Search Results (565)

Rheumatoid arthritis (RA) treatment is severely hindered by the systemic toxicity and limited joint accumulation of conventional therapeutics. To overcome these critical clinical challenges, we engineered a biomimetic dual-targeted nanoplatform (MTX@HSA@M@HA NPs) to precisely deliver methotrexate (MTX) to inflamed synovia. The rationally designed system encapsulates MTX within human serum albumin (HSA) nanoparticles, which are subsequently cloaked in red blood cell membranes (RBCMs) for robust immune evasion and prolonged systemic circulation. To achieve active targeting, the nanoparticle surface was functionalized with hyaluronic acid (HA) to selectively bind CD44 receptors, which are heavily overexpressed on RA-driving macrophages and fibroblast-like synoviocytes (FLSs). In vitro evaluations demonstrated significantly enhanced cellular internalization by activating RAW264.7 macrophages and FLS, resulting in the potent suppression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) with minimal baseline cytotoxicity. Furthermore, comprehensive in vivo studies using a collagen-induced arthritis (CIA) murine model confirmed that MTX@HSA@M@HA NPs significantly ameliorated joint inflammation, attenuated paw swelling, and rapidly improved functional outcomes compared to free MTX. By synergizing RBCM camouflage with HA-directed active targeting, this nanoplatform maximizes localized therapeutic efficacy while minimizing systemic toxicity, thereby presenting a highly promising and translatable strategy for targeted RA treatment. Full article

A continued interest in developing a low-cost, rapid screening method for quantifying Hg (II) and As (III) in biological samples stems from the toxic effects of human exposure to these heavy metal ions. This study reports the use of cysteine-capped gold nanoparticles (CysAuNPs) for chemical sensing, colorimetric detection, and quantification of As (III) and Hg (II) ions in human serum albumin (HSA) under physiological conditions. Zeta potential measurements indicated that the CysAuNPs have a negative surface charge, which was decreased in the presence of HSA and reversed to a positive value upon binding of As (III) and Hg (II) metal ions. Circular dichroism (CD) spectroscopy revealed changes in HSA conformation upon binding to As (III) and Hg (II) ions. X-ray fluorescence enables rapid qualitative screening for As (III) and Hg (II) ions before colorimetric quantification. The figures of merit (R² ≥ 0.940) and the low detection limits (0.05 ppm for As (III) ions and 0.02 ppm for Hg (II)) in serum albumin demonstrate the high sensitivity of the method. The developed calibration curves correctly quantified the concentration of As (III) and Hg (II) ions of independently prepared test validation samples in HSA with an accuracy of ≥95% over a period of seven months without recalibrations, demonstrating the stability of CysAuNPs in solution and the robustness of the method for analysis of As (III) and Hg (II) ions in serum albumin. Full article

Background/Objectives: This study investigates the induction of cuproptosis in A549 lung cancer cells by doxorubicin (DOX) complexes and the development of pH-responsive bovine serum albumin (BSA)-based nanocarriers for their delivery. We successfully synthesized and characterized two novel complexes: DOX–Cu, where DOX acts as a ligand for Cu(II), and DOX–BTZ, a conjugate formed between DOX and the proteasome inhibitor bortezomib (BTZ). Methods: Spectroscopic and NMR analyses were performed to confirm the formation of the complexes. In vitro assays were conducted to evaluate cytotoxicity in A549 cells, alongside assessment of DLAT aggregation as a marker of cuproptosis. The formulation of DOX into BSA nanoparticles (DOX–Cu@BSA NPs and DOX–BTZ@BSA NPs) was carried out to evaluate potential alleviation of DOX-induced cytotoxicity in cardiomyocytes in vitro. Fluorescence quenching and molecular docking studies were employed to investigate the binding interactions between the complexes and BSA. Cellular uptake experiments were performed to assess nanoparticle internalization into A549 cells. Results: Both complexes exhibited superior cytotoxicity against A549 cells compared to individual components. This enhanced cell death was associated with significant aggregation of dihydrolipoamide S-acetyltransferase (DLAT), a key marker of cuproptosis, suggesting the involvement of this copper-dependent cell death pathway. The BSA nanoparticles displayed favorable characteristics, including uniform size (~190 nm), high encapsulation efficiency (~75–79%), and colloidal stability. Crucially, they exhibited a pH-responsive drug release profile, with significantly accelerated release under acidic conditions (pH 5.7) mimicking the tumor microenvironment. Fluorescence quenching and molecular docking studies revealed strong, spontaneous binding between the complexes and BSA, primarily driven by hydrophobic interactions. Cellular uptake experiments confirmed efficient internalization of the nanoparticles into A549 cells. Conclusions: Collectively, this work offers a proof-of-concept for a strategy of utilizing BSA-based multidrug delivery systems for cuproptosis induction, offering a potential avenue to enhance therapeutic efficacy while reducing systemic toxicity in lung cancer treatment. Full article

