Surfactant‐Free,Self‐Assembled PVA‐Iron Oxide/Silica Core–Shell Nanocarriers for Highly Sensitive,Magnetically Controlled Drug Release and Ultrahigh Cancer Cell Uptake Efficiency

Surfactant‐free, self‐assembled iron oxide/silica core–shell (SAIO@SiO₂) nanocarriers were synthesized as bifunctional magnetic vectors that can be triggered for the controlled release of therapeutic agents by an external magnetic field. In addition, drug release profiles can be well‐regulated through an ultrathin layer of silica shell. The hydrophobic drug molecules were encapsulated within the iron oxide‐PVA core and then further covered with a thin‐layer silica shell to regulate the release pattern. Remote control of drug release from the SAIO@SiO₂ nanocarriers was achieved successfully using an external magnetic field where the core phase being structurally disintegrated to a certain extent while subjected to magnetic stimulus, resulting in a burst release of the encapsulated drug. However, a relatively slow and linear release restored immediately, directly after removal of the stimulus. The nanostructural evolution of the nanocarriers upon the stimulus was examined and the mechanism for controlled drug release is proposed for such a core–shell nanocarrier. Surprisingly, the surfactant‐free SAIO@SiO₂ nanocarriers demonstrated a relatively high uptake efficiency from the HeLa cell line. Together with a well‐regulated controlled release design, the nanocarriers may provide great advantages as an effective cell‐based drug delivery nanosystem for biomedical applications.     

Synthesis and Characterization of Positive‐Charge Functionalized Mesoporous Silica Nanoparticles for Oral Drug Delivery of an Anti‐Inflammatory Drug

We synthesized mesoporous silica nanoparticles (MSN) with different densities of surface positive charges. The positive surface charge was generated by incorporating trimethylammonium (TA) functional groups into the framework of MSN (MSN–TA) via direct co‐condensation of a TA‐silane and tetraethoxysilane (TEOS) in the presence of a base as a catalyst. These MSN–TA samples have well‐defined hexagonal structures with an average particle diameter of 100 nm, pore size of 2.7 nm, and surface area of about 1000 m² g^?1. Anionic drug molecules, Orange II (a fluorescent tracing molecule), and sulfasalazine (an anti‐inflammatory prodrug used for bowel disease), were effectively loaded into these MSN–TA samples and remained inside of the MSN–TA under acidic environment (pH 2–5). The amounts of loading of both Orange II and sulfasalazine were increased with increasing positive charge densities resulting from the increasing number of TA groups. When these drug‐loaded MSN–TA nanoparticles were placed in physiological buffer solution (pH 7.4), a partial negative surface charge on the MSN–TA was generated due to the deprotonation of silanol groups, and the strong electrostatic repulsion triggered a sustained release of the loaded molecules. MSN–TA as a nanovehicle for pH‐dependent loading and controllable release of anionic drug molecules can be used as an oral delivery drug systems targeting at intestine. These drugs can be remained trapped in the nanovehicle when passing through the stomach's acidic environment and be released in intestine where the environmental pH is close to neutral.     

Chitosan–Alginate Microcapsules Provide Gastric Protection and Intestinal Release of ICAM‐1‐Targeting Nanocarriers,Enabling GI Targeting In Vivo

When administered intravenously, active targeting of drug nanocarriers (NCs) improves biodistribution and endocytosis. Targeting may also improve NC oral delivery to treat gastrointestinal (GI) pathologies or for systemic absorption. However, GI instability of targeting moieties compromises this strategy. This study explores whether encapsulation of antibody‐coated NCs in microcapsules would protect against gastric degradation, providing NC release and targeting in intestinal conditions. Nanoparticles coated with antibodies against intercellular adhesion molecule‐1 (anti‐ICAM) or nonspecific immunoglobulin G (IgG) are encapsulated in chitosan (shell) ‐ alginate (core) microcapsules. Encapsulation efficiency is >95% and NC relase from microcapsules in storage is <10%. There is minimal NC release at gastric pH (<10%) and burst release at intestinal pH (75%–85%). Encapsulated NCs afford increased protection against degradation (threefold to fourfold) and increased cell targeting (8–20‐fold) after release versus the nonencapsulated NCs. Mouse oral gavage shows that microencapsulation provides 38%–65% greater protection of anti‐ICAM NCs in the GI tract, 40% lower gastric retention, and fourfold to ninefold enhanced intestinal biodistribution versus nonencapsulated NCs. Therefore, microencapsulation of antibody‐targeted NCs may enable active targeting strategies to be effective in the context of oral drug delivery.     

