Green synthesis of iron-doped graphene quantum dots: an efficient nanozyme for glucose sensing.

Single-atom nanozymes with well-defined atomic structures and electronic coordination environments can effectively mimic the functions of natural enzymes. However, the costly and intricate preparation processes have hindered further exploration and application of these single-atom nanozymes. In this study, we presented a synthesis technique for creating Fe-N central single-atom doped graphene quantum dot (FeN/GQDs) nanozymes using a one-step solvothermal process, where individual iron atoms form strong bonds with graphene quantum dots through nitrogen coordination. Unlike previous studies, this method significantly simplifies the synthesis conditions for single-atom nanozymes, eliminating the need for high temperatures and employing environmentally friendly precursors derived from pineapple (ananas comosus) leaves. The resulting FeN/GQDs exhibited peroxidase-like catalytic activity and kinetics comparable to that of natural enzymes, efficiently converting H2O2 into hydroxyl radical species. Leveraging their excellent peroxide-like activity, FeN/GQDs nanozymes have been successfully applied to construct a colorimetric biosensor system characterized by remarkably high sensitivity for glucose detection. This achievement demonstrated a promising approach to designing single-atom nanozymes with both facile synthesis procedures and high catalytic activity, offering potential applications in wearable sensors and personalized health monitoring.

Effect of Gravity on Bacterial Adhesion to Heterogeneous Surfaces.

Bacterial adhesion is the first step in the formation of surface biofilms. The number of bacteria that bind to a surface from the solution depends on how many bacteria can reach the surface (bacterial transport) and the strength of interactions between bacterial adhesins and surface receptors (adhesivity). By using microfluidic channels and video microscopy as well as computational simulations, we investigated how the interplay between bacterial transport and adhesivity affects the number of the common human pathogen Escherichia coli that bind to heterogeneous surfaces with different receptor densities. We determined that gravitational sedimentation causes bacteria to concentrate at the lower surface over time as fluid moves over a non-adhesive region, so bacteria preferentially adhere to adhesive regions on the lower, inflow-proximal areas that are downstream of non-adhesive regions within the entered compartments. Also, initial bacterial attachment to an adhesive region of a heterogeneous lower surface may be inhibited by shear due to mass transport effects alone rather than shear forces per se, because higher shear washes out the sedimented bacteria. We also provide a conceptual framework and theory that predict the impact of sedimentation on adhesion between and within adhesive regions in flow, where bacteria would likely bind both in vitro and in vivo, and how to normalize the bacterial binding level under experimental set-ups based on the flow compartment configuration.

Iron Oxide Nanoparticle-Mediated mRNA Delivery to Hard-to-Transfect Cancer Cells.

mRNA-based therapeutics have emerged as a promising strategy for cancer treatment. However, the effective delivery of mRNA into hard-to-transfect cancer cells remains a significant challenge. This study introduces a novel approach that utilizes iron oxide nanoparticles (NPs) synthesized through a layer-by-layer (LbL) method for safe and efficient mRNA delivery. The developed NPs consist of an iron oxide core modified with a thin charge-bearing layer, an mRNA middle layer, and an outer layer composed of perfluorinated polyethyleneimine with heparin (PPH), which facilitates efficient mRNA delivery. Through a comparative analysis of four nanoparticle delivery formulations, we investigated the effects of the iron oxide core's surface chemistry and surface charge on mRNA complexation, cellular uptake, and mRNA release. We identified an optimal and effective mRNA delivery platform, namely, (IOCCP)-mRNA-PPH, capable of transporting mRNA into various hard-to-transfect cancer cell lines in vitro. The (IOCCP)-mRNA-PPH formulation demonstrated significant enhancements in cellular internalization of mRNA, facilitated endosomal escape, enabled easy mRNA release, and exhibited minimal cytotoxicity. These findings suggest that (IOCCP)-mRNA-PPH holds great promise as a solution for mRNA therapy against hard-to-transfect cancers.

Ligand Chemistry in Antitumor Theranostic Nanoparticles.