Cancer remains a major global health challenge, characterized by abnormal cell growth and metastasis. Current limitations of conventional therapies, particularly non-specific toxicity harming healthy cells, highlight the need for more targeted approaches. Nanotechnology offers a revolutionary solution, utilizing nanoparticles (NPs) for precise drug delivery to tumor sites while minimizing off-target effects. These nanometer-scale particles enable superior binding to cancer cell membranes, the tumor microenvironment, or nuclear receptors, facilitating significantly higher local concentrations of therapeutic agents. NPs, synthesized via physical, chemical, or biological methods, are categorized as organic (organic material-based) or inorganic (metallic particle-based). Key delivery mechanisms include the Enhanced Permeability and Retention (EPR) effect and Active Transport and Retention (ATR). This review specifically examines NP applications for the most prevalent cancers in the US (2025): breast, prostate, and lung. Gold and magnetic NPs show significant promise for early breast cancer detection. For lung cancer, polymeric NPs like PCL, PLA, and PLGA are effective carriers for peptides, proteins, and nucleic acids. BIND-014, a docetaxel-loaded NP formulation, represents an emerging strategy for prostate cancer. Clinically established examples include liposomal doxorubicin and albumin-bound paclitaxel. We comprehensively discuss the synthesis methods, delivery mechanisms, and the current landscape of NPs in research and clinical trials for these cancers. This analysis underscores the potential of nanotechnology to provide more effective and targeted therapeutic options for cancer patients in the future. A distinctive feature of this review is its comparative cancer-specific analysis of NP platforms in breast, prostate, and lung cancers. Unlike previous generalized reviews, this work integrates synthesis strategies, delivery mechanisms, translational challenges, and clinically relevant formulations to provide a bench-to-bedside perspective on the future of nanomedicine in oncology. Full article

Intestinal dysfunction and parenteral nutrition (PN) can trigger a spectrum of liver disorders collectively referred to as intestinal failure-associated liver disease (IFALD), for which therapeutic options remain limited. In the present study, we investigated the modulatory effects of the bioactive xanthophyll carotenoid lutein in an in vitro IFALD model utilizing human THLE-2 hepatocytes exposed to lipopolysaccharide and Intralipid to mimic PN–associated inflammatory and metabolic stress. Because lutein is poorly water-soluble and patients receiving PN lack enteral intake of this compound, we also evaluated the cyto- and hemocompatibility of a human serum albumin–based lutein nanoformulation developed to enable intravenous administration. A bead-based multiplex immunoassay revealed that lutein attenuated dysregulation of inflammatory and metabolic signaling by modulating total and phosphorylated levels of MAPKs, NF-κB, Akt, STAT5, CREB, and p70S6K. Lutein also affected lipid metabolism–related gene expression, decreasing SREBF2 and restoring ABCA1 and PRKAA2 mRNA toward control levels, as determined by qPCR. Nanoformulated lutein, with a mean particle size of approximately 160 nm, was non-toxic in THLE-2 cells and exhibited hemocompatibility in a human erythrocyte hemolysis assay. Together, our findings provide both biological and technological rationale for further exploration of lutein-based strategies to mitigate IFALD in patients receiving PN. Full article

