Shuttle‐Mediated Nanoparticle Delivery to the Blood–Brain Barrier

Many therapeutic drugs are excluded from entering the brain due to their lack of transport through the blood–brain barrier (BBB). The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. To overcome this problem, a viral fusion peptide (gH625) derived from the glycoprotein gH of Herpes simplex virus type 1 is developed, which possesses several advantages including high cell translocation potency, absence of toxicity of the peptide itself, and the feasibility as an efficient carrier for delivering therapeutics. Therefore, it is hypothesized that brain delivery of nanoparticles conjugated with gH625 should be efficiently enhanced. The surface of fluorescent aminated polystyrene nanoparticles (NPs) is functionalized with gH625 via a covalent binding procedure, and the NP uptake mechanism and permeation across in vitro BBB models are studied. At early incubation times, the uptake of NPs with gH625 by brain endothelial cells is greater than that of the NPs without the peptide, and their intracellular motion is mainly characterized by a random walk behavior. Most importantly, gH625 peptide decreases NP intracellular accumulation as large aggregates and enhances the NP BBB crossing. In summary, these results establish that surface functionalization with gH625 may change NP fate by providing a good strategy for the design of promising carriers to deliver drugs across the BBB for the treatment of brain diseases.     

Protein Toxin Chaperoned by LRP‐1‐Targeted Virus‐Mimicking Vesicles Induces High‐Efficiency Glioblastoma Therapy In Vivo

Glioblastoma is a most intractable and high‐mortality malignancy because of its extremely low drug accessibility resulting from the blood–brain barrier (BBB). Here, it is reported that angiopep‐2‐directed and redox‐responsive virus‐mimicking polymersomes (ANG‐PS) (angiopep‐2 is a peptide targeting to low‐density lipoprotein receptor‐related protein‐1 (LRP‐1)) can efficiently and selectively chaperone saporin (SAP), a highly potent natural protein toxin, to orthotopic human glioblastoma xenografts in nude mice. Unlike chemotherapeutics, free SAP has a low cytotoxicity. SAP‐loaded ANG‐PS displays, however, a striking antitumor activity (half‐maximal inhibitory concentration, IC₅₀ = 30.2 × 10^?9m ) toward U‐87 MG human glioblastoma cells in vitro as well as high BBB transcytosis and glioblastoma accumulation in vivo. The systemic administration of SAP‐loaded ANG‐PS to U‐87 MG orthotopic human‐glioblastoma‐bearing mice brings about little side effects, effective tumor inhibition, and significantly improved survival rate. The protein toxins chaperoned by LRP‐1‐targeted virus‐mimicking vesicles emerge as a novel and highly promising treatment modality for glioblastoma.     

Antiamyloidogenic Activity of Aβ42‐Binding Peptoid in Modulating Amyloid Oligomerization

The oligomerization and aggregation of amyloid β (Aβ) play central role in the pathogenesis of Alzheimer's disease (AD). Molecular binding agents for modulating the formation of Aβ oligomers and fibrils have promising application potential in AD therapies. By screening a peptoid library using surface plasmon resonance imaging, amyloid inhibitory peptoid 1 (AIP1) that has high affinity to Aβ42 is identified. AIP1 is demonstrated to inhibit Aβ42 oligomerization and fibrillation and to rescue Aβ42‐induced cytotoxicity through decreasing the content of Aβ42 oligomers that is related to cell membrane permeability. Molecular docking suggests that the binding sites of AIP1 may be at the N‐terminus of Aβ42. The blood‐brain barrier (BBB) permeability of AIP1 using an in vitro BBB model is also revealed. This work provides a strategy for the design and development of peptoid‐based antiamyloidogenic agents. The obtained amyloid inhibitory peptoid shows prospects in the therapeutic application in AD.     