Theranostic nanoparticles' potential in tumor treatment has been widely acknowledged thanks to their capability of integrating multifaceted functionalities into a single nanosystem. Theranostic nanoparticles are typically equipped with an inorganic core with exploitable physical properties for imaging and therapeutic functions, bioinert coatings for improved biocompatibility and immunological stealth, controlled drug-loading-release modules, and the ability to recognize specific cell type for uptake. Integrating multiple functionalities in a single nanosized construct require sophisticated molecular design and precise execution of assembly procedures. Underlying the multifunctionality of theranostic nanoparticles, ligand chemistry plays a decisive role in translating theoretical designs into fully functionalized theranostic nanoparticles. The ligand hierarchy in theranostic nanoparticles is usually threefold. As they serve to passivate the nanoparticle's surface, capping ligands form the first layer directly interfacing with the crystalline lattice of the inorganic core. The size and shape of nanoparticles are largely determined by the molecular property of capping ligands so that they have profound influences on the nanoparticles' surface chemistry and physical properties. Capping ligands are mostly chemically inert, which necessitates the presence of additional ligands for drug loading and tumor targeting. The second layer is commonly utilized for drug loading. Therapeutic drugs can either be covalently conjugated onto the capping layer or noncovalently loaded onto nanoparticles via drug-loading ligands. Drug-loading ligands need to be equally versatile in properties to accommodate the diversity of drugs. Biodegradable moieties are often incorporated into drug-loading ligands to enable smart drug release. With the aid of targeting ligands which usually stand the tallest on the nanoparticle surface to seek and bind to their corresponding receptors on the target, theranostic nanoparticles can preferentially accumulate at the tumor site to attain a higher precision and quantity for drug delivery. In this Account, the properties and utilities of representative capping ligands, drug-loading ligands, and targeting ligands are reviewed. Since these types of ligands are often assembled in close vicinity to each other, it is essential for them to be chemically compatible and able to function in tandem with each other. Relevant conjugation strategies and critical factors with a significant impact on ligands' performance on nanoparticles are discussed. Representative theranostic nanoparticles are presented to showcase how different types of ligands function synergistically from a single nanosystem. Finally, the technological outlook of evolving ligand chemistry on theranostic nanoparticles is provided.

Enhanced Cell Penetration and Pluripotency Maintenance of hiPSCs in 3D Natural Chitosan Scaffolds.

Human-induced pluripotent stem cells (hiPSCs) cultured in 3D matrices hold great promise in disease modeling, drug discovery, and tissue regeneration. Uniform cell distribution in a 3D structure is critical to the growth and function of hiPSCs, yet cell seeding in 3D matrices often remains superficial, leading to limited cell proliferation and compromised pluripotency. Here, an approach to improve cell penetration depth of hiPSCs in 3D scaffolds modified with hiPSCs conditioned medium (CM) is reported. It is shown that extracellular matrix components are successfully deposited onto the scaffold wall surface after CM treatment and promoted homogeneous cell adhesion during initial seeding. Compared to plain, unmodified scaffolds, the CM treated scaffold improves spatial cell distribution uniformity and upregulates pluripotency markers. Notably, the expression of 29 genes associated with 11 signaling pathways participated in the pluripotency maintenance of hiPSCs exhibits >2-fold change in hiPSCs grown in the CM treated scaffolds than 2D counterparts, demonstrating that CM treated scaffolds can support a more primitive and undifferentiated phenotype of hiPSCs. This study introduces a simple and effective method to enhance cell penetration and maintain cell pluripotency in 3D matrices.

Enzymatic and Cellular Degradation of Carbon-Based Biconcave Nanodisks.

The assessment of the biodegradability of nanomaterials is of pragmatic importance for understanding the interactions between nanomaterials and biological systems and for the determination of ultimate fate of these materials as well as their potential use. We recently developed carbon-based biconcave nanodisks (CBBNs) serving as a versatile nanocarrier for enhanced accumulation in tumors and combined photothermal-chemotherapy. Here, we investigate both the enzymatic and cellular degradation of CBBNs by monitoring their cellular response with electron microscopy, near-infrared absorbance spectroscopy, and cell viability and oxidative stress assessments. Our results show that CBBNs underwent significant degradation in solutions catalyzed by horseradish peroxidase (HRP) and hydrogen peroxide (H2O2), or in the presence of macrophage cells. The ability of CBBNs to be degraded in biological systems provides suitability for their future biomedical applications.

Chitosan-Crosslinked Low Molecular Weight PEI-Conjugated Iron Oxide Nanoparticle for Safe and Effective DNA Delivery to Breast Cancer Cells.

