Pharmaceutics最新文献

Objective: To overcome the extremely low oral bioavailability of ginsenosides in traditional ginseng preparations, this study aimed to evaluate the efficacy of a novel ginseng-derived carbon quantum dots (G-CQDs) delivery system and to elucidate its core bioactive constituents and integrated mechanisms of action. Methods: G-CQDs were prepared from ginseng roots via ultrahigh-speed nitrogen jet pulverization combined with far-infrared pulse-assisted hydrothermal carbonization. Their physicochemical properties were characterized by transmission electron microscopy, Fourier-transform infrared spectroscopy, and fluorescence spectroscopy. The in vivo effects of G-CQDs versus traditional ginseng aqueous extract (G-AE) were compared in C57BL/6 mice (n = 12/group) using the PRO-MRRM-8 Comprehensive Laboratory Animal Monitoring System for real-time, non-invasive phenotyping of energy metabolism parameters (respiratory quotient, heat production, and oxygen consumption). Systemic exposure to ginseng bioactives was profiled using UHPLC-Q/Orbitrap/LTQ high-resolution mass spectrometry, followed by bivariate correlation analysis to identify key bioactive components linked to efficacy. Results: Compared with G-AE, G-CQDs significantly enhanced whole-body energy metabolism-respiratory quotient +2.8%, heat production +6.7%, and locomotor activity +22.9% (p < 0.05). A total of 110 in vitro constituents, 35 blood prototypes, and 29 metabolites were identified. Correlation analysis revealed eight core bioactive clusters linked to the metabolic benefits; all showed higher systemic exposure with G-CQDs (range +9.2% to +265.8%), notably ginsenoside Re +69.6%, cinnamic acid + O + SO₃ +157.4%, and linolenic acid-GSH conjugate +265.8%. Conclusions: Carbon quantum dot technology significantly enhances the systemic exposure of ginseng bioactivities by improving solubility and enhancing gastrointestinal absorption, providing a molecular basis for its superior efficacy in regulating energy metabolism compared to conventional extracts. This study establishes a novel framework for developing high-value, bioavailability-enhanced nano-preparations from traditional medicines.

The Journal retracts the article "Moringa concanensis-Mediated Synthesis and Characterizations of Ciprofloxacin Encapsulated into Ag/TiO₂/Fe₂O₃/CS Nanocomposite: A Therapeutic Solution against Multidrug Resistant E [...].

Background/Objectives: Curcumin (CUR), a natural polyphenol with poor solubility and significant first-pass metabolism, shows extremely low oral bioavailability. Although CUR-loaded nanostructured lipid carriers (CUR-NLCs) have demonstrated potential in enhancing oral absorption, direct evidence regarding their intestinal lymphatic transport mechanism remains insufficient, and current understanding largely relies on indirect speculation. Methods: CUR-NLCs were prepared by emulsion-ultrasonication and evaluated for their physicochemical properties including particle size, zeta potential, polydispersity index, encapsulation efficiency, drug loading, stability and release profile. A mesenteric lymph duct-jugular vein shunt rat model combined with transmission electron microscopy was employed to assess the pharmacokinetic behavior and lymphatic transport pathway. Results: CUR-NLCs had a mean size of 117.28 ± 1.32 nm, 99.99% encapsulation efficiency, and 1.73% drug loading. They exhibited good gastrointestinal stability and sustained release (<55% in 24 h). CUR-NLCs significantly enhanced oral absorption versus free CUR, with 5.13-fold higher relative bioavailability, 5.25-fold greater C_max, and extended half-life (33.49 ± 3.15 h). CUR was detected only in the lymph of the CUR-NLCs group, confirming intestinal lymphatic transport. TEM revealed abundant chylomicrons (0.1-2 μm) in jejunal epithelial cells, providing morphological support. Conclusions: This study directly demonstrates that CUR-NLCs improve oral bioavailability via intestinal lymphatic absorption, offering a viable strategy for delivering poorly soluble hydrophobic drugs.