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.     

Multifunctional Mesoporous Silica Nanoparticles for Cancer‐Targeted and Controlled Drug Delivery

Multifunctional mesoporous silica nanoparticles are developed in order to deliver anticancer drugs to specific cancer cells in a targeted and controlled manner. The nanoparticle surface is functionalized with amino‐β‐cyclodextrin rings bridged by cleavable disulfide bonds, blocking drugs inside the mesopores of the nanoparticles. Poly(ethylene glycol) polymers, functionalized with an adamantane unit at one end and a folate unit at the other end, are immobilized onto the nanoparticle surface through strong β‐cyclodextrin/adamantane complexation. The non‐cytotoxic nanoparticles containing the folate targeting units are efficiently trapped by folate‐receptor‐rich HeLa cancer cells through receptormmediated endocytosis, while folate‐receptor‐poor human embryonic kidney 293 normal cells show much lower endocytosis towards nanoparticles under the same conditions. The nanoparticles endocytosed by the cancer cells can release loaded doxorubicin into the cells triggered by acidic endosomal pH. After the nanoparticles escape from the endosome and enter into the cytoplasm of cancer cells, the high concentration of glutathione in the cytoplasm can lead to the removal of the β‐cyclodextrin capping rings by cleaving the pre‐installed disulfide bonds, further promoting the release of doxorubicin from the drug carriers. The high drug‐delivery efficacy of the multifunctional nanoparticles is attributed to the co‐operative effects of folate‐mediated targeting and stimuli‐triggered drug release. The present delivery system capable of delivering drugs in a targeted and controlled manner provides a novel platform for the next generation of therapeutics.     

One‐Step Solvent‐Free Synthesis and Characterization of Zn1−xMnxSe@C Nanorods and Nanowires

The carbon‐encapsulated, Mn‐doped ZnSe (Zn_1−xMn_xSe@C) nanowires, nanorods, and nanoparticles are synthesized by the solvent‐free, one‐step RAPET (reactions under autogenic pressure at elevated temperature) approach. The aspect ratio of the nanowires/nanorods is altered according to the Mn/Zn atomic ratio, with the maximum being observed for Mn/Zn = 1:20. A 10–20 nm amorphous carbon shell is evidenced from electron microscopy analysis. The replacement of Zn by Mn in the Zn_1−xMn_xSe lattice is confirmed by the hyperfine splitting values in the electron paramagnetic resonance (EPR) experiments. Raman experiments reveal that the Zn_1−xMn_xSe core is highly crystalline, while the shell consists of disordered graphitic carbon. Variable‐temperature cathodoluminescence measurements are performed for all samples and show distinct ZnSe near‐band‐edge and Mn‐related emissions. An intense and broad Mn‐related emission at the largest Mn alloy composition of 19.9% is further consistent with an efficient incorporation of Mn within the host ZnSe lattice. The formation of the core/shell nanowires and nanorods in the absence of any template or structure‐directing agent is controlled kinetically by the Zn_1−xMn_xSe nucleus formation and subsequent carbon encapsulation. Mn replaces Zn mainly in the (111) plane and catalyzes the nanowire growth in the [111] direction.     

pH‐Responsive,Light‐Triggered on‐Demand Antibiotic Release from Functional Metal–Organic Framework for Bacterial Infection Combination Therapy

To satisfy the ever‐growing demand in bacterial infection therapy and other fields of science, great effort is being devoted to the development of methods to precisely control drug release and achieve targeted use of an active substance at the right time and place. Here, a new strategy for bacterial infection combination therapy based on the light‐responsive zeolitic imidazolate framework (ZIF) is reported. A pH‐jump reagent is modified into the porous structure of ZIF nanoparticles as a gatekeeper, allowing the UV‐light (365 nm) responsive in situ production of acid, which subsequently induces pH‐dependent degradation of ZIF and promotes the release of the antibiotic loaded in the mesopores. The combination of the UV‐light, the pH‐triggered precise antibiotic release, and the zinc ions enables the light‐activated nanocomposite to significantly inhibit bacteria‐induced wound infection and accelerate wound healing, indicating a switchable and synergistic antibacterial effect. The light irradiated accumulation of acid ensures the controlled release of antibiotic and controlled degradation of ZIF, suggesting the therapeutic potential of the metal–organic frameworks‐based smart platform for controlling bacterial infection.     