Breast cancer has attracted tremendous research interest in treatment development as one of the major threats to public health. The use of non-viral carriers for therapeutic DNA delivery has shown promise in treating various cancer types, including breast cancer, due to their high DNA loading capacity, high cell transfection efficiency, and design versatility. However, cytotoxicity and large sizes of non-viral DNA carriers often raise safety concerns and hinder their applications in the clinic. Here we report the development of a novel nanoparticle formulation (termed NP-Chi-xPEI) that can safely and effectively deliver DNA into breast cancer cells for successful transfection. The nanoparticle is composed of an iron oxide core coated with low molecular weight (800 Da) polyethyleneimine crosslinked with chitosan via biodegradable disulfide bonds. The NP-Chi-xPEI can condense DNA into a small nanoparticle with the overall size of less than 100 nm and offer full DNA protection. Its biodegradable coating of small-molecular weight xPEI and mildly positive surface charge confer extra biocompatibility. NP-Chi-xPEI-mediated DNA delivery was shown to achieve high transfection efficiency across multiple breast cancer cell lines with significantly lower cytotoxicity as compared to the commercial transfection agent Lipofectamine 3000. With demonstrated favorable physicochemical properties and functionality, NP-Chi-xPEI may serve as a reliable vehicle to deliver DNA to breast cancer cells.

Inorganic Nanomaterial-Mediated Gene Therapy in Combination with Other Antitumor Treatment Modalities.

Cancer is a genetic disease originating from the accumulation of gene mutations in a cellular subpopulation. Although many therapeutic approaches have been developed to treat cancer, recent studies have revealed an irrefutable challenge that tumors evolve defenses against some therapies. Gene therapy may prove to be the ultimate panacea for cancer by correcting the fundamental genetic errors in tumors. The engineering of nanoscale inorganic carriers of cancer therapeutics has shown promising results in the efficacious and safe delivery of nucleic acids to treat oncological diseases in small-animal models. When these nanocarriers are used for co-delivery of gene therapeutics along with auxiliary treatments, the synergistic combination of therapies often leads to an amplified health benefit. In this review, an overview of the inorganic nanomaterials developed for combinatorial therapies of gene and other treatment modalities is presented. First, the main principles of using nucleic acids as therapeutics, inorganic nanocarriers for medical applications and delivery of gene/drug payloads are introduced. Next, the utility of recently developed inorganic nanomaterials in different combinations of gene therapy with each of chemo, immune, hyperthermal, and radio therapy is examined. Finally, current challenges in the clinical translation of inorganic nanomaterial-mediated therapies are presented and outlooks for the field are provided.

siRNA nanoparticle suppresses drug-resistant gene and prolongs survival in an orthotopic glioblastoma xenograft mouse model.

Temozolomide (TMZ) is the standard of care chemotherapy drug for treating glioblastomas (GBMs), the most aggressive cancer that affects people of all ages. However, its therapeutic efficacy is limited by the drug resistance mediated by a DNA repair protein, O6-methylguanine-DNA methyltransferase (MGMT), which eliminates the TMZ-induced DNA lesions. Here we report the development of an iron oxide nanoparticle (NP) system for targeted delivery of siRNAs to suppress the TMZ-resistance gene (MGMT). We show that our NP is able to overcome biological barriers, bind specifically to tumor cells, and reduce MGMT expression in tumors of mice bearing orthotopic GBM serially-passaged patient-derived xenografts. The treatment with sequential administration of this NP and TMZ resulted in increased apoptosis of GBM stem-like cells, reduced tumor growth, and significantly-prolonged survival as compared to mice treated with TMZ alone. This study introduces an approach that holds great promise to improve the outcomes of GBM patients.

Iron oxide nanoparticle targeted chemo-immunotherapy for triple negative breast cancer.