Background/Objectives: Beta amyloid (Aβ) aggregates play a central role in the pathophysiology of Alzheimer’s disease (AD), and their detection and modulation remain major challenges in developing effective therapeutic and diagnostic strategies. Previously, gold nanoparticles with plasmonic and optical properties in the near-infrared (NIR) region and photothermal capabilities have been designed for detecting and disaggregating Aβ aggregates. However, these systems often face limitations related to biodegradability, long-term accumulation, and safety. In this work, a degradable NIR-responsive nanosystem based on small gold nanoparticles (sAuNPs), potentially excretable due to their small size, encapsulated within bovine serum albumin (BSA) and functionalized with the all-D peptide D3, was developed to inhibit Aβ aggregation. Methods: sAuNPs (~5–6 nm), functionalized with HS-PEG-NH₂, were encapsulated into BSA nanoparticles using a desolvation method and subsequently conjugated to D3, resulting in the nanosystem f-sAuNPs-BSANPs-D3. The nanosystem was characterized by UV–Vis–NIR spectroscopy, dynamic light scattering, zeta potential analysis, electron microscopy, and nanoparticle tracking analysis. The effects of the nanosystem on Aβ_1–42 aggregation were evaluated using a thioflavin T assay and electron microscopy. Additionally, the effects of f-sAuNPs-BSANPs-D3 on cell viability and its stability against trypsin digestion were assessed. Results: The nanosystem exhibited a measurable photothermal response under NIR irradiation and significantly reduced fibril formation. It did not affect the viability of SH-SY5Y neuronal cells at the tested concentrations. Trypsin incubation experiments demonstrated that the nanosystem remained stable at low enzyme concentrations mimicking plasma conditions, whereas higher enzyme concentrations induced degradation of the albumin matrix and subsequent disaggregation of sAuNPs. Conclusions: Overall, this study presents a degradable, albumin-based sAuNP nanosystem with NIR-responsive properties and potential for nanomedicine applications to inhibit Aβ aggregation in AD. Full article

Background: Colistin (Col) resistance and heteroresistance in extensively drug-resistant (XDR) Acinetobacter baumannii severely limit therapeutic options. We investigated the activity and mechanism of human albumin nanoparticles (haNPs) as colistin potentiators against genetically characterized clinical isolates. Methods: Sixteen clinical isolates were analyzed. Col MICs were determined by broth microdilution, and heteroresistance by population analysis profiling. Potentiation of Col activity was assessed using both Col-loaded haNPs (Col/haNPs) and free Col co-administered with empty haNPs, alongside the proton motive force (PMF) uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Assays included checkerboard synergy (FICI), membrane potential analysis (DiOC₂(3)), intracellular Col quantification (UPLC–MS/MS), zeta potential measurements, transmission electron microscopy (TEM), protein leakage, and ROS detection. Results: Heteroresistance was detected in 9/16 isolates. Col/haNPs reduced Col MICs by 4–64-fold in resistant strains and shifted MICs to ≤2 mg/L in most heteroresistant isolates. Empty haNPs displayed no intrinsic antibacterial activity yet selectively potentiated Col, with strong synergy (FICI down to 0.035). Membrane depolarization and increased intracellular Col accumulation under haNP-treated conditions paralleled the effects of CCCP, indicating that haNPs elicit a CCCP-like functional response. These findings are compatible with perturbation of membrane energetics and possible downstream effects on PMF-dependent transport processes. TEM and surface charge analyses supported direct nanoparticle–envelope interaction and progressive membrane disruption. Conclusions: haNPs enhance Col activity across genetically diverse A. baumannii isolates, with particularly strong effects in heteroresistant strains. The combined effects of PMF modulation, increased intracellular drug availability, and envelope interaction provide a mechanistic rationale for the use of albumin-based nanoparticles, either as Col carriers or in combination with free drug, to overcome Col resistance and heteroresistance. Full article

This study reports a self-assembled ternary delivery system composed of bovine serum albumin (BSA), Fe^(III), and 8-Shogaol (BSA-Fe^(III)-8S) to enhance the stability of this labile ginger-derived bioactive compound. Optimized nanoparticles prepared via one-pot coprecipitation exhibited a particle size of 115.14 nm, polydispersity index (PDI) of 0.084, zeta potential of +52.23 mV, encapsulation efficiency of 94.93%, and loading capacity of 23.73%. Spectroscopic analyses (FT-IR, UV–Vis, XPS) and fluorescence quenching confirmed the formation of a core–shell metal–phenolic network, where Fe^(III) coordinates with 8-Shogaol and BSA forms the outer protein shell. Compared to free 8-Shogaol, the BSA-Fe^(III)-8S MPN nanoparticles demonstrated significantly enhanced thermal, UV, and storage stability. During simulated gastrointestinal digestion, the nanoparticles retained 64.04% of 8-Shogaol, compared to only 51.38% for the free compound. Cytotoxicity assays on HEK293 cells confirmed the biocompatibility of the nanoparticles. This BSA-Fe^(III)-8S delivery system offers a promising strategy for protecting bioactive phenolic compounds, with potential applications in functional foods and nutraceutical formulations. Full article

