Active loading and tunable release of doxorubicin from block copolymer vesicles

Vesicles are spherical bilayers that offer a hydrophilic reservoir, suitable for the incorporation of water-soluble molecules, as well as a hydrophobic wall that protects the loaded molecules from the external solution. The permeability of a vesicle wall made from polystyrene can be enhanced by adding a plasticizer such as dioxane. Tuning the wall permeability allows loading and release of molecules from vesicles to be controlled. In this study, vesicles are prepared from polystyrene(310)-b-poly(acrylic acid)(36) and used as model carriers for doxorubicin (DXR), a weak amine and a widely used anticancer drug. To increase the wall permeability, different amounts of dioxane are added to the vesicle solution. A pH gradient is created across the vesicle wall (inside acidic) and used as an active loading method to concentrate the drug inside the vesicles. The results show that a pH gradient of ca. 3.8 units can enhance the loading level up to 10-fold relative to loading in the absence of the gradient. After loading, the release of DXR from vesicles is followed as a function of the wall permeability. The diffusion coefficient of doxorubicin through polystyrene (D) is evaluated from the initial slope of the release curves; the value of D ranges from 8 x 10(-17) to 6 x 10(-16) cm(2)/s, depending on the degree of plasticization of the vesicle wall.     

Encapsulation of a Phase‐Change Material in Nanocapsules with a Well‐Defined Hole in the Wall for the Controlled Release of Drugs

As a class of biocompatible and biodegradable phase‐change materials, natural fatty acids have received considerable interest in recent years for temperature‐controlled release of drugs. However, the poor dispersibility and colloidal stability of their nanoparticles under physiological conditions place a major limitation on their applications in biomedicine. Herein, we report a facile method for encapsulating a mixture of two natural fatty acids (with a eutectic melting point at 39 °C) in a biocompatible, silica‐based nanocapsule to achieve both stable dispersion and controllable release of drugs. The nanocapsules have a well‐defined hole in the wall to ensure easy loading of fatty acids, together with multiple types of functional components such as therapeutics and near‐infrared dyes. The payloads can be released through the hole when the fatty acids are melted upon photothermal heating. The release profile can be controlled by varying the size of the hole and/or the duration of laser irradiation.     

Control of Drug Release through the In Situ Assembly of Stimuli‐Responsive Ordered Mesoporous Silica with Magnetic Particles

A site‐selective controlled delivery system for controlled drug release is fabricated through the in situ assembly of stimuli‐responsive ordered SBA‐15 and magnetic particles. This approach is based on the formation of ordered mesoporous silica with magnetic particles formed from Fe(CO)₅ via the surfactant‐template sol‐gel method and control of transport through polymerization of N‐isopropyl acrylamide inside the pores. Hydrophobic Fe(CO)₅ acts as a swelling agent as well as being the source of the magnetic particles. The obtained system demonstrates a high pore diameter (7.1 nm) and pore volume (0.41 cm³ g^?1), which improves drug storage for relatively large molecules. Controlled drug release through the porous network is demonstrated by measuring the uptake and release of ibuprofen (IBU). The delivery system displays a high IBU storage capacity of 71.5 wt %, which is almost twice as large as the highest value based on SBA‐15 ever reported. In vitro testing of IBU loading and release exhibits a pronounced transition at around 32 °C, indicating a typical thermosensitive controlled release.     

Polymer Nanoassembly as Delivery Systems and Anti‐Bacterial Toolbox: From PGMAs to MSN@PGMAs

Researches on cargo delivery systems have received burgeoning attention and advanced rapidly. For synthetic nanodevices, polymer nanoassemblies and their inorganic‐organic hybrid materials, especially smart mesoporous silica nanoparticle (MSN)‐polymer hybrids (e. g., MSN@PGMAs), have attracted increasing attention in recent years. Their superior characteristics and unique features such as dynamic transition of morphology endow them the ability to efficiently entrap cargo molecules and undergo smart cargo delivery and release in response to various external stimuli. In this Personal Account, we present our recent research progress in the construction of cargo delivery systems based on polymers, poly(glycidyl methacrylate) (PGMA) and its derivatives in particular, ranging from polymer nanoparticles, reverse micelles, to vesicles and reverse vesicles, and their performance in the delivery and controlled release of model molecules and therapeutic agents. Significantly, MSN‐PGMA hybrid nanoassemblies (MSN@PGMAs), constructed with the aid of atom transfer radical polymerization, host‐guest interactions, or layer‐by‐layer self‐assembly techniques, and their potential bio‐related applications and anti‐bacterial applications as new nanocarriers are reviewed. Finally, the prospects and challenges of such nanoplatforms are also discussed.     

