Journal of Drug Targeting最新文献

We aimed to synthesise carbon quantum dots (CQDs) from the active molecule gabapentin (GBP) and to evaluate their effects on pentylenetetrazol (PTZ)-induced seizures in rats. Gabapentin CQDs (GBPCQDs) were synthesised using a rapid, one-pot microwave-assisted method and characterised by particle size, polydispersity index, zeta potential and fluorescence properties. Adult male Wistar rats received GBP or GBPCQDs (15, 30, 60 or 120 mg/kg, intraperitoneally) 30 min before PTZ administration (50 mg/kg). Seizure onset times and severity were assessed, and locomotor activity was evaluated at the most effective doses. While GBP did not significantly affect seizure onset, GBPCQDs at 15 mg/kg significantly prolonged the onset time of PTZ-induced seizures. Both GBP and GBPCQDs significantly reduced seizure severity at all tested doses, however, GBPCQDs at 60 and 120 mg/kg were more effective than the corresponding doses of GBP. Neither treatment produced significant changes in locomotor activity. Fluorescence imaging demonstrated the presence of GBPCQDs in the prefrontal cortex, striatum and hippocampus, with the highest fluorescence intensity observed in the prefrontal cortex. These findings indicate that GBPCQDs may provide therapeutic advantages over conventional GBP and represent a promising fluorescent nanocarrier for brain-targeted drug delivery in epilepsy.

Organelle targeting systems are crucial for elucidating biological processes and pathologies associated with Golgi apparatus at the centre of the secretory pathway. While the range of fluorescent probes developed for mitochondria and lysosomes is quite extensive, Golgi-targeted probes have only gained momentum in recent years. This review addresses strategies and fluorescent probe designs targeting the Golgi apparatus. We compare lipid and protein binding motifs, and small molecule-based approaches based on performance criteria. Lipid/protein binding motifs provide strong binding but may affect membrane trafficking, small molecules enable rapid and modular labelling but carry the risk of mis-targeting to the ER and endosomal compartments. The review provides a framework for design principles and reporting standards to accelerate the rational design of selective and minimally invasive Golgi probes.

Valsartan (VAL) offers protection against atherosclerosis-associated diabetes mellitus (AADM) due to its antioxidant properties. However, VAL is hindered by poor bioavailability and effectiveness, which can be attributed to its low water solubility and significant first-pass metabolism. This research aimed to develop a nasal VAL-novasomes formulation (VNF) intended to enhance VAL's efficacy, sustainability, bioavailability and targeting for AADM treatment. The Box-Behnken design was utilised for the development and optimisation of VNF formulations. The optimum VNF was subsequently evaluated in vivo using an experimental rat model of AADM. Compared to free VAL, the optimum VNF improved sustainability and bioavailability by 66.02% and 3.32-fold, respectively. The VNF group demonstrated significant reductions of 70.58%, 74.15%, 77.74% and 83.87% in glucose, triglycerides, cholesterol and LDL levels, respectively, compared to the AADM group. In contrast, HDL levels increased notably by 1.67-fold. Additionally, the VNF group accumulated 4.30 times more VAL in the heart than the free VAL group. Histopathological analysis confirmed the anti-atherosclerotic effect of the optimum VNF formulation. Importantly, the VNF group did not show any toxicity when compared to the negative control group. These findings support our hypothesis that the optimum VNF, administered nasally, could serve as a potential therapy for AADM.