Background/Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) presents a serious hurdle in combating antibiotic-resistant skin infections. This study aimed to repurpose losartan potassium (LOS) through its incorporation into cerosomal nanocarriers (CERs) and further functionalization with carbon dots (CDs) to enhance antibacterial efficacy. Methods: LOS-CERs were fabricated by the thin-film hydration method and further optimized using a D-optimal mixture design. Results: The optimized CERs, composed of phytantriol (20 mg), ceramide (30 mg), and CTAB (20 mg), exhibited high entrapment efficiency (97.07 ± 0.07%), a nanoscale particle size (372.50 ± 0.50 nm), and a positive zeta potential (+33.24 ± 0.04 mV). FT-IR analysis confirmed successful conjugation of CDs to CERs through surface functional interactions. Ex vivo permeation and confocal microscopy studies demonstrated that the CD-CER formulation sustained LOS release and enhanced its deposition within skin layers compared with the LOS solution. Using a murine model of MRSA USA300-induced skin infection, the CD-CER formulation achieved superior antibacterial efficacy, reducing the bacterial load by 3.85 log₁₀ CFU relative to the untreated control, compared with a 3.04 log₁₀ CFU reduction for the LOS solution. Histological evaluation supported improved healing in CD-CER-treated groups. Conclusions: Overall, CD-functionalized CERs offer a promising multifunctional nanoplatform for repurposing LOS as a topical therapeutic against MRSA-associated skin infections.

Background/Objectives: Ochratoxin A (OTA) is a widespread foodborne mycotoxin linked to chronic kidney disease of unknown etiology. Despite evidence from animal models showing OTA accumulation in the kidney, the molecular mechanisms underlying its renal disposition in humans remain only partially understood. Here, we identify human renal transporters responsible for OTA kidney accumulation, elimination, and establish Michaelis-Menten kinetics under matched conditions to directly compare transport mechanisms. We also aim to identify inhibition potential of these transport mechanisms with common dietary polyphenols. Methods: Mammalian cells and membrane vesicles overexpressing human renal transporters were used to screen and profile the uptake and efflux of OTA. Miquelianin, (-)-Epicatechin-3-O-gallate, myricetin, luteolin, and caffeic acid were tested as potential concentration-dependent transporter inhibitors. Results: We demonstrate that OTA is a substrate for human organic anion transporter (hOAT) 1 (K_m: 2.10 ± 0.50 μM, V_max: 396.9 ± 27.0 pmol/mg/min), hOAT3 (K_m: 2.58 ± 0.83 μM, V_max: 141.4 ± 30.3 pmol/mg/min), hOAT4 (K_m: 6.38 ± 1.45 μM, V_max: 96.9 ± 18.8 pmol/mg/min), and human organic anion transporting polypeptide (hOATP) 1A2 (K_m: 37.3 ± 6.2 μM, V_max: 801.0 ± 133.9 pmol/mg/min). Among efflux transporters, OTA was transported only by human breast cancer resistance protein (hBCRP), which has minimal renal expression. While none of the uptake transporters were potently inhibited (>90%) by polyphenols at 10 μM, luteolin inhibited hBCRP-mediated transport of OTA with an IC₅₀ of 22 μM and caffeic acid stimulated hBCRP-mediated efflux with an EC₅₀ of 713.8 μM, both of which are physiologically relevant intestinal lumen concentrations. Conclusions: Our results confirm that exposure to OTA will lead to renal accumulation and increased health risks in affected populations, necessitating increased scrutiny of our food sources.