A Dynamic Hydrogen‐Bonded Azo‐Macrocycle for Precisely Photo‐Controlled Molecular Encapsulation and Release

A light‐responsive system constructed from hydrogen‐bonded azo‐macrocycles demonstrates precisely controlled propensity in molecular encapsulation and release process. A significant decrease in the size of the cavity is observed in the course of the E→Z photoisomerization based on the results from DFT calculations and traveling wave ion mobility mass spectrometry. These macrocyclic hosts exhibit a rare 2:1 host–guest stoichiometry and guest‐dependent slow or fast exchange on the NMR timescale. With the slow host–guest exchange and switchable shape change of the cavity, quantitative release and capture of bipyridinium guests is achieved with the maximum release of 68 %. This work underscores the importance of slow host–guest exchange on realizing accurate release of organic cations in a stepwise manner under light irradiation. The light‐responsive system established here could advance further design of novel photoresponsive molecular switches and mechanically interlocked molecules.     

Fuel‐Responsive Allosteric DNA‐Based Aptamers for the Transient Release of ATP and Cocaine

We show herein that allostery offers a key strategy for the design of out‐of‐equilibrium systems by engineering allosteric DNA‐based nanodevices for the transient loading and release of small organic molecules. To demonstrate the generality of our approach, we used two model DNA‐based aptamers that bind ATP and cocaine through a target‐induced conformational change. We re‐engineered these aptamers so that their affinity towards their specific target is controlled by a DNA sequence acting as an allosteric inhibitor. The use of an enzyme that specifically cleaves the inhibitor only when it is bound to the aptamer generates a transient allosteric control that leads to the release of ATP or cocaine from the aptamers. Our approach confirms that the programmability and predictability of nucleic acids make synthetic DNA/RNA the perfect candidate material to re‐engineer synthetic receptors that can undergo chemical fuel‐triggered release of small‐molecule cargoes and to rationally design non‐equilibrium systems.     

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

Cyclodextrin‐based controlled delivery materials have previously been developed for controlled release of different therapeutic drugs. In this study, a supramolecular hydrogel made from cyclodextrin‐based macromonomers is subjected to molecular imprinting to investigate the impact on release kinetics and drug loading, when compared with non‐imprinted, or alternately imprinted hydrogels. Mild synthesis conditions are used to molecularly imprint three antibiotics—novobiocin, rifampicin, and vancomycin—and to test two different hydrogel chemistries. The release profile and drug loading of the molecularly imprinted hydrogels are characterized using ultraviolet spectroscopy over a period of 35 days and compared to non‐imprinted, and alternately imprinted hydrogels. While only modest differences are observed in the release rate of the antibiotics tested, a substantial difference is observed in the total drug‐loading amount possible for hydrogels releasing drugs which has been templated by those drugs. Hydrogels releasing drugs which are templated by other drugs do not show improved release or loading. Analysis by FTIR does not show substantial incorporation of drug into the polymer. Lastly, bioactivity assays confirmed long‐term stability and release of incorporated antibiotics.     

Folding Up of Gold Nanoparticle Strings into Plasmonic Vesicles for Enhanced Photoacoustic Imaging

The stepwise self‐assembly of hollow plasmonic vesicles with vesicular membranes containing strings of gold nanoparticles (NPs) is reported. The formation of chain vesicles can be controlled by tuning the density of the polymer ligands on the surface of the gold NPs. The strong absorption of the chain vesicles in the near‐infrared (NIR) region leads to a much higher efficiency in photoacoustic (PA) imaging than for non‐chain vesicles. The chain vesicles were further employed for the encapsulation of drugs and the NIR light triggered release of payloads. This work not only offers a new platform for controlling the hierarchical self‐assembly of NPs, but also demonstrates that the physical properties of the materials can be tailored by controlling the spatial arrangement of NPs within assemblies to achieve a better performance in biomedical applications.     

羟基喜树碱-类水滑石纳米杂化的共组装制备及表征

采用共组装法在水溶液中制备羟基喜树碱(HCPT)-层状双金属氢氧化物(LDH)纳米杂化物.先利用微通道反应器通过共沉淀法制备了Zn₂Al-NO₃ LDH纳米片,然后与羧酸盐型HCPT在水介质中共组装,制备了HCPT插层LDH的纳米杂化物.利用酸处理,可将层间HCPT由非生物活性的羧酸盐型转化为生物活性的内酯型,这对高生物活性HCPT-LDH纳米杂化物的绿色制备具有重要意义.共组装法制备HCPT-LDH纳米杂化物,耗时短、载药量高、分散性好,且利用原料配比可方便地调控载药量. HCPT分子在LDH层间以其长轴倾斜于层板呈双层排列.所制备的HCPT-LDH纳米杂化物具有良好的药物缓释性能,颗粒内部扩散是药物释放过程的控速步骤.药物释放过程可用准二级动力学模型描述.可以用于构筑LDH基药物输送-控释体系.     