Methotrexate (MTX) is widely used for its chemotherapeutic and immunosuppressive properties, but is limited by oxidative stress-mediated hepatotoxicity. Nanoantioxidant delivery systems can enhance the stability, solubility, and in vivo efficacy of natural antioxidants. This study investigated the hepatoprotective effects of myricetin (MYR), a flavonoid with potent antioxidant activity, and its liposomal nanoantioxidant formulation (MYR-loaded liposomal nanoparticles, MYR-LNPs) against MTX-induced liver injury in male albino Sprague Dawley rats. Sixty rats were randomly allocated to six groups: control, MTX, MYR, MYR-LNPs, and combinations of MTX with MYR-LNPs. MYR-LNPs were successfully formulated and physicochemically characterized, exhibiting a mean particle size of 95.6 nm, a zeta potential of −32 mV, and a narrow polydispersity index, collectively confirming their colloidal stability and suitability for hepatic delivery. MTX markedly disrupted liver function, increasing serum AST, ALT, ALP, and bilirubin and decreasing total protein, albumin, and globulin, whereas co-treatment with MYR-LNPs substantially restored these parameters and outperformed free MYR. MTX-induced oxidative stress, reflected by depleted hepatic GSH and antioxidant enzymes (GPx, SOD, CAT, GST), elevated reactive oxygen species (ROS), malondialdehyde (MDA), and protein carbonyls and downregulated NRF2/HO-1, was significantly counteracted by MYR-LNPs. In addition, MYR-LNPs mitigated MTX-evoked inflammation and nitrosative stress by reducing NF-κB, TNF-α, IL-1β, nitric oxide, and iNOS expression. They corrected apoptotic imbalance by lowering Bax and caspase 3 while increasing Bcl-2. Histopathological and ultrastructural assessments confirmed that MYR-LNPs preserved hepatic architecture and mitochondrial integrity. These findings indicate that MYR-loaded liposomal nanoantioxidants provide superior protection against MTX-induced hepatotoxicity by modulating oxidative stress, inflammation, and apoptosis, supporting their potential as an advanced nanodrug delivery strategy for antioxidant therapy. Full article

Current efforts to improve photodynamic therapy focus on nanomaterials that integrate deep tissue imaging with efficient reactive oxygen species generation. Gold nanoclusters (Au NCs) are promising alternatives to conventional photosensitizers due to their effective ROS production and enhanced biocompatibility when stabilized by a protein corona. However, both photosensitizers and Au NCs are typically activated by ultraviolet or visible light, which cannot penetrate deeper into tissues and is limited to superficial applications. Here, we report a near-infrared (NIR)-activated photodynamic nanoplatform based on core–shell upconverting nanoparticles (UCNPs; NaGdF₄:Yb³⁺,Er³⁺@NaGdF₄:Yb³⁺,Nd³⁺), functionalized with a protein corona containing bovine serum albumin-stabilized Au NCs (BSA–Au NCs) and photosensitizer chlorin e6 (Ce6). Spectroscopic data confirmed the formation of the UCNP-BSA–Au-Ce6 nanoplatform and demonstrated 32% energy transfer efficiency from UCNPs to Ce6, resulting in efficient reactive oxygen species generation under 808 nm irradiation. Cellular experiments confirmed the effective internalization and optimal biocompatibility of the nanoplatform in human breast cancer and healthy cells. Upon irradiation at 808 nm, the nanoplatform significantly reduced the viability of MDA-MB-231 cancer cells. These findings indicate that the UCNP-BSA–Au-Ce6 nanoplatform couples NIR activation with enhanced singlet oxygen production, providing a multifunctional platform for deep tissue imaging and NIR-activated photodynamic therapy. Full article