Ofirnoflast is a first-in-class, orally bioavailable NEK7 inhibitor currently undergoing Phase 2 clinical evaluation. It disrupts NLRP3 inflammasome assembly by targeting NEK7's scaffolding function-blocking complex formation independently of NLRP3 activation status, upstream of caspase activation, pyroptosis, and inflammatory cytokine release. This mechanism offers a novel therapeutic approach for chronic inflammation. Unlike NSAIDs, corticosteroids, cytokine-neutralising biologics, and NLRP3-directed small molecules-which are frequently limited by off-target effects, immunosuppression, or incomplete efficacy-ofirnoflast provides a targeted approach with fewer anticipated liabilities. We demonstrate that ofirnoflast engages an allosteric site adjacent to NEK7's ATP-binding pocket, inducing conformational shifts that impair its scaffolding function. In THP-1 macrophages and iPSC-derived microglia, ofirnoflast suppresses ASC specks, IL-1β release, and pyroptotic cell death. Biophysical assays and molecular dynamics simulations confirm that ofirnoflast stabilises NEK7 in a unique conformation and suggest a type-2 kinase-inhibitor binding mode. In vivo, ofirnoflast exhibits oral bioavailability, achieving systemic exposures well above cellular potency thresholds. In a DSS-induced colitis model, treatment significantly reduces cytokine levels and improves phsyiological outcomes. Collectively, these findings validate NEK7 as a druggable checkpoint for NLRP3 inflammasome control and position Ofirnoflast as a mechanistically distinct, clinically advanced candidate for treating inflammation driven by aberrant inflammasome activation.

Wound infections significantly impair healing and often result in chronic wounds, burdening healthcare systems substantially. The principal pathogen in such infections is Staphylococcus aureus (S. aureus), which forms biofilms that resist host defences and conventional therapies. To overcome these challenges, recombinant lysostaphin (rLyso) was encapsulated in niosomes using thin-film hydration and evaluated with N-acetylcysteine (NAC) against standard and clinical S. aureus strains. Antibacterial and antibiofilm activities were assessed by determining the minimum inhibitory concentration (MIC) and minimum biofilm eradication concentration (MBEC), complemented by fluorescence and confocal microscopy. Cytotoxicity was assessed in L929 fibroblasts, and in vivo efficacy was investigated in BALB/c mouse wound models. The NAC/niosomal rLyso formulation exhibited the most potent antibacterial and antibiofilm effects, significantly lowering the MIC values (standard: 1250/5.9 μg/ml; clinical: 1250/2 μg/ml) and achieving notable biofilm eradication (MBEC: standard: 5000/23.6 μg/ml; clinical: 1250/2 μg/ml). Cytotoxicity assays confirmed high bio-compatibility, with nearly 100% cell viability at MIC, while NAC alone was highly toxic. The combination of two agents achieved full bacterial clearance in vivo and accelerated wound healing. These findings suggest that NAC combined with niosomal rLyso synergistically disrupts S. aureus biofilms, enhances antimicrobial activity, and promotes wound repair, making it a promising therapeutic strategy against resistant staphylococcal infections.

The combination therapy strategy exerts a significant anti-tumour effect by synergistically eliminating tumour cells through the use of two or more treatments. Nanomedicine delivery systems are widely employed in cancer therapy owing to their ability to effectively improve drug solubility and enhance drug targeting. To this end, we have designed and developed a nano-targeted drug delivery platform PAE-PEG-ss-Ce6/DOX nanoparticles (PPCD NPs), for the co-delivery of the photosensitiser chlorin e6 (Ce6) and the chemotherapeutic agent doxorubicin (DOX). The nanoparticles exhibit a mean particle size of 128.74 ± 0.80 nm, demonstrating excellent serum stability and pH/glutathione (GSH)-responsive release characteristics in vitro. Compared to monotherapy, PPCD NPs exhibited enhanced cytotoxicity and cellular uptake, effectively inhibiting cell proliferation by inducing reactive oxygen species (ROS) production. The results of the immunogenic cell death (ICD) experiments demonstrated that PPCD NPs induced a robust ICD effect through the synergistic action of DOX and Ce6, thereby activating anti-tumour immunity and achieving combination therapy. In vivo experiments and histopathological analysis demonstrated that PPCD NPs exhibit excellent tumour targeting, high anti-tumour efficacy and low biotoxicity. These findings demonstrated the superiority of the phototherapy-chemotherapy-immunotherapy synergistic treatment strategy and indicate that PPCD NPs hold promise as a safe and effective anti-tumour nanoscale targeted drug delivery system.