Effect of tetracaine on model and erythrocyte membranes by DSC and EPR

Summary DSC and EPR experiments were performed on human erythrocyte membranes and DPPC vesicles in order to study the effect of the anaesthetic drug tetracaine on structure and dynamics of the lipid region. Experiments using spin label technique showed that tetracaine induced fluidity changes of the lipid region in the environment of the fatty acid probe molecules incorporated into the membranes in the vicinity of the lipid-water interface. Similarly to EPR observations, DSC measurements reported decrease of the main melting and the pretransition temperature in comparison to control DPPC vesicles, which is the sign of destabilisation of the structure in the head group region of the lipids. Similar effect was observed in the case of erythrocytes where the protein conformation was also controlled in the presence of drug. A separated membrane melting with well distinguished membrane protein phase transition was found that was affected significantly by tetracaine. These results suggest that tetracaine is able to modify not only the internal dynamics of erythrocyte membranes and produce destabilisation of the lipid structure, but the protein system as well. These might lead to further damage of the biological functions.     

Light‐Triggered Capture and Release of DNA and Proteins by Host–Guest Binding and Electrostatic Interaction

The development of an effective and general delivery method that can be applied to a large variety of structurally diverse biomolecules remains a bottleneck in modern drug therapy. Herein, we present a supramolecular system for the dynamic trapping and light‐stimulated release of both DNA and proteins. Self‐assembled ternary complexes act as nanoscale carriers, comprising vesicles of amphiphilic cyclodextrin, the target biomolecules and linker molecules with an azobenzene unit and a charged functionality. The non‐covalent linker binds to the cyclodextrin by host–guest complexation with the azobenzene. Proteins or DNA are then bound to the functionalized vesicles through multivalent electrostatic attraction. The photoresponse of the host–guest complex allows a light‐induced switch from the multivalent state that can bind the biomolecules to the low‐affinity state of the free linker, thereby providing external control over the cargo release. The major advantage of this delivery approach is the wide variety of targets that can be addressed by multivalent electrostatic interaction, which we demonstrate on four types of DNA and six different proteins.     

Ion Exchange Controlled Drug Release from Polymerized Ionic Liquids

In this work ion functionalized hydrogels as potent drug delivery systems are presented. The ion functionalization of the hydrogel enables the retention of ionic drug molecules and thus a reduction of burst release effects. Timolol maleate in combination with polymerized anionic 3‐sulfopropylmethacrylate potassium and ibuprofen combined with cationic poly‐[2‐(methacryloyloxy)ethyl] trimethylammonium chloride are investigated in respect to their drug release profile. The results are showing an ion exchange depending release behavior instead of a diffusion‐controlled drug release as it is known from common drug delivery systems. Furthermore, the suitability of such hydrogels for standard methods for sterilization is investigated.     

Elastic excitations in polycarbonate membranes

Brillouin light scattering was used to probe acoustic waves propagating with both longitudinal and transverse polarizations in the surface and the bulk of self‐supported particle track‐etched polycarbonate membranes with 15‐ and 80‐nm nanopores. The recorded scattering line shape at gigahertz frequencies reveals changes in the surface waves of the membranes which are more pronounced for the 80‐nm nanopores despite the low porosity (0.7 and 0.05%). Because the measured elastic constants (1.2 and 6.2 GPa) were found to compare very well with the values for thick polycarbonate film, modifications of the elasto‐optical coefficients and/or the transparency might be the reason for the different scattering line shapes. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 3311–3317, 2004     

An Oxygen Paradox: Catalytic Use of Oxygen in Radical Photopolymerization

A peculiar radical polymerization reaction is presented in which oxygen serves as a cocatalyst, alongside triethylamine, to provide activation with light in the far‐red (690 nm, 3 mW cm^?2) of the PET‐RAFT process in the presence of zinc(II) (2,3,7,8,12,13,17,18‐octaethyl‐5,10,15,20‐tetraphenylporphyrin) as photocatalyst. Apart from the ability to exert temporal control by switching the light on or off, this system possesses the exciting capability of inducing temporal control by removal or reintroduction of oxygen. Furthermore, this multicomponent catalytic system was typified by controlled polymerizations of various acrylate and acrylamide monomers, which all resulted in well‐defined polymers with low dispersity (<1.2). The process displayed excellent living characteristics that were demonstrated through chain extensions and a range of degrees of polymerization (200–1600).     

Photo-crosslinked and pH sensitive polymersomes for triggering the loading and release of cargo

Crosslinkable and pH-sensitive amphiphilic block copolymers are promising candidates to establish pH-stable and permeable vesicles for synthetic biology. Here, we report the fabrication of crosslinked and pH-stable polymersomes as swellable vesicles for the pH-dependent loading and release of small dye molecules.     