Unraveling In Vivo Brain Transport of Protein‐Coated Fluorescent Nanodiamonds

Nanotheranostics, combining diagnostics and therapy, has the potential to revolutionize treatment of neurological disorders. But one of the major obstacles for treating central nervous system diseases is the blood–brain barrier (BBB) preventing systemic delivery of drugs and optical probes into the brain. To overcome these limitations, nanodiamonds (NDs) are investigated in this study as they are a powerful sensing and imaging platform for various biological applications and possess outstanding stable far‐red fluorescence, do not photobleach, and are highly biocompatible. Herein, fluorescent NDs encapsulated by a customized human serum albumin–based biopolymer (polyethylene glycol) coating (dcHSA‐PEG) are taken up by target brain cells. In vitro BBB models reveal transcytosis and an additional direct cell–cell transport via tunneling nanotubes. Systemic application of dcHSA‐NDs confirms their ability to cross the BBB in a mouse model. Tracking of dcHSA‐NDs is possible at the single cell level and reveals their uptake into neurons and astrocytes in vivo. This study shows for the first time systemic NDs brain delivery and suggests transport mechanisms across the BBB and direct cell–cell transport. Fluorescent NDs are envisioned as traceable transporters for in vivo brain imaging, sensing, and drug delivery.     

Reversible Cavitation‐Induced Junctional Opening in an Artificial Endothelial Layer

Targeting pharmaceuticals through the endothelial barrier is crucial for drug delivery. In this context, cavitation‐assisted permeation shows promise for effective and reversible opening of intercellular junctions. A vessel‐on‐a‐chip is exploited to investigate and quantify the effect of ultrasound‐excited microbubbles—stable cavitation—on endothelial integrity. In the vessel‐on‐a‐chip, the endothelial cells form a complete lumen under physiological shear stress, resulting in intercellular junctions that exhibit barrier functionality. Immunofluorescence microscopy is exploited to monitor vascular integrity following vascular endothelial cadherin staining. It is shown that microbubbles amplify the ultrasound effect, leading to the formation of interendothelial gaps that cause barrier permeabilization. The total gap area significantly increases with pressure amplitude compared to the control. Gap opening is fully reversible with gap area distribution returning to the control levels 45 min after insonication. The proposed integrated platform allows for precise and repeatable in vitro measurements of cavitation‐enhanced endothelium permeability and shows potential for validating irradiation protocols for in vivo applications.     

Precise Deciphering of Brain Vasculatures and Microscopic Tumors with Dual NIR‐II Fluorescence and Photoacoustic Imaging

Diagnostics of cerebrovascular structures and microscopic tumors with intact blood–brain barrier (BBB) significantly contributes to timely treatment of patients bearing neurological diseases. Dual NIR‐II fluorescence and photoacoustic imaging (PAI) is expected to offer powerful strength, including good spatiotemporal resolution, deep penetration, and large signal‐to‐background ratio (SBR) for precise brain diagnostics. Herein, biocompatible and photostable conjugated polymer nanoparticles (CP NPs) are reported for dual‐modality brain imaging in the NIR‐II window. Uniform CP NPs with a size of 50 nm are fabricated from microfluidics devices, which show an emission peak at 1156 nm with a large absorptivity of 35.2 L g^?1 cm^?1 at 1000 nm. The NIR‐II fluorescence imaging resolves hemodynamics and cerebral vasculatures with a spatial resolution of 23 µm at a depth of 600 µm. The NIR‐II PAI enables successful noninvasive mapping of deep microscopic brain tumors (<2 mm at a depth of 2.4 mm beneath dense skull and scalp) with an SBR of 7.2 after focused ultrasound‐induced BBB opening. This study demonstrates that CP NPs are promising contrast agents for brain diagnostics.     

Crossing the blood–brain barrier with graphene nanostructures

Therapeutic approaches for the delivery of drugs to the central nervous system are hampered by the presence of the blood–brain barrier (BBB); overcoming this barrier is the clinical goal for the treatment of neurological disorders, including Alzheimer’s disease and Parkinson’s disease. The BBB is a cellular barrier of a highly impermeable nature that is predominantly formed by a tightly bound continuous layer of endothelial cells; it acts as a gatekeeper to restrict the free diffusion of bloodborne pathogens into the central nervous system. Targeted drug delivery systems have been explored over the past decade for crossing the BBB. Very recently, graphene nanostructures have shown great potential for crossing the BBB due to their exceptional features such as high electron mobility, ease of synthesis and functionalization, as well as control over size, shape, and the drug release profile. Graphene is evolving as a system not only to detect diseased lesions but also, in parallel, to treat neurological disorders while demonstrating minimal side effects. Given the rapid developments of innovative graphene-based delivery platforms, the present review sheds light on the status and prospects of graphene for crossing the BBB by improving, preserving, or rescuing brain energetics, with a specific focus on how graphene alters neuronal cell function.     