The excellent biocompatibility and favorable physicochemical properties of iron oxide nanoparticles have made them attractive candidates for magnetic resonance imaging. However, it remains challenging to synthesize high-performance T₁ contrast agents with controlled sizes and biocompatible coating materials. In this study, we demonstrate a simple and environmentally friendly approach for synthesizing ultra-small iron oxide nanoparticles using bovine serum albumin (BSA) as a template. Following synthesis, the iron oxide nanoparticles (Fe₃O₄) were oxidized to Fe₂O₃ via the addition of hydrogen peroxide, which resulted in enhanced T₁-weighted magnetic resonance contrast. The use of BSA not only stabilized the nanoparticles but also enabled precise control over nanoparticle size by adjusting the Fe-to-BSA molar ratio. This method yielded highly uniform and crystalline ultra-small nanoparticles ranging from approximately 3.7 to 7.9 nm in diameter. The T₁ contrast performance of the Fe₂O₃@BSA nanoparticles was evaluated at 3 T magnetic field. Among the synthesized samples, nanoparticles with sizes of 4.6 nm exhibited the strongest T₁ contrast enhancement along with low r₂/r₁ ratios. These features highlight their potential as promising alternatives to gadolinium-based contrast agents. In addition to their superior performance, this synthesis method is low-cost and non-toxic, making it suitable for scalable biomedical applications. Full article

Biocompatible nanocomposite hydrogels are emerging as versatile platforms in nanomedicine, particularly when natural proteins are used as both structural and chemical components. In this work, we report a green, simple, and rapid in situ synthesis of ultrasmall silver nanoparticles (uAgNPs) within a bovine serum albumin (BSA) hydrogel, in which albumin simultaneously acts as the reducing agent and three-dimensional scaffold. The confined reaction environment generated uniformly dispersed Ag nanostructures with diameters in the 4–40 nm range, as confirmed by DLS and TEM. High-resolution TEM revealed clear Face-Centered Cubic (FCC, 111) lattice fringes, demonstrating the crystalline nature of the embedded uAgNPs. Quantitative image analysis showed narrow size distributions and high circularities, consistent with cluster stabilization through protein–metal interactions. Rheological measurements further indicated that the incorporation of uAgNPs enhanced hydrogel stiffness and delayed yielding, reflecting a reinforcement effect mediated by the nanoparticles acting as additional cross-linking points. Moreover, when very small embedded uAgNPs are formed, the presence of emissive silver nanoclusters was found using fluorescence emission spectroscopy. Overall, our results show that BSA hydrogels provide an effective matrix for directing green uAgNP nucleation, ensuring high stability, controlled growth in less than 2 min, and improved mechanical properties. The resulting protein–nanoparticle composite constitutes a promising soft material for imaging, sensing, and other biomedical applications requiring stable, biocompatible nanoscale architectures. Full article

Bovine rotavirus (BRV) is one of the leading causes of neonatal diarrhea in calves and remains a major concern in veterinary medicine due to its high morbidity and economic impact. Rapid, sensitive, and cost-effective diagnostic approaches are therefore required for early detection and disease control. In this study, electrochemical immunosensors were developed for the detection of BRV with the aim of improving existing multiplex diagnostic strategies. Screen-printed carbon electrodes (SPEs) were employed as the sensing platform and modified with molybdenum disulfide nanoparticles (MoS₂ NPs) to enhance electrochemical performance. Mouse monoclonal antibodies against the BRV VP6 protein were immobilized onto the electrode surface, followed by blocking with bovine serum albumin. BRV detection was carried out using differential pulse voltammetry, cyclic voltammetry, and electrochemical impedance spectroscopy. To further improve sensitivity, a sandwich immunoassay format was constructed using gold nanoparticle-labeled secondary antibodies. The MoS₂-modified sandwich immunosensor exhibited superior analytical performance, achieving a limit of detection of 1.11 ng/mL, a limit of quantification of 3.72 ng/mL, a relative standard deviation of 1.89% (n = 5), and a linear response with R² = 0.99. The developed immunosensors demonstrated reliable performance in real sample analysis, with a selectivity rate of 100 ± 2.95%. These findings suggest that MoS₂-based electrochemical immunosensors offer a promising platform for rapid and sensitive BRV detection and have potential applications in veterinary diagnostics. Full article