Lateral cavity acoustic transducer as an on-chip cell/particle microfluidic switch

A novel on-chip microfluidic switch is demonstrated that utilizes the acoustic microstreaming generated by an oscillating air-liquid interface to switch cells/particles into bifurcating microchannels. The air-liquid interface of the Lateral Cavity Acoustic Transducers (LCATs) can be actuated by an external acoustic energy source causing the interface to oscillate. The oscillating interface results in the generation of vortex-like microstreaming flow within a localized region of the surrounding liquid. This streaming was utilized here to deflect cells/particles into a collection outlet. It was demonstrated that the switching zone could be controlled by varying the actuation time of the LCAT. An LCAT based microfluidic switch is capable of achieving theoretical switching rates of 800 cells/particles per second. It was also demonstrated that K562 cells could be switched into a collection channel with cell viability comparable to that of controls as determined by Trypan blue exclusion assay.     

Vesicles Formation Induced by Layered Double Hydroxides in Mixture of Lauryl Sulfonate Betaine and Sodium Dodecyl Benzenesulfonate

This paper reports that structurally positively charged layered double hydroxides (LDHs) nanoparticles induce the vesicle formation in a mixture of a zwitterionic surfactant, lauryl sulfonate betaine (LSB), and an anionic surfactant, sodium dodecyl benzenesulfonate (SDBS). The existence of vesicles was demonstrated by negative‐staining (NS‐TEM) and freeze‐fracture (FF‐TEM) transmission electron microscopy and confocal laser scanning microscopy (CLSM). The size of vesicles increased with the increase of volume ratio (Q) of Mg₃Al‐LDHs sol to the SDBS/LSB solution. A new composite of LDHs nanoparticles encapsulated in vesicles was formed. A possible mechanism of LDHs‐induced vesicle formation was suggested. The positive charged LDHs surface attracted negatively charged micelles or free amphiphilic molecules, which facilitated their aggregation into a bilayer membrane. The bilayer membranes could be closed to form vesicles that have LDHs particles encapsulated. It was also found that an adsorbed compound layer of LSB and SDBS micelles or molecules on the LDHs surface played a key role in the vesicle formation.     

Loading of Vesicles into Soft Amphiphilic Nanotubes using Osmosis

The facile assembly of higher‐order nanoarchitectures from simple building blocks is demonstrated by the loading of vesicles into soft amphiphilic nanotubes using osmosis. The nanotubes are constructed from rigid interdigitated bilayers which are capped with vesicles comprising phospholipid‐based flexible bilayers. When a hyperosmotic gradient is applied to these vesicle‐capped nanotubes, the closed system loses water and the more flexible vesicle bilayer is pulled inwards. This leads to inclusion of vesicles inside the nanotubes without affecting the tube structure, showing controlled reorganization of the self‐assembled multicomponent system upon a simple osmotic stimulus.     

Poly(DL‐Lactide‐co‐ε‐Caprolactone)/Poly(Acrylic Acid) Composite Implant for Controlled Delivery of Cationic Drugs

Poly(DL‐lactide‐co‐ε‐caprolactone)/poly(acrylic acid) implantable composite reservoirs for cationic drugs are synthesized by sequentially applying photoirradiation and liquid phase inversion. The chemical composition and microstructure of reservoirs are characterized with Fourier transform infrared spectroscopy‐attenuated total reflection (FTIR‐ATR) and scanning electron microscopy (SEM), respectively. Drug loading and release properties are investigated using methylene blue as the drug model. Biocompatibility of reservoirs is examined through a series of in vitro tests and an in vivo experiment of subcutaneous implantation in Dark Agouti rats. Reservoirs show good ion‐exchange capacity, high water content, and fast reversible swelling with retained geometry. Results of drug loading and release reveal excellent loading efficiency and diffusion‐controlled release during 2 weeks. Biocompatibility tests in vitro demonstrate the lack of implant proinflammatory potential and hindered adhesion of L929 cells on the implant surface. Implants exhibit low acute toxicity and elicit a normal acute foreign body reaction that reaches the early stages of fibrous capsule formation after 7 days.     

Photo‐controlled Hierarchical Assembly and Fusion of Coumarin‐containing Polydiacetylene Vesicles

Herein, we synthesize a coumarin‐substituted diacetylene monomer (CODA) and report the novel photo‐controlled reversible assembly and disassembly behavior of the polymerized CODA (PCODA) vesicles. The photo‐triggered dimerization and cleavage reactions of the coumarin groups within the surface of the adjacent PCODA vesicles can be utilized as the driving force to induce assembly and disassembly of PCODA vesicles. Moreover, the boundary of PCODA vesicles in the aggregates becomes more obscure when the irradiation time exceeds 30 min. Fusion occurs upon close docking of target membranes, driven by sufficient dimerization of the coumarin groups within the surface of PCODA vesicles.