Self‐Assembling Peptide as a Potential Carrier for Hydrophobic Anticancer Drug Ellipticine: Complexation,Release and In Vitro Delivery

The self‐assembling peptide EAK16‐II is capable of stabilizing hydrophobic compounds to form microcrystal suspensions in aqueous solution. Here, the ability of this peptide to stabilize the hydrophobic anticancer agent ellipticine is investigated. The formation of peptide‐ellipticine suspensions is monitored with time until equilibrium is reached. The equilibration time is found to be dependent on the peptide concentration. When the peptide concentration is close to its critical aggregation concentration, the equilibration time is minimal at 5 h. With different combinations of EAK16‐II and ellipticine concentrations, two molecular states (protonated or cyrstalline) of ellipticine could be stabilized. These different states of ellipticine significantly affect the release kinetics of ellipticine from the peptide‐ellipticine complex into the egg phosphatidylcholine vesicles, which are used to mimic cell membranes. The transfer rate of protonated ellipticine from the complex to the vesicles is much faster than that of crystalline ellipticine. This observation may also be related to the size of the resulting complexes as revealed from the scanning electron micrographs. In addition, the complexes with protonated ellipticine are found to have a better anticancer activity against two cancer cell lines, A549 and MCF‐7. This work forms the basis for studies of the peptide‐ellipticine suspensions in vitro and in vivo leading to future development of self‐assembling peptide‐based delivery of hydrophobic anticancer drugs.     

Microfabricated Drug Delivery Devices: Design,Fabrication, and Applications

Microfabrication technology has enabled the development of novel controlled‐release devices that possess an integration of structural, mechanical, and perhaps electronic features, which may address challenges associated with conventional delivery systems. In this feature article, microfabricated devices are described in terms of materials, mechanical design, working principles, and fabrication methods, all of which are key features for production of multifunctional, highly effective drug delivery systems. In addition, the current status and future prospects of different types of microfabricated devices for controlled drug delivery are summarized and analyzed with an emphasis on various routes of administration including ocular, oral, transdermal, and implantable systems. It is likely that microfabrication technology will continue to offer new, alternative solutions to design advanced and sophisticated drug delivery devices that promise to significantly improve medical care.     

One‐Step Synthesis and Optical Properties of Benzoate‐ and Biphenolate‐Capped ZrO2 Nanoparticles

A simple one‐pot approach based on the “benzyl alcohol route” is used for the preparation of benzoate‐ and biphenolate‐capped zirconia and, benzoate‐capped Eu‐doped zirconia nanoparticles. Powder X‐ray diffraction studies and high‐ resolution transmission electron microscopy (HR‐TEM) showed that the nanoparticles present high crystallinity and uniform particle sizes ranging from 3 to 4 nm. FT‐IR and solid state NMR (SS‐NMR) studies revealed that the nanoparticles are coated with a large amount of organic species when the reaction temperature is above 300 °C. It was found that the alcohol used as solvent is oxidized at the surface of the nanoparticles to the respective carboxylic acid which acts as a stabilizer, controlling the nanoparticles growth. The optical properties of these hybrid nanoparticles were studied by room and low (12K) temperature photoluminescence spectroscopy, time‐resolved spectroscopy and absolute emission quantum yield. The as‐synthesized benzoate‐ and biphenolate‐capped nanoparticles exhibit interesting emission properties in the UV and blue spectral regions together with values of emission quantum yields much higher than those reported for zirconia nanoparticles of similar size. The photoluminescent properties were attributed to a cooperative effect of the capping ligands and the defects associated to the ZrO₂ nanoparticles. Due to the overlapping of the various emission components involved (i.e., the emission of europium(III) intra‐4f⁶ transitions, defects in the zirconia and capping ligands) a tunable emission color ranging from purplish‐pink to greenish‐blue could be obtained for the europium‐doped zirconia nanoparticles by simply selecting different excitation wavelengths.     

