Photoresponsive Sponge‐Like Coating for On‐Demand Liquid Release

Many publications report on stimuli responsive coatings, but only a few on the controlled release of species in order to change the coating surface properties. A sponge‐like coating that is able to release and absorb a liquid upon exposure to light has been developed. The morphology of the porous coating is controlled by the smectic liquid crystal properties of the monomer mixture prior to its polymerization, and homeotropic order is found to give the largest contraction. The fast release of the liquid can be induced by a macroscopic contraction of the coating caused by a trans to cis conversion of a copolymerized azobenzene moiety. The liquid secretion can be localized by local light exposure or by creating a surface relief. The uptake of liquid proceeds by stimulating the back reaction of the azo compound by exposure at higher wavelength or by thermal relaxation. The surface forces of the sponge‐like coating in contact with an opposing surface can be controlled by light‐induced capillary bridging revealing that the controlled release of liquid gives access to tunable adhesion.     

Light‐Responsive,Singlet‐Oxygen‐Triggered On‐Demand Drug Release from Photosensitizer‐Doped Mesoporous Silica Nanorods for Cancer Combination Therapy

Smart drug delivery systems with on‐demand drug release capability are rather attractive to realize highly specific cancer treatment. Herein, a novel light‐responsive drug delivery platform based on photosensitizer chlorin e6 (Ce6) doped mesoporous silica nanorods (CMSNRs) is developed for on‐demand light‐triggered drug release. In this design, CMSNRs are coated with bovine serum albumin (BSA) via a singlet oxygen (SO)‐sensitive bis‐(alkylthio)alkene (BATA) linker, and then modified with polyethylene glycol (PEG). The obtained CMSNR‐BATA‐BSA‐PEG, namely CMSNR‐B‐PEG, could act as a drug delivery carrier to load with either small drug molecules such as doxorubicin (DOX), or larger macromolecules such as cis‐Pt (IV) pre‐drug conjugated third generation dendrimer (G3‐Pt), both of which are sealed inside the mesoporous structure of nanorods by BSA coating. Upon 660 nm light irradiation with a rather low power density, CMSNRs with intrinsic Ce6 doping would generate SO to cleave BATA linker, inducing detachment of BSA‐PEG from the nanorod surface and thus triggering release of loaded DOX or G3‐Pt. As evidenced by both in vitro and in vivo experiments, such CMSNR‐B‐PEG with either DOX or G3‐Pt loading offers remarkable synergistic therapeutic effects in cancer treatment, owing to the on‐demand release of therapeutics specifically in the tumor under light irradiation.     

Mechanically Activated Microcapsules for “On‐Demand” Drug Delivery in Dynamically Loaded Musculoskeletal Tissues

Delivery of biofactors in a precise and controlled fashion remains a clinical challenge. Stimuli‐responsive delivery systems can facilitate “on‐demand” release of therapeutics in response to a variety of physiologic triggering mechanisms (e.g., pH, temperature). However, few systems to date have taken advantage of mechanical inputs from the microenvironment to initiate drug release. Here, mechanically activated microcapsules (MAMCs) are designed to deliver therapeutics in response to the mechanically loaded environment of regenerating musculoskeletal tissues, with the ultimate goal of furthering tissue repair. To establish a suite of microcapsules with different thresholds for mechanoactivation, MAMC physical dimensions and composition are first manipulated, and their mechano‐response under both direct 2D compression and in 3D matrices mimicking the extracellular matrix properties and dynamic loading environment of regenerating tissue, is evaluated. To demonstrate the feasibility of this delivery system, an engineered cartilage model is used to test the efficacy of mechanically instigated release of transforming growth factor‐β3 on the chondrogenesis of mesenchymal stem cells. These data establish a novel platform by which to tune the release of therapeutics and/or regenerative factors based on the physiologic mechanical loading environment and will find widespread application in the repair and regeneration of musculoskeletal tissues.     

Light‐Controlled Reversible Manipulation of Microgel Particle Size Using Azobenzene‐Containing Surfactant

The light‐induced reversible switching of the swelling of microgel particles triggered by photo‐isomerization and binding/unbinding of a photosensitive azobenzene‐containing surfactant is reported. The interactions between the microgel (N‐isopropylacrylamide, co‐monomer: allyl acetic acid, crosslinker: N,N′‐methylenebisacrylamide) and the surfactant are studied by UV‐Vis spectroscopy, dynamic and electrophoretic light scattering measurements. Addition of the surfactant above a critical concentration leads to contraction/collapse of the microgel. UV light irradiation results in trans‐cis isomerization of the azobenzene unit incorporated into the surfactant tail and causes an unbinding of the more hydrophilic cis isomer from the microgel and its reversible swelling. The reversible contraction can be realized by blue light irradiation that transfers the surfactant back to the more hydrophobic trans conformation, in which it binds to the microgel. The phase diagram of the surfactant‐microgel interaction and transitions (aggregation, contraction, and precipitation) is constructed and allows prediction of changes in the system when the concentration of one or both components is varied. Remote and reversible switching between different states can be realized by either UV or visible light irradiation.     