Triple negative breast cancer is difficult to treat effectively, due to its aggressiveness, drug resistance, and lack of the receptors required for hormonal therapy, particularly at the metastatic stage. Here, we report the development and evaluation of a multifunctional nanoparticle formulation containing an iron oxide core that can deliver doxorubicin, a cytotoxic agent, and polyinosinic:polycytidylic acid (Poly IC), a TLR3 agonist, in a targeted and simultaneous fashion to both breast cancer and dendritic cells. Endoglin-binding peptide (EBP) is used to target both TNBC cells and vasculature epithelia. The nanoparticle demonstrates favorable physicochemical properties and a tumor-specific targeting profile. The nanoparticle induces tumor apoptosis through multiple mechanisms including direct tumor cell killing, dendritic cell-initiated innate and T cell-mediated adaptive immune responses. The nanoparticle markedly inhibits tumor growth and metastasis and substantially extends survival in an aggressive and drug-resistant metastatic mouse model of triple negative breast cancer (TNBC). This study points to a promising platform that may substantially improve the therapeutic efficacy for treating metastatic TNBC.

A highly selective iron oxide-based imaging nanoparticle for long-term monitoring of drug-induced tumor cell apoptosis.

The ability to visualize and quantify apoptosis in vivo is critical to monitoring the disease response to treatment and providing prognostic information. However, the application of current apoptosis labeling probes faces significant challenges including nonspecific tissue uptake, inefficient apoptotic cell labeling and short monitoring windows. Here we report a highly specific apoptosis labeling nanoparticle (NP) probe with Pisum sativum agglutinin (PSA) as a tumor targeting ligand for prolonged in vivo apoptosis imaging. The NP (namely, IONP-Neu-PSA) consists of a magnetic iron oxide core (IONP) conjugated with PSA, and a reporter fluorophore. IONP-Neu-PSA demonstrated minimal cytotoxicity and high labeling specificity towards apoptotic cells in vitro. When applied in vivo, IONP-Neu-PSA tracks apoptotic tumors for a prolonged period of two weeks under near-IR imaging with low background noise. Moreover, IONP-Neu-PSA possesses T2 contrast enhancing properties that can potentially enable apoptosis detection by magnetic resonance imaging (MRI). The high specificity for apoptotic cells, sustained fluorescence signals, and non-invasive imaging capability exhibited by IONP-Neu-PSA make it a versatile tool for cancer treatment monitoring and pathological research.

Enhancing the Efficiency of a Forward Osmosis Membrane with a Polydopamine/Graphene Oxide Layer Prepared Via the Modified Molecular Layer-by-Layer Method.

Water scarcity is one of the most critical problems that humans have to face. Working toward solving this problem, we have developed a thin-film composite (TFC) membrane using the modified molecular layer-by-layer (modified mLBL) method to fabricate polyamide (PA) active layers on different substrates. Besides, it has been found that graphene oxide (GO) contains abundant functional groups such as hydroxyl and epoxide groups, which are able to improve both the physical and chemical properties of the forward osmosis (FO) membrane. Thus, we have employed graphene oxide (GO) as the substrate and used the modified mLBL method to prepare active polydopamine/graphene oxide (PDA/GO) layers to enhance the water flux of the forward osmosis (FO) membrane. PDA/GO-coated layers could enhance the hydrophilic nature of the substrate and lower its surface roughness, which would facilitate the formation of the PA layer. Moreover, the PDA/GO coating can be applied to all substrates because of the high degree of adhesion of PDA to different substrates. In this study, the highly hydrophilic poly(vinylidene fluoride) membrane is superior in FO properties, with a water flux of 17.32 LMH and a reverse solute flux of 4.34 gMH. In addition, an excellent performance of 60.15 LMH and 14.88 gMH can be achieved when the pressure-retarded osmosis (PRO) test mode with a draw solution concentration of 2.0 M is used in the test. It shows that the membrane prepared using the novel method showed excellent FO performance, which has high potential in industrial applications such as desalination.

Cocaine analogue conjugated magnetic nanoparticles for labeling and imaging dopaminergic neurons.

Molecular imaging of the dopamine transporter (DAT) with Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) has been widely used in studies of neurological and psychiatric disorders. Nevertheless, there is a great interest in expanding molecular imaging to include magnetic resonance technology, because of the superior spatial resolution this technology may provide. Here we present a magnetic nanoparticle (NP) that specifically targets dopaminergic neurons and allows DAT imaging with magnetic resonance imaging (MRI). The nanoparticle (namely, NP-DN) is composed of an iron oxide core and a polyethylene glycol (PEG) coating to which a DAT specific dopaminergic neurolabeler (DN) is conjugated. NP-DN displayed long-term stability with favorable hydrodynamic size and surface charge suitable for in vivo application. In vitro studies showed NP-DN was non-toxic, displayed specificity towards DAT-expressing neurons, and demonstrated a 3-fold increase in DAT labeling over non-targeted NP. Our study shows NP-DN provides excellent contrast enhancement for MRI and demonstrates great potential for neuroimaging.

