Journal of Drug Targeting最新文献

This study investigates the anti-diabetic potential of rosiglitazone-metformin adduct (RZM), a 1:1 molar co-crystal complex, in spontaneous diabetic KK mice and streptozotocin-induced diabetic rats. Diabetic models were divided into four groups: vehicle control, physical mixture (R + M), low-dose RZM, and high-dose RZM. Metabolic parameters including fasting glucose and lipid profiles were assessed over time, alongside hepatic histopathology and molecular analyses of AMPK/TXNIP pathways. In vitro validation employed high glucose-exposed MIN6 and INS-1 β-cells. RZM treatment significantly reduced hyperglycaemia, enhanced glucose tolerance, and ameliorated dyslipidemia, with dose-dependent efficacy. Histopathology demonstrated RZM's hepatoprotective effects through reduced steatosis and inflammation. Mechanistically, RZM activated AMPK phosphorylation while suppressing TXNIP overexpression in both pancreatic β-cells and metabolic tissues, a conserved pathway confirmed across species and in vitro models. Compared to conventional combination therapy, the stoichiometrically optimised RZM formulation exhibited superior glycemic control and liver protection via coordinated AMPK-TXNIP modulation. These findings establish RZM as a dual-targeting agent with translatable therapeutic advantages, providing preclinical evidence for its development as a next-generation antidiabetic drug through synergistic pathway regulation.

Cancer continues to be a major public health challenge due to therapeutic resistance, rising incidence and financial burden. Although anti-programmed cell death-ligand 1 (PD-L1) immunotherapy has revolutionised cancer treatment, its efficacy as monotherapy remains limited. Combining chemotherapy with immunotherapy offers the potential to amplify therapeutic outcomes and reduce side effects. Paclitaxel can induce immunogenic cell death (ICD) and improve tumour response to anti-PD-L1 therapy, thereby improving immunotherapy effectiveness. Meanwhile, small interfering RNA (siRNA) therapy can selectively suppress PD-L1 expression on the cell membrane and in the cytoplasm, though efficient delivery remains a challenge. We developed nanoparticles composed of trimethyl chitosan (TMC) and hyaluronic acid (HA) for delivering PD-L1 siRNA. These spherical nanoparticles (∼190 nm) demonstrated favourable physicochemical properties, high siRNA encapsulation efficiency, robust serum stability, a non-toxic nature and effective internalisation by cancer cells. The sequential therapy of sub-therapeutic doses of paclitaxel with siRNA PD-L1 in a 4T1 Balb/c mouse model compared to each monotherapy led to a substantial boost to antitumor immunity, suppression of tumour growth and increased infiltration of effector CD8+ T-cells within the tumour microenvironment. This study presents a novel siRNA delivery system and therapeutic approach that enhances the efficacy of breast cancer immunotherapy.

Acute exposure to diisopropylfluorophosphate (DFP), an organophosphate (OP), produces chronic neurological effects such as spontaneous seizures and behavioural comorbidities. Achieving optimal drug bioavailability in the brain by conventional routes to treat OP-induced neurotoxicity is challenging. Therefore, we investigated polyanhydride nanoparticles (NPs)-mediated drug delivery via the intramuscular route in rats for improved bioavailability of an antioxidant, NADPH oxidase inhibitor mitoapocynin (MPO). We evaluated the tolerability of blank NPs (4 mg, i.m.), MPO-encapsulated NPs (MPO-NP, 4 mg, i.m., single dose) and free MPO-oral (60 mg/kg, daily for three days) after exposure to DFP. Bodyweight, serum biochemistry, and kidney, lung and liver histology revealed no adverse responses to blank NPs. Markers of oxidative stress, neuronal loss and astrocyte reactivity were also no different from control. In DFP-exposed animals treated with MPO-NP and MPO-oral, there was significant weight loss, abnormal liver and kidney parameters, and elevated GP91phox and astrocytes in the brain. Our findings demonstrate that NP delivery via the intramuscular route is safe. DFP and MPO induced off-target effects, but not DFP or MPO treatment alone, which highlights the complexity of dosing regimens in OP models. Intranasal MPO-NP delivery and dose optimisation in the DFP model are required to determine the efficacy of MPO in future studies.

The pursuit of effective, non-invasive cancer therapies has propelled the development of oral delivery systems capable of overcoming the limitations of conventional chemotherapy. A novel furo[2,3-d]pyrimidine-based chalcone derivative, MMK-1931, was successfully encapsulated into chitosan-coated liposomes (chitosomes) to create an oral anticancer nanomedicine. Both MMK-1931-loaded liposomes and chitosomes were formulated, producing spherical nanoparticles (NPs) with a nanometric size range and high entrapment efficiency. Optimisation studies were conducted to select the most effective formulation. Structural characterisation using FTIR and differential scanning calorimetry (DSC) confirmed drug encapsulation and formulation integrity. In vivo evaluation in an Ehrlich ascites carcinoma (EAC) mouse model demonstrated that MMK-1931-loaded chitosomes (MMK-1931-Chitosomes) significantly suppressed tumour growth, as evidenced by substantial reductions in tumour volume and weight. They also activated apoptotic pathways, as demonstrated by the upregulation of Bax and caspase-9 and the downregulation of Bcl-2. Moreover, they modulated oncogenic signalling by reducing cyclin D and MDM2 levels while enhancing the expression of p53 and PTEN. Histopathological analysis confirmed widespread tumour necrosis and membrane damage. Notably, the antitumor efficacy of orally administered MMK-1931-Chitosomes was comparable to that of intraperitoneally delivered cisplatin, underscoring their potential as a safer, more patient-friendly alternative and establishing them as a promising oral nano-system for solid tumour therapy.

Polymyxin B (PMB) serves as the last-line drug for treating multidrug-resistant Gram-negative bacterial infections. However, its clinical application is limited due to significant nephrotoxicity and neurotoxicity. In recent years, smart drug delivery systems have emerged as a research hotspot, aiming to optimise the functions and therapeutic effects of PMB. This article systematically reviews the structural characteristics and antibacterial mechanisms of PMB, as well as the challenges it faces in treating drug-resistant bacterial infections. The progress in smart delivery strategies for PMB is also discussed, including multidrug-resistant delivery, anti-biofilm technologies, targeted delivery, local administration, and synergistic treatment strategies. These strategies offer new directions for the precise treatment of PMB by increasing local drug concentration, reducing toxicity, enhancing the antibacterial spectrum, and inhibiting drug resistance.

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.