Background: Silver nanoparticles (AgNPs) trigger apoptosis in cancer cells, while albumin nanoparticles enable effective drug delivery. This study compares the antitumor and cytotoxic effects of albumin-coated AgNPs (AgNPs-Alb) versus AgNPs on human prostate cancer cell lines. Method: AgNPs-Alb were synthesized and tested against PC3 and LNCaP prostate cancer cell lines. Characterization via Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and Ultraviolet-Visible (UV-Vis) spectroscopy confirmed their properties. IC50 values were determined using MTT assay, with apoptosis assessed by Annexin-V/PI staining. DNA cell cycle was analyzed by PI staining. Migration, proliferation, and nuclear morphology were evaluated through scratch-wound, colony-forming, and Hoechst staining assays. Gene expression of Snail, E-cadherin, VEGF-C, VEGF-A, Bcl2, Bax, and P53 was analyzed using real-time PCR. Results: The IC50 values for AgNPs and AgNPs-Alb were 48 μM and 32 μM in PC3 cells, and 110 μM and 95 μM in LNCaP cells, respectively. AgNPs-Alb significantly inhibited PC3 cell migration compared to AgNPs (p < 0.001) and Bicalutamide (p < 0.0001). In both cell lines, AgNPs-Alb significantly reduced colony formation compared to AgNPs and Bicalutamide (p < 0.05). Flow cytometry revealed a higher percentage of apoptotic cells in PC3 with AgNPs-Alb treatment compared to AgNPs and Bicalutamide. In LNCaP cells, AgNPs-Alb induced a significantly higher percentage of Sub-G1 cells. AgNPs-Alb treatment caused greater mRNA suppression of VEGF-A and a higher Bax/Bcl2 ratio in PC3 and LNCaP cells (p < 0.05). Additionally, a significant increase in P53 and E-cadherin, alongside a decrease in VEGF-C expression in LnCAP cells, was observed (p < 0.05). Conclusions: This study suggests that AgNPs-Alb have stronger anticancer and cytotoxic effects compared to AgNPs alone against PCa cell lines and higher effects were observed on PC3 cells compared to LnCAP cells. Full article

Background/Objectives: Poor aqueous solubility and limited nasal permeability remain key challenges in the intranasal delivery of carbamazepine. In this study, biocompatible bovine serum albumin nanoparticles functionalized with sulfobutyl-β-cyclodextrin (SβCD-BSA NPs), comprising individually cytocompatible components with confirmed physical interactions), were formulated for intranasal delivery of carbamazepine (CBZ). Methods: The ethanolic desolvation method was utilised for the preparation of the nanoparticles, with the functional moiety incorporated during nanoparticle preparation. The effects of different molar ratios of SβCD-BSA and different ethanol volume ratios were studied. For crosslinking, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), a non-toxic crosslinker, was utilised. To determine the role of the SβCD, two preparation samples were formulated, with and without SβCD. Results: The formulation without SβCD incorporation had a mean particle size of 125 ± 0.64 nm, polydispersity index (PDI) of 0.34, encapsulation efficiency (EE%) of 61.5 ± 1.40%, and drug-loading ratio (DL%) of 31.9 ± 1.50%. Conversely, the SβCD-functionalized formulation showed a mean particle size of 128 ± 2.12 nm, PDI of 0.21 ± 0.03, EE of 64.6 ± 0.35%, and DL of 34.28 ± 1.60%. Statistical analysis revealed that the incorporation of SβCD resulted in a statistically significant increase in both DL% and EE% (p < 0.05). Conversely, the observed differences in particle size and PDI were not statistically significant (p > 0.05). This addition provides precise context regarding the comparability of the formulations while highlighting SβCD’s functional benefits in solubility and permeation. The interaction between CBZ and SβCD-BSA was confirmed using Fourier-transform infrared spectroscopy. Lastly, the prepared formulations were characterised by their physicochemical attributes and in vitro biopharmaceutical studies. It was discovered that SβCD plays a dual role, enhancing the solubility of CBZ in one scenario while promoting its nasal permeation, suggesting its potential use in epilepsy treatment. Conclusions: These findings highlight the potential of SβCD-BSA NPs as a versatile pharmaceutics platform for the intranasal delivery of poorly soluble CNS drugs. Full article