Single-layer boron-doped graphene quantum dots for contrast-enhanced in vivo T1-weighted MRI.

Gadolinium (Gd)-based chelates are used as clinical T1 contrast agents for magnetic resonance imaging (MRI) due to their demonstrated high sensitivity and positive contrast enhancement capability. However, there has been an increasing safety concern about their use in medicine because of the toxicity of the metal ions released from these contrast agents when used in vivo. Although significant effort has been made in developing metal-free MRI contrast agents, none have matched the magnetic properties achieved by the gold standard clinical contrast agent, Gd diethylene penta-acetic acid (Gd-DTPA). Here, we report the development of a single-layer, boron-doped graphene quantum dot (termed SL-BGQD) that demonstrates better T1 contrast enhancement than Gd-DTPA. The SL-BGQD is shown to provide significantly higher positive contrast enhancement than the Gd-DTPA contrast agent in imaging vital organs, including kidneys, liver, and spleen, and especially, vasculatures. Further, our results show that the SL-BQGD is able to bypass the blood-brain barrier and allows sustained imaging for at least one hour with a single injection. Hematological and histopathological analyses show that the SL-BGQD demonstrates a non-toxic profile in wild-type mice and may, therefore, serve as an improved, safer alternative to currently available clinical MRI contrast agents.

In vivo Serum Enabled Production of Ultrafine Nanotherapeutics for Cancer Treatment.

Systemic delivery of hydrophobic anti-cancer drugs with nanocarriers, particularly for drug-resistant and metastatic cancer, remain a challenge because of the difficulty to achieve high drug loading, while maintaining a small hydrodynamic size and colloid stability in blood to ensure delivery of an efficacious amount of drug to tumor cells. Here we introduce a new approach to address this challenge. In this approach, nanofibers of larger size with good drug loading capacity are first constructed by a self-assembly process, and upon intravascular injection and interacting with serum proteins in vivo, these nanofibers break down into ultra-fine nanoparticles of smaller size that inherit the drug loading property from their parent nanofibers. We demonstrate the efficacy of this approach with a clinically available anti-cancer drug: paclitaxel (PTX). In vitro, the PTX-loaded nanoparticles enter cancer cells and induce cellular apoptosis. In vivo, they demonstrate prolonged circulation in blood, induce no systemic toxicity, and show high potency in inhibiting tumor growth and metastasis in both mouse models of aggressive, drug-resistant breast cancer and melanoma. This study points to a new strategy toward improved anti-cancer drug delivery and therapy.

Catalase-Functionalized Iron Oxide Nanoparticles Reverse Hypoxia-Induced Chemotherapeutic Resistance.

Intratumoral hypoxia is a major contributor to multiple drug resistance (MDR) in cancer, and can lead to poor prognosis of patients receiving chemotherapy. Development of an MDR-inhibitor that mitigates the hypoxic environment is crucial for cancer management and treatment. Reported is a biocompatible and biodegradable catalase-conjugated iron oxide nanoparticle (Cat-IONP) capable of converting reactive oxygen species to molecular oxygen to supply an oxygen source for the hypoxic tumor microenvironment. Cat-IONP demonstrates initial enzymatic activity comparable to free catalase while providing a nearly threefold increase in long-term enzymatic activity. It is demonstrated that Cat-IONP significantly reduces the in vitro expression of hypoxia-inducible factors at the transcription level in a breast cancer cell line. Co-treatment of Cat-IONP and paclitaxel (PTX) significantly increases the drug sensitivity of hypoxic-cultured cells, demonstrating greater than twofold and fivefold reduction in cell viability in comparison to cells treated only with 80 and 120 × 10-6 m PTX, respectively. These findings demonstrate the ability of Cat-IONP to act as an MDR-inhibitor at different biological levels, suggesting a promising strategy to combat cancer-MDR and to optimize cancer management and treatment outcomes.

Polysaccharidic spent coffee grounds for silver nanoparticle immobilization as a green and highly efficient biocide.