Neuroinflammation is a pathophysiological feature of several neurological disorders, including Parkinson's disease, Alzheimer's disease and traumatic brain injury, resulting from various intrinsic and environmental triggers. However, effective treatments are hindered by challenges in drug delivery to the central nervous system, primarily due to the blood-brain barrier. In this study, we investigated the potential of rosuvastatin-loaded nanoemulsions for neuroinflammation treatment. The mean diameter and zeta potential of developed RSV-NEs were 124.8 ± 1.23 nm and -40.5 ± 3.2 mV, respectively. TEM analysis revealed the spherical morphology and uniformity of nano-droplets. A cell viability study on the PC12 cell line confirmed the safety of RSV-NEs up to the concentration of 300 µg/mL. The protective efficacy of orally administrated RSV-NEs against LPS-induced neuroinflammation and oxidative stress was assessed in SD rats. According to histopathological assessments, LPS-induced damage was prevented by RSV-NEs through a neuroprotective effect linked to a reduction in GFAP⁺ cells. Moreover, TBARS levels in the rat brain cortex decreased by 3.9 times, and the cerebellum's SH increased by 1.7 times in the RSV-NEs-treated group compared to the LPS group. These findings suggest that utilising nanoemulsion delivery systems may offer improved efficacy for CNS disorders, addressing significant challenges in the management of neuroinflammatory diseases.

Gastrointestinal tumours pose a significant threat to human health. Small extracellular vesicles (sEVs) have emerged as a promising approach for drug delivery in the treatment of gastrointestinal tumours. sEVs exhibit intrinsic advantages over synthetic nanoparticles, including native targeting ligands, the ability to cross biological barriers via membrane fusion, and reduced immune clearance mediated by surface CD47, thereby overcoming limitations of conventional nanocarriers such as rapid opsonisation and hepatic sequestration. These minute vesicles are surrounded by a stable phospholipid bilayer and can be engineered with specific targeting ligands or loaded with diverse therapeutic cargoes, thereby overcoming the limitations of conventional drug delivery systems (DDSs) and improving tumour-specific accumulation while minimising off-target effects. In this review, we explore the recent advancements in sEV-based DDSs, with a focus on design approaches for engineered sEVs, immunotherapy-related engineered sEVs technologies and the utilisation of engineered sEVs in gastrointestinal tumours. Additionally, we discuss the current challenges and future prospects of sEV-based DDSs in clinical practice, underscore the innovative role of engineered sEVs in cancer therapy, and provide promising avenues for enhancing the treatment of gastrointestinal tumours and improving patient outcomes.

Background: Prognostic therapy for treating cutaneous wounds requires information about antioxidants and clotting factors in the tissue-remodeling phases.

Purpose: To find the differential expression of potential biomarkers in diabetic rat wounds post-healing after confirming the stability of Mentha piperita-silver nanoparticles (MPAgNPs).

Methods: MPAgNPs were characterized, and their bioactive compounds were identified by Liquid chromatography-tandem mass spectrometry (LC-MS/MS). Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) is used to find differential protein expression in diabetic healed rat skin, followed by Quantitative Reverse transcriptase polymerase chain reaction (qRT-PCR) for their confirmation.

Results: Scanning and transmission electron microscopy revealed spherical core metallic sizes of 50 nm. Dynamic light scattering determines the MPAgNPs' hydrodynamic size of 127 nm. The zeta potential value of -15.4 mV confirmed the NP's stability. Medioresinol, rosmarinic acid, caffeic acid, salvianolic acid, and methyl syringate were the bioactive compounds identified in M. piperita by LC-MS/MS. SDS-PAGE shows differential expression of anti-inflammatory, anti-apoptotic, antioxidant, and defense proteins. Antioxidant assays show increased levels of superoxide dismutase and glutathione peroxidase with decreased malondialdehyde. qRT-PCR confirmed enhanced expression of transforming growth factor, Thrombin, and Glutathione S-transferase P. At the same time, Tumor necrosis factor alpha, and Interleukin show reduced expression 16-D after MPAgNPs treatment.