Silver nanoparticles crossing through and distribution in the blood-brain barrier in vitro

Silver nanoparticles (SNPs) translocate to the brain through the blood stream after they are implanted in vivo. The aim of this study was to investigate the distribution of SNPs that crossed through the blood-brain barrier (BBB). An in vitro BBB model established by co-cultures of rat brain microvessel vascular endothelial cells (BMVECs) with astrocytes (ACs) was cultured with cell culture medium containing 100 microg/mL of either SNPs or silver microparticles (SMPs). After 4 hours of culture, the ultrastructure and its silver content of BBB was evaluated with transmission electronic microscopy (TEM) and inductively-coupled plasma mass spectrometry (ICP-MS) respectively. Results demonstrated that SNPs crossed the BBB and accumulated inside BMVECs, while the SMPs did not. The data indicated a special distribution of SNPs in the BBB and suggested that SNPs pass the BBB mainly by transcytosis of capillary endothelial cells. Further study would be necessary to evaluate the actual biological effects of SNPs on the brain.     

Guiding Brain‐Tumor Surgery via Blood–Brain‐Barrier‐Permeable Gold Nanoprobes with Acid‐Triggered MRI/SERRS Signals

Surgical resection is a mainstay in the treatment of malignant brain tumors. Surgeons, however, face great challenges in distinguishing tumor margins due to their infiltrated nature. Here, a pair of gold nanoprobes that enter a brain tumor by crossing the blood–brain barrier is developed. The acidic tumor environment triggers their assembly with the concomitant activation of both magnetic resonance (MR) and surface‐enhanced resonance Raman spectroscopy (SERRS) signals. While the bulky aggregates continuously trap into the tumor interstitium, the intact nanoprobes in normal brain tissue can be transported back into the blood stream in a timely manner. Experimental results show that physiological acidity triggers nanoparticle assembly by forming 3D spherical nanoclusters with remarkable MR and SERRS signal enhancements. The nanoprobes not only preoperatively define orthotopic glioblastoma xenografts by magnetic resonance imaging (MRI) with high sensitivity and durability in vivo, but also intraoperatively guide tumor excision with the assistance of a handheld Raman scanner. Microscopy studies verify the precisely demarcated tumor margin marked by the assembled nanoprobes. Taking advantage of the nanoprobes' rapid excretion rate and the extracellular acidification as a hallmark of solid tumors, these nanoprobes are promising in improving brain‐tumor surgical outcome with high specificity, safety, and universality.     

Intelligent Nanocomposites with Intrinsic Blood–Brain‐Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma

The blood–brain barrier (BBB) is the most important obstacle to improving the clinical outcomes of diagnosis and therapy of glioblastoma. Thus, the development of a novel nanoplatform that can efficiently traverse the BBB and achieve both precise diagnosis and therapy is of great importance. Herein, an intelligent nanoplatform based on holo‐transferrin (holo‐Tf) with in situ growth of MnO₂ nanocrystals is constructed via a reformative mild biomineralization process. Furthermore, protoporphyrin (ppIX), acting as a sonosensitizer, is then conjugated into holo‐Tf to obtain MnO₂@Tf‐ppIX nanoparticles (TMP). Because of the functional inheritance of holo‐Tf during fabrication, TMP can effectively traverse the BBB for highly specific magnetic resonance (MR) imaging of orthotopic glioblastoma. Clear suppression of tumor growth in a C6 tumor xenograft model is achieved via sonodynamic therapy. Importantly, the experiments also indicate that the TMP nanoplatform has satisfactory biocompatibility and biosafety, which favors potential clinical translation.     