Nanoliter Liquid Packaging in a Bioresorbable Microsystem by Additive Manufacturing and its Application as a Controlled Drug Delivery Device

Precise packaging of nanoliter amounts of liquid in a microsystem is important for many biomedical applications. However, existing liquid encapsulation technologies have limitations in terms of liquid waste, evaporation, trapped bubbles, and liquid degradation. In this study, multiple additive manufacturing techniques for nanoliter liquid packaging in bioresorbable microsystems is used. Two-photon photolithography is used for bioresorbable reservoir fabrication, while inkjet printing (IJP) is used for precise nanoliter liquid packaging. Dual IJP allows for micro-reservoirs to be filled with precise amounts of drug solution and subsequently and rapidly sealed with a layer of lipids mixed with Fe₃O₄ nanoparticles. Combining these two printing techniques can overcome the previous limitations of liquid encapsulation technologies. To demonstrate the relevance of this technique, a wirelessly activated, bioresorbable multi-reservoir microcapsule that can be used for controlled drug delivery is presented. The microcapsules and their content are shown to be stable during fabrication, storage, and operation. Multiple cargo release events are triggered independently by the local melting of the sealing layer, resulting from magnetically induced Fe₃O₄ nanoparticle heating. The operation of the capsule is demonstrated in tissue phantoms and in vitro cell cultures.     

A One‐Step and Binder‐Free Method to Fabricate Hierarchical Nickel‐Based Supercapacitor Electrodes with Excellent Performance

Research is currently being carried out in the search for alternative electrode materials to replace the expensive and toxic RuO₂‐based electrode. As a typical example, nickel oxide or hydroxide has been widely studied but the results are far from satisfactory. Here, using a facile one‐step anodization method, a hierarchical nickel compound (HNC) film with an interconnecting 3D nanoflake structure is obtained, providing large electrochemically active surface area and interconnecting nanoscale pore channels for ion transport. The HNC electrode demonstrates significantly improved capacitance, 70 times higher than the reported NiO‐TiO₂ nanotube array electrode with similar thickness. The charge/discharge kinetics are also superior, showing only a 24% capacitance reduction when the scan rate is increased by 50 times, as compared with the typical 70% capacitance reduction for pseudocapacitor electrodes under the same conditions. HNC exhibits an extraordinary excellent cycle life; capacitance increases to 115% after 4500 test cycles. Furthermore, because HNC is in intimate contact with the current collector, it is not necessary to use conducting agents or binders, which reduces the electrode weight and facilitates the electrode preparation process. The method is low cost, facile, scalable, additive free, and is promising for fabricating supercapacitor electrode with excellent performance.     

Dual‐Action Flexible Antimicrobial Material: Switchable Self‐Cleaning,Antifouling, and Smart Drug Release

A switchable material with a smart antimicrobial dual‐action functionality, which is based on a highly stretchable silicon polymer gradiently doped with polyyrrole, is proposed. The material exhibits superhydrophobic and self‐cleaning properties, high aerophilicity as well as the possibility of smart, electrically triggerable release of an incorporated drug. During the immersion of the material in water, an air gap is formed on its surface which prevents a formation of biofouling, attachment of microorganisms, and burst release of the incorporated drug. An application of external electric field switches the surface properties from the superhydrophobic to highly hydrophilic state that enables a wetting of the material surface and electrically triggered release of a loaded drug. After the electric field switching off and sample drying, the material surface returns to its intrinsic superhydrophobic state with the original self‐cleaning properties so that the material surface can be simply cleaned, removing the bacteria. High flexibility and stretchability are additional favorable properties of the proposed smart antimicrobial material, making it a suitable candidate for a range of medical and related applications.     

Packing of Emulsion Droplets: Structural and Functional Motifs for Multi‐Cored Microcapsules

Advances in microfluidic emulsification have enabled the creation of multiphase emulsion drops, which have emerged as promising templates for producing functional microcapsules. However, most previous micro‐encapsulation methods have limitations in terms of capsule stability, functionality, and simplicity of fabrication procedures. Here, we report a simple single‐step encapsulation technique that uses an optofluidic platform to efficiently and precisely encapsulate a specific number of emulsion droplets in photocurable shell droplets. In particular, we show, for the first time, that densely confined core droplets within an oily shell droplet rearrange into a unique configuration that minimizes the interfacial energy, as confirmed here from theory. These structures are then consolidated into multi‐cored microcapsules with structural and mechanical stability through in situ photopolymerization of the shell in a continuous mode, which are capable of isolating active materials and releasing them in a controlled manner using well‐defined nanohole arrays or nanoscopic silver architectures on thin membranes.     

