Journal of Drug Targeting最新文献

The Golgi apparatus, a central hub for protein processing and transportation, plays a critical role in cancer progression and has thus emerged as a highly promising therapeutic target. This review discusses the molecular mechanisms underlying Golgi dysfunction in cancer, along with recent advancements in Golgi imaging techniques that enable precise visualisation of structural and functional alterations within tumours. Furthermore, we highlighted representative applications of Golgi-targeting strategies in cancer diagnosis and treatment, and also discussed future directions for Golgi-targeted therapies, emphasising the potential of the Golgi apparatus as a multidimensional target for cancer management. This study will provide valuable insights for research related to cancer therapeutics.

The aim of this study was to fabricate a crosslinker free hydrogel coating composed of chitosan and HPMC (CH) containing gentamicin (GEM) as a promising strategy to prevent infections associated with orthopedic implants. The developed hydrogel exhibited good hemocompatibility, no cytotoxicity and the capability for long-term and slow release of GEM. In vivo study revealed that the WBC and NEUT values significantly reduced in rats treated with CH-GEM (WBC: 120%, NEUT: 131%) compared to those untreated and treated with CH alone (WBC: 172%, NEUT: 264%). According to X-ray findings, the group treated with CH-GEM exhibited slight periosteal reaction and screw loosening. Histological evaluation confirmed a significant reduction in inflammatory cells in the rats treated with CH-GEM compared to the other groups. The CFU counting results displayed a significant reduction in bacterial load on the bone, decreasing from 8.5 × 10⁸ CFU in the CH group to approximately 750 CFU in the CH-GEM group. Additionally, bacterial presence in the surrounding tissues was completely eradicated, with CFU counts dropping from approximately 3000 CFU to 0 CFU. The present findings revealed that CH-GEM coating might provide a promising platform for preventing post-operative osteomyelitis.

Tuberculosis (TB) remains a global health concern due to complex and lengthy treatment, suboptimal drug concentrations in alveolar macrophages (AMs) and increasing drug resistance. This study investigates dectin-1 receptor-targeted dry powder inhalation (DPI) system for rifampicin (Rif) using β-glucan microparticles (GMPs) for enhanced delivery to AMs. Rif-loaded GMP (GMP-R) exhibited >55% drug entrapment and favourable aerodynamic properties (fine particle fraction: 36%, mass median aerodynamic diameter: 4-5 μm) for deep lung deposition. Sustained in vitro drug release fitting Korsmeyer-Peppas model indicated Fickian diffusion as the predominant mechanism. Drug release was more sustained at lysosomal pH. GMP-R demonstrated >99% uptake into RAW 264.7 macrophages within 1 h and minimal cytotoxicity. No significant changes in particle size and aerosolisation characteristics were observed during the 6-month accelerated stability testing (40°C ± 2°C/75% ± 5%RH). In vivo pharmacokinetics in rats revealed ∼23-fold higher drug concentration in AMs and extended lung residence (∼48 h) with intratracheal GMP-R compared to oral Rif. GMP-R exhibited targeting index of 5.01, with intracellular inhibitory concentrations maintained for ∼20 h. Overall, dectin-1 receptor-targeted inhalable GMP-R enhances lung deposition and intracellular concentrations, while reducing systemic toxicity. Pharmacokinetic outcomes indicate its potential for reducing dosing frequency, while warranting further validation of therapeutic efficacy in infection models.

Investigating the molecular mechanisms underlying metastasis is crucial for addressing metastatic breast cancer. Two common chemotherapy drugs, doxorubicin and paclitaxel, partially work by triggering the unfolded protein response (UPR), with glucose-regulated protein 78 (GRP78) serving as a significant regulator of this process. This research aimed to develop a post-surgery hydrogel nanocomposite with anti-metastatic properties and evaluate its effects on breast cancer metastasis and GRP78 localization. Chitosan nanoparticles (CsNPs) were produced and integrated into a hydrogel, which was then analyzed using various imaging and sizing methods.Biological evaluations using MTT assay against mouse fibroblast NIH/3T3 and hemolysis assay showed that the hydrogels' biocompatibility and hemocompatibility. Anticancer evaluations (MTT assay, apoptosis analysis, intracellular ROS detection, mitochondrial potential measurements, and caspase activity assay against MCF-7 cells) revealed potent anticancer potential of the structure. Mechanistic studies using quantitative analysis of GRP78 expression showed that the hydrogel promotes GRP78 translocation from the cytoplasm to the tumor cell surface, enhancing GRP78 expression and supporting anticancer and anti-metastatic effects via UPR activation. These findings suggest that the developed hydrogel nanocomposite may serve as a multifunctional anti-metastatic strategy for breast cancer treatment in the post-surgical context.