Detection of β‐Amyloid by Sialic Acid Coated Bovine Serum Albumin Magnetic Nanoparticles in a Mouse Model of Alzheimer's Disease

The accumulation and formation of β‐amyloid (Aβ) plaques in the brain are distinctive pathological hallmarks of Alzheimer's disease (AD). Designing nanoparticle (NP) contrast agents capable of binding with Aβ highly selectively can potentially facilitate early detection of AD. However, a significant obstacle is the blood brain barrier (BBB), which can preclude the entrance of NPs into the brain for Aβ binding. In this work, bovine serum albumin (BSA) coated NPs are decorated with sialic acid (NP‐BSA_x‐Sia) to overcome the challenges in Aβ imaging in vivo. The NP‐BSA_x‐Sia is biocompatible with high magnetic relaxivities, suggesting that they are suitable contrast agents for magnetic resonance imaging (MRI). The NP‐BSA_x‐Sia binds with Aβ in a sialic acid dependent manner with high selectivities toward Aβ deposited on brains and cross the BBB in an in vitro model. The abilities of these NPs to detect Aβ in vivo in human AD transgenic mice by MRI are evaluated without the need to coinject mannitol to increase BBB permeability. T₂*‐weighted MRI shows that Aβ plaques in mouse brains can be detected as aided by NP‐BSA_x‐Sia, which is confirmed by histological analysis. Thus, NP‐BSA_x‐Sia is a promising new tool for noninvasive in vivo detection of Aβ plaques.     

Ultrathin Dual‐Scale Nano‐ and Microporous Membranes for Vascular Transmigration Models

Selective cellular transmigration across the microvascular endothelium regulates innate and adaptive immune responses, stem cell localization, and cancer cell metastasis. Integration of traditional microporous membranes into microfluidic vascular models permits the rapid assay of transmigration events but suffers from poor reproduction of the cell permeable basement membrane. Current microporous membranes in these systems have large nonporous regions between micropores that inhibit cell communication and nutrient exchange on the basolateral surface reducing their physiological relevance. Here, the use of 100 nm thick continuously nanoporous silicon nitride membranes as a base substrate for lithographic fabrication of 3 µm pores is presented, resulting in a highly porous (≈30%), dual‐scale nano‐ and microporous membrane for use in an improved vascular transmigration model. Ultrathin membranes are patterned using a precision laser writer for cost‐effective, rapid micropore design iterations. The optically transparent dual‐scale membranes enable complete observation of leukocyte egress across a variety of pore densities. A maximal density of ≈14 micropores per cell is discovered beyond which cell–substrate interactions are compromised giving rise to endothelial cell losses under flow. Addition of a subluminal extracellular matrix rescues cell adhesion, allowing for the creation of shear‐primed endothelial barrier models on nearly 30% continuously porous substrates.     

Anti‐VEGF‐Aptamer Modified C‐Dots—A Hybrid Nanocomposite for Topical Treatment of Ocular Vascular Disorders

The vascular endothelial growth factor (VEGF) induces pathological angiogenetic ocular diseases. It is a scientific challenge to develop carriers for the controlled release of inhibitors for VEGF present in the back of the eye domain. Carbon dots (C‐dots) functionalized with the VEGF aptamer are introduced and the hybrid nanoparticles are used for ocular nanomedicine. The C‐dots are applied as effective carriers of the anti‐VEGF aptamer across the cornea, yielding therapeutic levels upon topical administration. The hybrids show no toxicity for both in vitro and in vivo murine animal model, and further enable noninvasive intraocular concentration monitoring through the C‐dots inherent fluorescence. In addition, the hybrid C‐dots effectively inhibit VEGF‐stimulated angiogenesis in choroidal blood vessels. This inhibition is comparable to two commercially available anti‐VEGF drugs, bevacizumab and aflibercept. The hybrid aptamer‐modified C‐dots provide a versatile nanomaterial to treat age‐related macular degeneration and diabetic retinopathy.     