pH‐Responsive Catalytic Janus Motors with Autonomous Navigation and Cargo‐Release Functions

The fabrication of multifunctional polymeric Janus colloids that display catalytically driven propulsion, change their size in response to local variations in pH, and vary cargo release rate is demonstrated. Systematic investigation of the colloidal trajectories reveals that in acidic environments the propulsion velocity reduces dramatically due to colloid swelling. This leads to a chemotaxis‐like accumulation for ensembles of these responsive particles in low‐pH regions. In synergy with this chemically defined accumulation, the colloids also show an enhancement in the release rate of an encapsulated cargo molecule. Together, these effects result in a strategy to harness catalytic propulsion for combined autonomous transport and cargo release directed by a chemical stimulus, displaying a greater than 30 times local cargo‐accumulation enhancement. Lactic acid can be used as the stimulus for this behavior, an acid produced by some tumors, suggesting possible eventual utility as a drug‐delivery method. Applications for microfluidic transport are also discussed.     

A Gene Therapy Technology‐Based Biomaterial for the Trigger‐Inducible Release of Biopharmaceuticals in Mice

Gene therapy scientists have developed expression systems for therapeutic transgenes within patients, which must be seamlessly integrated into the patient's physiology by developing sophisticated control mechanisms to titrate expression levels of the transgenes into the therapeutic window. However, despite these efforts, gene‐based medicine still faces security concerns related to the administration of the therapeutic transgene vector. Here, molecular tools developed for therapeutic transgene expression can readily be transferred to materials science to design a humanized drug depot that can be implanted into mice and enables the trigger‐inducible release of a therapeutic protein in response to a small‐molecule inducer. The drug depot is constructed by embedding the vascular endothelial growth factor (VEGF₁₂₁) as model therapeutic protein into a hydrogel consisting of linear polyacrylamide crosslinked with a homodimeric variant of the human FK‐binding protein 12 (F_M), originally developed for gene therapeutic applications, as well as with dimethylsuberimidate. Administrating increasing concentrations of the inducer molecule FK506 triggers the dissociation of F_M thereby loosening the hydrogel structure and releasing the VEGF₁₂₁ payload in a dose‐adjustable manner. Subcutaneous implantation of the drug depot into mice and subsequent administration of the inducer by injection or by oral intake triggers the release of VEGF₁₂₁ as monitored in the mouse serum. This study is the first demonstration of a stimuli‐responsive hydrogel that can be used in mammals to release a therapeutic protein on demand by the application of a small‐molecule stimulus. This trigger‐inducible release is a starting point for the further development of externally controlled drug depots for patient‐compliant administration of biopharmaceuticals.     

Microneedle‐Array Patch Fabricated with Enzyme‐Free Polymeric Components Capable of On‐Demand Insulin Delivery

Achieving persistent glycemic control in a painless and convenient way is the ultimate goal of diabetes management. Herein, an “enzyme‐free” polymeric microneedle (MN)‐array patch composed of a boronate‐containing hydrogel semi‐interpenetrated by biocompatible silk fibroin is developed. Consistent with the previous reports, the presence of the boronate‐hydrogel allows for glucose‐responsive diffusion‐control of insulin, while the crystalline fibroin component serves as a matrix‐stiffener to validate skin penetration. Remarkably, this “enzyme‐free” smart artificial on‐skin pancreas prototype remains stable for at least 2 months in an aqueous environment. Furthermore, it establishes sustained as well as acute glucose‐responsive insulin delivery, and is to the authors' knowledge, the first successful material design addressing such two technical challenges at once on an MN format. This long‐acting, on‐demand insulin delivery technology may offer a candidate for a next‐generation diabetes therapy that is remarkably stable, safe, economically efficient, and capable of providing both acute‐ and continuous glycemic control in a manner minimally dependent on patient compliance.     

Theranostic USPIO‐Loaded Microbubbles for Mediating and Monitoring Blood‐Brain Barrier Permeation

Efficient and safe drug delivery across the blood‐brain barrier (BBB) remains one of the major challenges of biomedical and (nano‐) pharmaceutical research. Here, it is demonstrated that poly(butyl cyanoacrylate)‐based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles within their shell, can be used to mediate and monitor BBB permeation. Upon exposure to transcranial ultrasound pulses, USPIO‐MB are destroyed, resulting in acoustic forces inducing vessel permeability. At the same time, USPIO are released from the MB shell, they extravasate across the permeabilized BBB and they accumulate in extravascular brain tissue, thereby providing non‐invasive R ₂*‐based magnetic resonance imaging information on the extent of BBB opening. Quantitative changes in R ₂* relaxometry are in good agreement with 2D and 3D microscopy results on the extravascular deposition of the macromolecular model drug fluorescein isothiocyanate (FITC)‐dextran into the brain. Such theranostic materials and methods are considered to be useful for mediating and monitoring drug delivery across the BBB and for enabling safe and efficient treatment of CNS disorders.     