Diabetic peripheral neuropathic pain (DPNP) is a debilitating complication of longstanding type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. DPNP patients experience mechanical and thermal pain hypersensitivity. Despite its clinical significance and high prevalence, treatment for DPNP remains challenging due to its unclear pathogenesis. We investigated whether hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, known to be involved in other PNP types, also contribute to DPNP. We used two DPNP rat models: (a) streptozotocin (STZ) model of T1DM induced by a single STZ injection (60 mg/kg, i.p.), and (b) high fat diet-fed STZ model (HFD/STZ) of T2DM induced by feeding the rats with HFD (60% calories as fat) for 2 weeks followed by a low-dose STZ injection (35 mg/kg, i.p.). We found that: (a) diabetic (hyperglycaemic) and non-diabetic (normoglycemic) STZ rats, as well as normoglycemic HFD/ZTZ rats, exhibit mechanical and heat hypersensitivity, evidenced by reduced paw withdrawal thresholds and latencies, respectively, and (b) ivabradine (10 mg/kg, i.p.), the clinically approved HCN blocker, was as effective as the positive control gabapentin in attenuating mechanical, but not heat, hypersensitivity, in both models. These findings reinforce that factors beyond hyperglycaemia contribute to DPNP and highlight HCN channels as potential therapeutic targets for treating DPNP.

Bacterial infections are a major challenge in wound healing, increasing complications and delaying recovery. This study developed alginate-based composite films incorporating three essential oils (EOs) - Hypericum perforatum (healing), Laurus nobilis (antibacterial) and Lavandula angustifolia (analgesic) - individually and in combinations, into a 3% sodium alginate matrix via solvent casting. Films were characterised for thickness, water solubility, swelling capacity and water vapour transmission rate (WVTR), as well as structural features (Fourier-transform infra-red spectroscopy (FTIR), scanning electron microscopy (SEM)) and antibacterial activity against Escherichia coli and Staphylococcus aureus. Essential oil incorporation enhanced moisture retention, maintained an optimal WVTR (1799-1906 g·m^-2·day^-1), and improved antibacterial activity, particularly against S. aureus (inhibition zones up to 16.3 mm). SEM analysis revealed increased surface roughness and porosity, while FTIR confirmed interactions between alginate and phenolic EO components. These results suggest that EO-loaded alginate films are promising, biocompatible wound dressings with infection-control and moist-healing capabilities, warranting further in vivo studies.

Cardiac dysfunction is a major cause of death in endotoxemia. Previously, we showed that methotrexate (MTX) carried in lipid-core nanoparticles (LDE) can modulate immune response and increase myocardial angiogenesis. The aim was to test the effects of LDE-methotrexate (LDEMTX) in rats with endotoxemia. Twenty male rats received I.P. injections of lipopolysaccharides (LPS, 10 mg/kg twice, 24h interval) and were allocated to 3 groups: LPS-LDEMTX, injected I.P. with 1 mg/kg MTX associated with LDE; LPS-MTX with conventional MTX (1 mg/kg, I.P.); LPS-LDE, injected with LDE only. A control group (CT) without endotoxemia was included. Echocardiography was performed 72h after endotoxemia induction. Animals were euthanized for analysis. LPS-LDE developed LV diastolic dysfunction, which was prevented in both LPS-LDEMTX and LPS-MTX groups. LPS-LDEMTX, but not LPS-MTX, developed compensatory LV hypertrophy. In LPS-LDEMTX, cellular hypoxia was lower, and angiogenesis was higher than in LPS-MTX and LPS-LDE, indicated by expression of hypoxia-inducible factor 1α, vascular endothelial growth factor and angiopoietin 1/2, respectively. Intracellular adenosine was increased in LPS-LDEMTX, with higher adenosine receptor expression. LPS-MTX but not LPS-LDEMTX showed hepatic toxicity. In conclusion, both LDEMTX and MTX prevented diastolic dysfunction in endotoxemia, but LDEMTX was further capable of improving several other parameters and had no toxicity.