A Dual‐FRET‐Based Versatile Prodrug for Real‐Time Drug Release Monitoring and In Situ Therapeutic Efficacy Evaluation

A dual‐Förster resonance energy transfer (FRET)‐based versatile prodrug (V‐prodrug), in which the fluorescence of both 5(6)‐carboxylfluorescein (FAM) and doxorubicin (DOX) can be quenched by 4‐(dimethylaminoazo)benzene‐4‐carboxylic acid (Dabcyl) with high quenching efficiency, is developed in this paper. The V‐prodrug can selectively bind to the α_vβ₃ integrin overexpressed cancer cells through the Arg‐Gly‐Asp (RGD) targeting moiety. After that, the acid‐mediated DOX release of the V‐prodrug can be real‐time monitored by the increase of the red fluorescence from DOX. Thereafter, DOX‐induced cell apoptosis can also be in situ assessed by the fluorescence recovery of the FAM, due to the caspase‐3‐mediated Asp‐Glu‐Val‐Asp (DEVD) peptide sequence cleavage. This novel prodrug provides a cascaded imaging of real‐time drug release and subsequent cell apoptosis, which enables the in situ detection of the cancer response and the therapeutic efficacy evaluation of the prodrug.     

Halogenated Antimonene: One‐Step Synthesis,Structural Simulation,Tunable Electronic and Photoresponse Property

Surface functionalization is considered to be an effective and versatile strategy to tailor intrinsic electronic and optoelectronic properties of 2D materials. In this work, surface‐decorated few‐layer antimonene is synthesized by a one‐step electrochemical exfoliation and synchronous halogenation method in halogen‐containing an ionic liquid–based electrolyte at room temperature. The prepared halogenated antimonene nanosheets are composed of oxygen‐ and halogen‐decorated amorphous and crystalline domains. The structural reconstructions and evolutions of halogenated antimonene are further revealed by ab initio molecular dynamics simulations and first‐principles calculations. The band structures and optical properties of antimonene can be tailored after amorphization and surface functionalization, depending on the reactivity of different halogens. The photoresponse performance of the halogenated antimonene is further evaluated by photoelectrochemical measurement. Exhibiting self‐powered photoresponse behavior, their photocurrent density increases with the increases of external bias potential and light intensity. This work proposes a new idea of tuning the optoelectronic properties of 2D materials by synchronous halogenation in the facile one‐step electrochemical synthesis process. Benefiting from this facile synthesis procedure, the halogenation of antimonene may shed light on chemical functionalization of other 2D materials for electronic and optoelectronic applications.     

Polymer‐Coated Radioluminescent Nanoparticles for Quantitative Imaging of Drug Delivery

Some theranostic nanoparticle (NP) drug delivery systems are capable of measuring drug release rates in situ. This can provide quantitative information regarding drug biodistribution, and drug dose that is delivered to cells or tissues. Here, X‐ray excited optical luminescent (XEOL) NPs coated with poly(glycolide)‐poly(ethylene glycol) (XGP) are used measure the amount of drug released into cells. The photoactive drug protoporphyrin IX (PpIX) is loaded into XGP and is able to attenuate the XEOL NP emission. Measuring an increase in XEOL intensity as PpIX is released enables the measurement of drug release into glioblastoma cells (GBM). Biodistribution studies in a BALB/c mouse GBM intracranial xenograft model show significant XGP accumulation at the site of the GBM xenograft within the brain, and not in adjacent healthy brain tissues. There is no uptake of XGP in the heart or kidneys, the primary organs associated with drug and gadolinium ion toxicity. NP toxicity is tested with U‐138MG GBM in vitro, and NPs show low cytotoxicity at concentrations of 100 μg/mL. In vivo dose escalation studies in BALB/c mice show no adverse effects at doses up to 75 mg/kg. These theranostic NPs offer an approach to quantitatively measure drug release into cells.     

Biocompatible,Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer‐Targeted Drug Delivery In Vivo

Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.