From Membrane to Skin: Aqueous Permeation Control Through Light‐Responsive Amphiphilic Polymer Co‐Networks

The functionalization of amphiphilic polymer co‐networks with light‐responsive spiropyran and spirooxazine derivatives leads to a new type of light‐responsive materials. The material consisting of hydrophilic nanochannels shows desirable properties such as light‐responsive permeability changes of aqueous caffeine solutions, an exceptional repeatability of the photochromism, and tunable basic permeability rates. The versatility of the system is demonstrated by using different functionalization routes such as copolymerization of light‐responsive monomers or crosslinker as well as postmodification of the preformed amphiphilic network. Moreover, light‐responsive spirobenzopyran and novel spirooxazine derivatives are synthesized, which changes the properties of the light‐responsive membranes after inclusion into the amphiphilic co‐networks. Finally, the permeability of the delivery membrane can be tailored to match the properties of porcine skin, an in vitro model of human neonatal skin. One possible application might be the use of the light‐responsive membranes as key‐unit of a transdermal caffeine‐delivery system for preterm neonates.     

A Fluorinated Bola‐Amphiphilic Dendrimer for On‐Demand Delivery of siRNA,via Specific Response to Reactive Oxygen Species

Functional materials capable of responding to stimuli intrinsic to diseases are extremely important for specific drug delivery at the disease site. However, developing on‐demand stimulus‐responsive vectors for targeted delivery is highly challenging. Here, a stimulus‐responsive fluorinated bola‐amphiphilic dendrimer is reported for on‐demand delivery of small interfering RNA (siRNA) in response to the characteristic high level of reactive oxygen species (ROS) in cancer cells. This dendrimer bears a ROS‐sensitive thioacetal in the hydrophobic core and positively charged poly(amidoamine) dendrons at the terminals, capable of interacting and compacting the negatively charged siRNA into nanoparticles to protect the siRNA and promote cellular uptake. The ROS‐sensitive feature of this dendrimer boosts specific and efficient disassembly of the siRNA/vector complexes in ROS‐rich cancer cells for effective siRNA delivery and gene silencing. Moreover, the fluorine tags in the vector enable ¹⁹F‐NMR analysis of the ROS‐responsive delivery process. In addition, this ingenious and distinct bola‐amphiphilic dendrimer is also able to combine the advantageous delivery features of both lipid and dendrimer vectors. Therefore, it represents an innovative on‐demand stimulus‐responsive delivery platform.     

Biocompatible Poly(2‐hydroxyethyl methacrylate)‐b‐poly(L‐histidine) Hybrid Materials for pH‐Sensitive Intracellular Anticancer Drug Delivery

A series of synthetic polymer bioconjugate hybrid materials consisting of poly(2‐hydroxyethyl methacrylate) (p(HEMA)) and poly(l‐ histidine) (p(His)) are synthesized by combining atom transfer radical polymerization of HEMA with ring opening polymerization of benzyl‐N‐carboxy‐L ‐histidine anhydride. The resulting biocompatible and membranolytic p(HEMA)₂₅‐b‐p(His)_n (n = 15, 25, 35, and 45) polymers are investigated for their use as pH‐sensitive drug‐carrier for tumor targeting. Doxorubicin (Dox) is encapsulated in nanosized micelles fabricated by a self‐assembly process and delivered under different pH conditions. Micelle size is characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM) observations. Dox release is investigated according to pH, demonstrating the release is sensitive to pH. Antitumor activity of the released Dox is assessed using the HCT 116 human colon carcinoma cell line. Dox released from the p(HEMA)‐b‐p(His) micelles remains biologically active and has the dose‐dependent capability to kill cancer cells at acidic pH. The p(HEMA)‐b‐p(His) hybrid materials are capable of self‐assembling into nanomicelles and effectively encapsulating the chemotherapeutic agent Dox, which allows them to serve as suitable carriers of drug molecules for tumor targeting.     