Through Scalp and Skull NIR‐II Photothermal Therapy of Deep Orthotopic Brain Tumors with Precise Photoacoustic Imaging Guidance

Brain tumor is one of the most lethal cancers owing to the existence of blood–brain barrier and blood–brain tumor barrier as well as the lack of highly effective brain tumor treatment paradigms. Herein, cyclo(Arg‐Gly‐Asp‐D‐Phe‐Lys(mpa)) decorated biocompatible and photostable conjugated polymer nanoparticles with strong absorption in the second near‐infrared (NIR‐II) window are developed for precise photoacoustic imaging and spatiotemporal photothermal therapy of brain tumor through scalp and skull. Evidenced by the higher efficiency to penetrate scalp and skull for 1064 nm laser as compared to common 808 nm laser, NIR‐II brain‐tumor photothermal therapy is highly effective. In addition, via a real‐time photoacoustic imaging system, the nanoparticles assist clear pinpointing of glioma at a depth of almost 3 mm through scalp and skull with an ultrahigh signal‐to‐background ratio of 90. After spatiotemporal photothermal treatment, the tumor progression is effectively inhibited and the survival spans of mice are significantly extended. This study demonstrates that NIR‐II conjugated polymer nanoparticles are promising for precise imaging and treatment of brain tumors.     

Novel Tunnel‐Contact‐Controlled IGZO Thin‐Film Transistors with High Tolerance to Geometrical Variability

Thin insulating layers are used to modulate a depletion region at the source of a thin‐film transistor. Bottom contact, staggered‐electrode indium gallium zinc oxide transistors with a 3 nm Al₂O₃ layer between the semiconductor and Ni source/drain contacts, show behaviors typical of source‐gated transistors (SGTs): low saturation voltage (V_{D_SAT} ≈ 3 V), change in V_{D_SAT} with a gate voltage of only 0.12 V V^?1, and flat saturated output characteristics (small dependence of drain current on drain voltage). The transistors show high tolerance to geometry: the saturated current changes only 0.15× for 2–50 µm channels and 2× for 9‐45 µm source‐gate overlaps. A higher than expected (5×) increase in drain current for a 30 K change in temperature, similar to Schottky‐contact SGTs, underlines a more complex device operation than previously theorized. Optimization for increasing intrinsic gain and reducing temperature effects is discussed. These devices complete the portfolio of contact‐controlled transistors, comprising devices with Schottky contacts, bulk barrier, or heterojunctions, and now, tunneling insulating layers. The findings should also apply to nanowire transistors, leading to new low‐power, robust design approaches as large‐scale fabrication techniques with sub‐nanometer control mature.     

Human‐on‐Leaf‐Chip: A Biomimetic Vascular System Integrated with Chamber‐Specific Organs

The vascular network is a central component of the organ‐on‐a‐chip system to build a 3D physiological microenvironment with controlled physical and biochemical variables. Inspired by ubiquitous biological systems such as leaf venation and circulatory systems, a fabrication strategy is devised to develop a biomimetic vascular system integrated with freely designed chambers, which function as niches for chamber‐specific vascularized organs. As a proof of concept, a human‐on‐leaf‐chip system with biomimetic multiscale vasculature systems connecting the self‐assembled 3D vasculatures in chambers is fabricated, mimicking the in vivo complex architectures of the human cardiovascular system connecting vascularized organs. Besides, two types of vascularized organs are built independently within the two halves of the system to verify its feasibility for conducting comparative experiments for organ‐specific metastasis studies in a single chip. Successful culturing of human hepatoma G2 cells (HepG2s) and mesenchymal stem cells (MSCs) with human umbilical vein endothelial cells (HUVECs) shows good vasculature formation, and organ‐specific metastasis is simulated through perfusion of pancreatic cancer cells and shows distinct cancer encapsulation by MSCs, which is absent in HepG2s. Given good culture efficacy, study design flexibility, and ease of modification, these results show that the bioinspired human‐on‐leaf‐chip possesses great potential in comparative and metastasis studies while retaining organ‐to‐organ crosstalk.     