Background/Objectives: Cerebral ischemia-reperfusion injury (CIRI) remains a major challenge in the treatment of ischemic stroke, characterized by intertwined oxidative stress and neuroinflammation. Existing monotherapies often fail to address this dual pathology effectively. We developed PLSCZ, a biomimetic nanoplatform integrating a catalytic core of imidazolate framework-8 (ZIF-8)-encapsulated superoxide dismutase (SOD) and catalase (CAT) enzymes with a hybrid platelet membrane shell. This design strategically employs metal-organic frameworks (MOFs) to effectively overcome the critical limitations of enzyme instability and provide a cascade catalytic environment, while the biomimetic surface modification enhances targeting capability, thereby enabling dual-pathway intervention against CIRI. Methods: PLSCZ was engineered by co-encapsulating SOD and CAT within a ZIF-8 core to form a cascade antioxidant system (SCZ). The core was further coated with a hybrid membrane composed of rapamycin-loaded phospholipids and natural platelet membranes. The nanoparticle was characterized by size, structure, enzyme activity, and targeting capability. In vitro and in vivo efficacy was evaluated using oxygen-glucose deprivation/reoxygenation (OGD/R) models and a transient middle cerebral artery occlusion/reperfusion (tMCAO/r) rat model. Results: In vitro, PLSCZ exhibited enhanced enzymatic stability and cascade catalytic efficiency, significantly scavenging reactive oxygen species (ROS) and restoring mitochondrial function. The platelet membrane conferred active targeting to ischemic brain regions and promoted immune evasion. PLSCZ effectively polarized microglia toward the anti-inflammatory M2 phenotype, reduced pro-inflammatory cytokine levels, restored autophagic flux, and preserved blood-brain barrier integrity. In vivo, in tMCAO/r rats, PLSCZ markedly targeted the ischemic hemisphere, reduced infarct volume, improved neurological function, and attenuated neuroinflammation. Conclusions: By synergistic ROS scavenging and anti-inflammatory action, the PLSCZ nanozyme overcomes the limitations of conventional monotherapies for CIRI. This biomimetic, multi-functional platform effectively reduces oxidative stress, modulates the phenotype of microglia, decreases infarct volume, and promotes neurological recovery, offering a promising multi-mechanistic nanotherapeutic for CIRI and a rational design model for MOF-based platforms.

Background/Objectives: Heterofunctional cationic polyester dendrimers derived from a 2-(bromomethyl)-2-(hydroxymethyl)propane-1,3-diol (BHP-diol) based AB₂C monomer were evaluated as efficient and biodegradable nonviral carriers for siRNA delivery. Methods: These dendrimers feature dual internal and external charge architectures, enabling precise control of charge distribution and siRNA interaction strength. Results: They achieved complete siRNA complexation at nitrogen-to-phosphate (N/P) ratios of 0.50-2.14 and provided up to 93% RNase protection, outperforming amino-functional scaffolds based on 2,2-bis(methylol)propionic acid (bis-MPA). In human (T98G) and murine (GL261) glioblastoma cells, the dendrimers exhibited minimal cytotoxicity while achieving 52-61% target protein knockdown, a two- to three-fold improvement over conventional polyester dendrimers, and approaching the silencing efficiency of the commercial Interferin^® reagent. Conclusions: The combination of high complexation efficiency, strong nuclease resistance, and excellent biocompatibility establishes these heterofunctional dendrimers as a new generation of precisely tunable, biodegradable vectors for therapeutic siRNA delivery.

Background/Objectives: Direct-acting antivirals vary by lineage and face rapid resistance. We identified the oxazole-4-carboxamide lead KB-2777 and aimed to define its in vitro activity across α/β-coronaviruses, time-of-addition (TOA) profile, host-response signatures, and combinability with benchmark DAAs. Methods: We tested KB-2777 (≤25 μM) against HCoV-NL63 (LLC-MK2), HCoV-OC43 (Vero E6; MRC-5 for transcript profiling), and PEDV (Vero E6). We quantified extracellular viral RNA by RT-qPCR at 72 h (n = 3) and confirmed activity by spike-protein immunofluorescence (IFA), cytopathic effect (CPE) protection, and TCID₅₀. We compared TOA regimens (full, pre, co, post), evaluated combinations with nirmatrelvir (NL63) or GS-441524 (OC43) using ZIP scores, and profiled infection-context transcripts (IL6, IFNB1, ISG15, NRF2/antioxidant, UPR). Results: KB-2777 reduced viral RNA with EC₅₀ 5.27 μM (NL63), 1.83 μM (OC43), and 1.59 μM (PEDV) without cytotoxicity in the tested range. In NL63 post-treatment, inhibition was minimal at 24 h but clear at 48-72 h (EC₅₀ 2.42 μM at 48 h; 5.25 μM at 72 h). TCID₅₀ decreased at 48 h (12.5-25 μM, n = 3, p < 0.0001), and IFA/CPE corroborated antiviral activity. TOA ranked full > pre ≈ post > co. Combinations were additive to synergistic (ZIP 5.16 with nirmatrelvir; 8.40 with GS-441524). In OC43-infected MRC-5 cells, KB-2777 attenuated IL6, IFNB1, ISG15, and selected UPR transcripts, with limited changes in uninfected cells (n = 3). Conclusions: KB-2777 shows reproducible cell-based anti-coronavirus activity across α/β lineages, a TOA signature consistent with early post-entry host modulation, and favorable, non-antagonistic combinability with DAAs. These findings support target deconvolution, SAR/ADME optimization, and evaluation in primary airway and in vivo models.

