release properties of the capsules. This electrode, if loaded with electrochemical fuels, can possess electrochemically controlled switching between "open/closed" states of the capsule shell and be of practical interest for a new type of chemically rechargeable batteries or fuel cells. A special explanation for the potential depending loading and unloading of the capsule inner volume may be related to the fact that the polyelectrolyte capsules experience a potential gradient in the polypyrrole matrix within which the polyions of the shell can be moved.     

Mechanical properties of polyelectrolyte-filled multilayer microcapsules studied by atomic force and confocal microscopy

By using a combination of atomic force and confocal microscopy, we explore the deformation properties of multilayer microcapsules filled with a solution of strong polyelectrolyte. Encapsulation of polyelectrolyte was performed by regulation of the multilayer shell permeability in water-acetone solutions. The "filled"capsules prepared by this method were found to be stiffer than "hollow" ones, which reflects the contribution of the excess osmotic pressure to the capsule stiffness. The force-deformation curves contain three distinct regimes of reversible, partially reversible, and irreversible deformations depending on the degree of compression. The analysis of the shape of compressed capsules and of the inner polyelectrolyte spacial distribution allowed one to relate the deformation regimes to the permeability of the multilayer shells for water and inner polyelectrolyte at different stage of compression.     

胶束增强型聚电解质胶囊对罗丹明B的包埋和释放

研究了胶束增强型的聚电解质胶囊对正电荷小分子罗丹明B的包埋和释放情况. 胶囊对正电荷水溶性物质罗丹明B的包埋动力学和包埋量的研究结果表明, 这种胶束增强型聚电解质胶囊能够快速而高效地包埋水溶性物质. 释放研究结果表明, 胶囊在不同的pH条件下的释放行为有一定的区别, 但趋势相同, 分为突释区、释放诱导区、快速释放区和缓释区, 呈现多区释放, 前期胶囊的突释现象相当明显. 同时, 盐离子的浓度对胶囊的释放行为影响不大.     

Entrapment of α‐Chymotrypsin into Hollow Polyelectrolyte Microcapsules

Stable hollow polyelectrolyte capsules were produced by the layer‐by‐layer assembling of non‐biodegradable polyelectrolytes – poly(allylamine) and poly(styrenesulfonate) on melamine formaldehyde microcores followed by the core decomposition at low pH. A proteolytic enzyme, α‐chymotrypsin, was encapsulated into these microcapsules with high yields of up to 100%. The encapsulation procedure was based on the protein adsorption onto the capsule shells and on the pH‐dependent opening and closing of capsule wall pores. The protein in the capsules retained a high activity, and thermo‐ and storage stability. The nanostructured polyelectrolyte shell protected the proteinase from a high molecular weight inhibitor. Such enzyme‐loaded capsules can be used as microreactors for biocatalysis.     

Release mechanisms for polyelectrolyte capsules

Polyelectrolyte capsules have recently been introduced as new microscopic vehicles which could have high potential in the biomedical field. In this critical review we give an introduction to the layer-by-layer (LbL) technique which is used to fabricate these polyelectrolyte capsules as well as to the different triggers that have been exploited to obtain drug release from these capsules. Furthermore, other types of triggered delivery systems are compared and critically discussed with regard to their clinical relevance. (171 references.).