Spent coffee grounds (SCGs) contain abundant polysaccharides and several components with bioactivities. Despite many bio-functionalities, their bioactivities are not always satisfactory. Modifications of SCGs may overcome this issue. This work describes the method for reusing the SCGs as biological macromolecular supports and reducing agents to prepare silver nanoparticle (AgNP)/SCGS composites (AgNPs@SCGs) by biogenic synthesis. The AgNPs anchored on the surface of SCGs were synthesized by mixing the SCGs in AgNO3 solution with various pH conditions at room temperature. Scanning electron microscopy (SEM) and X-ray diffractometer (XRD) analysis confirmed the reduction of silver ions to AgNPs, and showed that the pH 4.5 condition could generate uniform and impurity-free AgNPs on the surface of SCGs. Fourier-transform infrared spectroscopy (FTIR), energy-dispersive X-ray spectroscopy (EDX), and thermal gravimetric analysis (TGA) showed that the reducing process of AgNPs was mild and could preserve the original nature of the SCGs. The AgNPs@SCGs composites exhibited an excellent antimicrobial ability against S. aureus and E. coli compared to SCGs. The transformation of the polysaccharidic SCGs to AgNPs@SCGs composites by the green and sustainable method makes them highly valuable for developing the applications on antimicrobial products.

Iron oxide-carbon core-shell nanoparticles for dual-modal imaging-guided photothermal therapy.

Nanostructured materials that have low tissue toxicity, multi-modal imaging capability and high photothermal conversion efficiency have great potential to enable image-guided near infrared (NIR) photothermal therapy (PTT). Here, we report a bifunctional nanoparticle (BFNP, ∼16 nm) comprised of a magnetic Fe3O4 core (∼9.1 nm) covered by a fluorescent carbon shell (∼3.4 nm) and prepared via a one-pot solvothermal synthesis method using ferrocene as the sole source. The BFNP exhibits excitation wavelength-tunable, upconverted and near-infrared (NIR) fluorescence property due to the presence of the carbon shell, and superparamagnetic behavior resulted from the Fe3O4 core. BFNPs demonstrate dual-modal imaging capacity both in vitro and in vivo with fluorescent imaging excited under a varying wavelength from 405 nm to 820 nm and with T2-weighted magnetic resonance imaging (r2 = 264.76 mM-1 s-1). More significantly, BFNPs absorb and convert NIR light to heat enabling photothermal therapy as demonstrated mice bearing C6 glioblastoma. These BFNPs show promise as an advanced nanoplatform to provide imaging guided photothermal therapy.

A Real-Time Contactless Pulse Rate and Motion Status Monitoring System Based on Complexion Tracking.

Subject movement and a dark environment will increase the difficulty of image-based contactless pulse rate detection. In this paper, we detected the subject's motion status based on complexion tracking and proposed a motion index (MI) to filter motion artifacts in order to increase pulse rate measurement accuracy. Additionally, we integrated the near infrared (NIR) LEDs with the adopted sensor and proposed an effective method to measure the pulse rate in a dark environment. To achieve real-time data processing, the proposed framework is constructed on a Field Programmable Gate Array (FPGA) platform. Next, the instant pulse rate and motion status are transmitted to a smartphone for remote monitoring. The experiment results showed the error of the pulse rate detection to be within -3.44 to +4.53 bpm under sufficient ambient light and -2.96 to + 4.24 bpm for night mode detection, when the moving speed is higher than 14.45 cm/s. These results demonstrate that the proposed method can improve the robustness of image-based contactless pulse rate detection despite subject movement and a dark environment.

Gemcitabine and Chlorotoxin Conjugated Iron Oxide Nanoparticles for Glioblastoma Therapy.

Many small-molecule anti-cancer drugs have short blood half-lives and toxicity issues due to non-specificity. Nanotechnology has shown great promise in addressing these issues. Here, we report the development of an anti-cancer drug gemcitabine-conjugated iron oxide nanoparticle for glioblastoma therapy. A glioblastoma targeting peptide, chlorotoxin, was attached after drug conjugation. The nanoparticle has a small size (~32 nm) and uniform size distribution (PDI ≈ 0.1), and is stable in biological medium. The nanoparticle effectively enter cancer cells without losing potency compared to free drug. Significantly, the nanoparticle showed a prolonged blood half-life and the ability to cross the blood-brain barrier in wild type mice.