Active Regulation of On‐Demand Drug Delivery by Magnetically Triggerable Microspouters

Triggerable devices capable of on‐demand, controlled release of therapeutics are attractive options for the treatment of local diseases because of their potential to enhance therapeutic effectiveness with reduced systemic toxicity. Here, the design and fabrication of a miniaturized device, termed a microspouter, is described. This device is shown to provide active and precise control of localized delivery of drugs on demand. The microspouter is composed of a magnetic sponge to provide the force for drug release through magnetic field‐induced reversible deformation, a reservoir for the sponge installation and drug loading, and a soft membrane for sealing the device. Following application of a magnetic field to the microspouter, the shrinking of the sponge may trigger a spouting of drug through a membrane's microaperture. The efficiency of the device in controlling the dose and time course of drug release under different external magnetic fields has been demonstrated using methylene blue and docetaxel as model drugs. Additionally, the microspouter is found to have low background drug leakage that allows for tunable drug release in an ex vivo implantation experiment. All the results confirm the microspouter as a potential device for safe, long‐time, and controlled drug release in local disease treatment.     

Light‐Up Probe for Targeted and Activatable Photodynamic Therapy with Real‐Time In Situ Reporting of Sensitizer Activation and Therapeutic Responses

Integrated systems that offer traceable cancer therapy are highly desirable for personalized medicine. Herein, a probe is reported that is composed of a red‐emissive photosensitizer (PS) with aggregation‐induced emission characteristics and a built‐in apoptosis sensor with activatable green emission for targeted cancer cell ablation and real‐time monitoring of PS activation and therapeutic response. The probe is nonemissive in aqueous media and can be selectively uptaken by α_vβ₃ integrin overexpressed cancer cells. Cleavage of the probe by intracellular glutathione leads to release of the apoptosis sensor and red fluorescence turn‐on to report the PS activation. Upon light irradiation, the PS can generate reactive oxygen species to induce cell apoptosis and activate caspase‐3/‐7, which will cleave the apoptosis sensor to yield intense green fluorescence. Both the red and green emission can be obtained through a single wavelength excitation, which makes the probe very convenient for therapeutic protocol development.     

Recent Progress in High‐Efficiency Blue‐Light‐Emitting Materials for Organic Light‐Emitting Diodes

Organic light‐emitting diodes (OLEDs) are increasingly used in displays replacing traditional flat panel displays; e.g., liquid crystal displays. Especially, the paradigm shifts in displays from rigid to flexible types accelerated the market change from liquid crystal displays to OLEDs. However, some critical issues must be resolved for expansion of OLED use, of which blue device performance is one of the most important. Therefore, recent OLED material development has focused on the design, synthesis and application of high‐efficiency and long‐life blue emitters. Well‐known blue fluorescent emitters have been modified to improve their efficiency and lifetime, and blue phosphorescent emitters are being investigated to overcome the lifetime issue. Recently, thermally activated delayed fluorescent emitters have received attention due to the potential of high‐efficiency and long‐living emitters. Therefore, it is timely to review the recent progress and future prospects of high‐efficiency blue emitters. In this feature article, we summarize recent developments in blue fluorescent, phosphorescent and thermally activated delayed fluorescent emitters, and suggest key issues for each emitter and future development strategies.     

A Red Light Activatable Multifunctional Prodrug for Image‐Guided Photodynamic Therapy and Cascaded Chemotherapy

A multifunctional prodrug, designated as TPP‐L‐GEM, is fabricated to realize image‐guided in situ tumor photodynamic therapy (PDT) with red light activatable chemotherapy. Gemcitabine is conjugated with a fluorescent photosensitizer, meso‐tetraphenylporphyrin (TPP), by a reactive oxygen species cleavable thioketal linker. Under the irradiation of low‐energy red light, TPP can generate singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the thioketal linkage can be cleaved by singlet oxygen and result in a cascaded gemcitabine release, causing sustained cell damage by chemotherapy. With the combination of PDT and cascaded chemotherapy, TPP‐L‐GEM shows significant tumor therapeutic efficacy in vitro and in vivo. Furthermore, the inherent fluorescent property of TPP endows the TPP‐L‐GEM prodrug with noninvasive drug tracking capability, which is favorable for image‐guided tumor therapy.     

Design and Fabrication of Magnetically Functionalized Core/Shell Microspheres for Smart Drug Delivery

The fabrication of magnetically functionalized core/shell microspheres by using the microfluidic flow‐focusing (MFF) approach is reported. The shell of each microsphere is embedded with magnetic nanoparticles, thereby enabling the microspheres to deform under an applied magnetic field. By encapsulating a drug, for example, aspirin, inside the microspheres, the drug release of the microspheres is enhanced under the compression–extension oscillations that are induced by an AC magnetic field. This active pumping mode of drug release can be controlled by varying the frequency and magnitude of the applied magnetic field as well as the time profile of the magnetic field. UV absorption measurements of cumulative aspirin release are carried out to determine the influence of these factors. The drug release behavior is found to be significantly different depending on whether the applied field varies sinusoidally or in a step‐function manner with time.