Background/Objectives: A meta-analysis was conducted to study the in vitro release of hydrophilic therapeutics from contact lenses, loaded using the soaking method. Fifty-three experiments were studied that measure the cumulative release of therapeutics from (mostly) commercial contact lenses placed in a vial. Methods: A mathematical model and a parameter-fitting algorithm are presented to estimate the diffusion coefficient (D) and 50% therapeutic release time (T50) of all the experimental lens-therapeutic combinations. Statistical methods were used to analyze the relationships between lens materials, therapeutic properties, and predicted parameter values (D and T50). Results: The mathematical framework was validated against previous studies. It was found that lens water content directly and moderately influences the estimated diffusion coefficient. More specifically, the median diffusivity of silicone hydrogel (SH) contact lenses was statistically different from that of conventional hydrogel (CH) lenses. The dependencies of other lens and therapeutic properties on diffusivity were complex, with special cases studied to elicit dependencies. A predictive tool was constructed to estimate the logarithm of 50% therapeutic release time (log(T50)), given the lens water content and the therapeutic molecular volume and density. Conclusions: The conducted meta-analysis found that the kinetic release of therapeutics from contact lenses depends on the properties of both the contact lens and therapeutics. The statistical model explained 64% of the variability of the log(T50) and can be used in the preliminary stages of contact lens drug delivery development.

Background/Objectives: This review summarizes and analyzes current data on the toxicological effects of cerium dioxide nanoparticles (nanoceria) on various anatomical and functional systems in healthy murine models, as reported in both in vivo and ex vivo experimental settings. Methods: This systematic review was conducted and reported in accordance with the PRISMA 2020 guidelines and was prospectively registered in PROSPERO (CRD42024503240). A systematic literature search was conducted using the PubMed and ScienceDirect databases for the period 2019-2025, with the inclusion of earlier publications having significant scientific relevance. The final search update was conducted in July 2025 to ensure inclusion of the most recent studies. Results and Conclusions: Only in vivo and ex vivo studies in healthy murine models were included. Risk of bias was evaluated using the OHAT tool for animal studies, and data were synthesized narratively due to heterogeneity among studies. A total of 29 studies met the inclusion criteria. The pharmacokinetic properties of nanoceria were considered, encompassing biodistribution, elimination pathways (including oral, intravenous, intraperitoneal, inhalation, intratracheal, and instillation routes), and the influence of physicochemical characteristics on bioavailability and toxicity. The toxicological impact (TI) was assessed across major organ systems-respiratory, digestive, urinary, visual, reproductive, nervous, cardiovascular, immune, hematopoietic, endocrine, musculoskeletal, and skin. The liver, spleen, lungs, and kidneys were identified as primary accumulation sites, with clearance dependent on particle size and coating. The TI spectrum ranged from the absence of morphological changes to inflammation, fibrosis, or organ dysfunction, depending on dose, exposure route, and physicochemical parameters. The main limitations include variability of nanoparticle formulations and incomplete toxicity reporting. In general, CeO₂ nanoparticles with sizes of 2-10 nm and doses ≤ 5 mg/kg showed no signs of systemic toxicity in short-term studies on healthy mice, provided that optimal coating and dosing intervals were used.