Breast cancer is still a major global health issue and calls for innovative approaches for both early detection and effective treatment. Because of their distinct optical characteristics, biocompatibility and ease of surface functionalisation, carbon nanodots (CANDs), a novel class of carbon-based nanomaterials, have become effective agents in cancer nanomedicine. This review comprehensively explores the synthesis, physicochemical characteristics and functionalisation strategies of CANDs relevant to oncological applications. The review entails their mechanisms of action, including cellular uptake, tumour microenvironment (TME) modulation and reactive oxygen species generation. CANDs offer remarkable potential in breast cancer diagnosis through fluorescence imaging, photoacoustic and MRI enhancement, and biosensing, with advances towards point-of-care diagnostics. Therapeutically, CANDs serve as carriers for drug, gene and small interfering RNA (siRNA) delivery, and enable modalities such as photothermal, photodynamic and chemo-phototherapy, with emerging applications in immunotherapy. Additionally, theranostic systems integrating diagnostic and therapeutic functionalities are highlighted. The review also addresses clinical progress, patents and translational challenges while projecting future directions involving AI and hybrid nanodots, paving the way for next-generation breast cancer management.

Hyperglycaemia contributes to vascular dysfunction in coronary artery disease (CAD) by causing damage to endothelial cells and smooth muscle in the blood vessels. Carvedilol (CRD), a non-selective β- and α1-blocker, is approved for treating diabetes-associated CAD. However, CRD's short half-life and poor solubility limit its oral bioavailability and effectiveness. This study aimed to develop a nasal formulation of in-situ pH-sensitive CRD-loaded novasomes (ISCLN) to enhance CRD's sustainability, bioavailability, and efficacy as a therapy for diabetes-associated CAD. The Box-Behnken design was employed to determine the optimised formulation of CRD-loaded novasomes. This formulation was subsequently combined with chitosan and glyceryl monooleate to create ISCLN. The ISCLN was then evaluated in vivo using a rat model of experimental diabetes and CAD. Compared to free CRD, ISCLN significantly improved sustainability, bioavailability, targeting, and permeability of CRD. Relative to the positive control group, the ISCLN group exhibited decreased levels of glucose, cholesterol, triglycerides, low-density lipoprotein, lactate dehydrogenase, and creatine kinase-MB. Additionally, this group showed increased levels of high-density lipoprotein. Histopathological and toxicity studies confirmed the efficacy and safety of the ISCLN. These findings suggest that a nasal ISCLN formulation may serve as a potential therapy for diabetes-associated CAD.

Colorectal cancer is major cause of mortality, necessitating improved treatments. Lapatinib-loaded chitosan nanoparticles conjugated with lactoferrin and melatonin (LAP-CS-LF-MLT-NPs) developed using ionic gelation and carbodiimide coupling to improve bioavailability and minimise toxicity. Nanoparticles had a size of 184.36 ± 1.25 nm, a zeta potential of +31.88 ± 1.21 mV, and an entrapment efficiency of 68.23 ± 1.69%. FTIR, XRD, DSC, Raman, and NMR validated drug encapsulation, whereas FE-SEM, TEM, and AFM displayed uniform, smooth, spherical structures. In vitro, LAP-CS-LF-MLT-NPs displayed an IC₅₀ of 0.17 µg/mL in HCT116 cells compared to 127 µg/mL for free lapatinib, indicating a 700-fold enhancement in potency. Further investigations revealed a 48.29% arrest in G1-phase, a 233.44% disruption of mitochondrial membrane potential, and a 4.15% occurrence of late apoptosis, while ROS levels decreased to 54.13%, indicating melatonin's facilitation of ROS-independent apoptosis. Molecular docking demonstrated strong binding to EGFR (-12.014), SRC (-10.778), and MAPK14 (-10.298). Pharmacokinetic studies in Wistar rats showed a longer half-life (9.69 vs. 5.28 h), higher AUC₀-∞ (452.880 vs. 159.715 µg/mL·h), and improved MRT (15.260 vs. 7.696 h). Focused colon retention (8.20 ± 1.38 µg/g), minimal toxicity, and confirmed safety and stability underscore its potential as an accurate, efficient treatment for colon cancer.