Dual‐Modal NIR‐Fluorophore Conjugated Magnetic Nanoparticle for Imaging Amyloid‐β Species In Vivo

Senile plaques, the extracellular deposit of amyloid‐β (Aβ) peptides, are one of the neuropathological hallmarks found in Alzheimer's disease (AD) brain. The current method of brain imaging of amyloid plaques based on positron emission tomography (PET) is expensive and invasive with low spatial resolution. Thus, the development of sensitive and nonradiative amyloid‐β (Aβ)‐specific contrast agents is highly important and beneficial to achieve early AD detection, monitor the disease progression, and evaluate the effectiveness of potential AD drugs. Here a neuroprotective dual‐modal nanoprobe developed by integrating highly Aβ‐specific and turn‐on fluorescence cyanine sensors with superparamagnetic iron oxide nanoparticles as an effective near‐infrared imaging (NIRI)/magnetic resonance imaging (MRI) contrast agent for imaging of Aβ species in vivo is reported. This Aβ‐specific probe is found not only nontoxic and noninvasive, but also highly blood brain barrier permeable. It also shows a potent neuroprotective effect against Aβ‐induced toxicities. This nanoprobe is successfully applied for in vivo fluorescence imaging with high sensitivity and selectivity to Aβ species, and MRI with high spatial resolution in an APP/PS1 transgenic mice model. Its potential as a powerful in vivo dual‐modal imaging tool for early detection and diagnosis of AD in humans is affirmed.     

Mineral Oil Barrier Testing of Cellulose‐Based and Polypropylene‐Based Films

Recycled cardboard has been identified as a major source of mineral oil hydrocarbon (MOH) contamination of foods. Identifying and using appropriate functional barriers is a mechanism through which this problem can be addressed. A number of cellulose‐based and biaxially oriented polypropylene (BOPP) films were evaluated as potential functional MOH barriers. The films were tested using a donor material, a paper containing MOH placed on one side of the film barrier and a paper which acted as the receptor on the other. Testing was performed at accelerated conditions of 60°C, the receptor analysed periodically for MOH. The results demonstrated that the cellulose‐based film types provided an MOH barrier of >3.5 years. This contrasted with the BOPP selected films, for which only the proprietary acrylic‐coated BOPP film provided an effective barrier to MOH migration. Further investigation of the MOH barrier properties of the proprietary acrylic‐coated BOPP film was undertaken. Various coating strategies were employed including increasing the coating application weight, increasing the number of coating lay downs and coating one or both surfaces of the film. It was found that an MOH barrier of 1.5 years when tested at 40°C could be achieved for the proprietary acrylic‐coated BOPP film; however, barrier effectiveness was dependent on the coating integrity of the film. Further work with a vertical form filler packaging machine and the use of a staining technique with transmission microscopy proved effective at highlighting and assessing the coating integrity of packets during a typical packaging operation. Copyright © 2014 John Wiley & Sons, Ltd.     

One‐Step Hydrothermal Synthesis of Nitrogen‐Doped Conjugated Carbonized Polymer Dots with 31% Efficient Red Emission for In Vivo Imaging

Carbon dots with long‐wavelength emissions, high quantum yield (QY) and good biocompatibility are highly desirable for biomedical applications. Herein, a green, facile hydrothermal synthesis of highly efficient red emissive nitrogen‐doped carbonized polymer dots (CPDs) with optimal emission at around 630 nm are reported. The red emissive CPDs possess a variety of superior properties including excellent water dispersibility, good biocompatibility, narrow bandwidth emission, an excitation‐independent emission, and high QY (10.83% (in water) and 31.54% (in ethanol)). Further studies prove that such strong red fluorescence is ascribed to the efficient conjugated aromatic π systems and hydrogen bonds of CPDs. And the fluorescence properties of CPDs can be regulated by adjusting the dosage of HNO₃ before the reaction. Additionally, the as‐prepared CPDs are successfully used as a fluorescent probe for bioimaging, both in vitro and in vivo. More importantly, biodistribution results demonstrate that most CPDs and their metabolites are not only excreted in urine but also excreted by hepatobiliary system in a rapid manner. Besides, the CPDs could easily cross the blood brain barrier, which may provide a valuable strategy for the theranostics of some brain diseases through real‐time tracking.