Journal of Drug Targeting最新文献

Lung cancer is the malignant tumour with the highest growing morbidity and mortality rates worldwide. Lung adenocarcinoma is the most prevalent type of non-small cell lung cancer (NSCLC). It is highly malignant and may lead to distant metastasis at an early stage. The standard treatment for lung adenocarcinoma involves a combination of surgery and chemotherapy, which is frequently associated with severe side effects. In response to this challenge, a safe and effective drug carrier has been designed to facilitate drug delivery. The surface of this polymer micelle is modified with reactive oxygen species (ROS)-responsive targeting ligands and cell-penetrating ligands. Pemetrexed (PMX) and baicalein (BAI) are encapsulated within the micelle. The micelles exploit the high expression of ROS in the tumour microenvironment and cell-penetrating peptides to deliver drugs safely and efficiently into tumour cells, thereby inhibiting the invasion and metastasis of these cells and ultimately suppressing tumour growth. This carrier holds significant potential for guiding clinical treatment strategies for lung adenocarcinoma.

Carvedilol (CRD) is an oral beta-adrenergic antagonist approved for treating heart failure (HF). However, due to its short half-life and poor solubility, CRD has limited bioavailability and effectiveness. This study aimed to develop a nasal spray of CRD-loaded novasomes (CLNs) to enhance CRD's sustainability, targeting, bioavailability and efficacy as a therapy for diabetes mellitus-associated HF (DMHF). Several CLN formulations were created using Box-Behnken's design and characterised in vitro to identify the optimised formulation, which was later evaluated in vivo using an experimental DMHF rat model. The selected optimised CLN formulation consists of 30.079 mg of oleic acid, 56.897 mg of Span 60, and 60 mg of cholesterol. The optimised CLN demonstrated significant improvements over free CRD, enhancing CRD's sustainability and permeability by 71.39% and 6.08-fold, respectively. When compared to oral free CRD, the nasal CLN increased the bioavailability and target efficiency of CRD by 5.74-fold and 4.24-fold, respectively. In relation to DMHF positive control, the nasal CLN significantly lowered glucose, LDH and CK-MB levels by 93.68%, 94.29% and 96.50%, respectively, showcasing its efficacy. Histopathological and toxicity studies further validated the activity and safety of the optimised CLN. These findings indicate that the nasal CLN spray shows potential as a therapy for DMHF.

Rosmarinic acid, an ester between caffeic acid and 3,4-dihydroxyphenyllactic acid, is distributed in broad distribution throughout plants within the Boraginaceae family and Nepetoideae subfamily of Lamiaceae. It has been identified with its multifaceted biological and pharmacological activities and thus has been the subject of significant interest for therapeutic application. Diclofenac sodium is a widely used NSAID for pain relief and inflammation control. Here, a transethosomal delivery form of rosmarinic acid & diclofenac sodium (RD-TE) was prepared and formulated into a gel for local application. Optimisation was performed utilising the Box-Behnken design, determining the effect of three independent variables Phospholipid 90 G, sodium cholate, and ethanol on vesicle size, polydispersity index (PDI), and entrapment efficiency. The optimised formulation (RD-TE-Opt) had a vesicle size of 110.9 nm, PDI of 0.37, zeta potential of -20.76 mV, % entrapment efficiency of romarinic acid and diclofenac sodium was found to be 82.44 and 81.23% respectively. In vivo evaluation using an arthritic rat model demonstrated a significant reduction in paw volume, from 3.65 ± 0.03 to 3.42 ± 0.04, along with an RBC count of 8.23 ± 0.03 in the group treated with RD-TE-OptG. Radiographic analysis confirmed the therapeutic efficacy of the formulation. RD-TE gel shows potential as a topical arthritis treatment.

Among the many emerging strategies in precision medicine, surface receptor-directed drugs offer a promising pathway for the targeted and effective delivery of a cure. Histamine receptor (H₃R) antagonists have been demonstrated to target and effectively suppress cancer cells that overexpress H₃R. The present study aimed to evaluate the anticancer potential of (E)-3-(3,4,5-trimethoxyphenyl)-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)prop-2-en-1-one (AR71), a hybrid H₃R antagonist/inverse agonist featuring a piperidinylpropoxy motif conjugated to trimethoxychalcone, which mimics colchicine and disrupts microtubule assembly. Following incubation with AR71, we observed significant inhibition of growth and cell cycle arrest at G2/M in glioblastoma and neuroblastoma cells, which correlated with their H₃R expression levels. AR71 treatment decreased the invasion potential of cancer cells by 60-80% along with a decrease in MMP-2 release. In-depth immunocytochemical investigations revealed dose-dependent impairment of microtubule organisation after treatment with AR71. Consequently, tubulin polymerisation and cytokinesis failure led to a greater incidence of aneuploid cells and tripolar mitotic events. We also observed an increase in mitochondrial reactive oxygen species in cancer cells following exposure to AR71. As a result, the mitochondrial membrane potential decreased significantly. In summary, targeting dual molecules with AR71 may create favourable conditions for the selective and synergistic action of combined anticancer compounds against glioblastoma and neuroblastoma.

Objective: This study aimed to unveil the effect of glucosamine hydrochloride (GAH) and eperisone combined with exercise therapy on inflammatory markers and knee joint function in patients with knee osteoarthritis (KOA).

Methods: Sixty KOA patients were randomly assigned into two groups. Group A (n = 30) received GAH plus exercise therapy, while Group B (n = 30) received GAH combined with eperisone and exercise therapy. Serum inflammatory factors, knee symptom scores (pain, stiffness, daily function), and functional measures [knee flexion range of motion (ROM), Lysholm score, five-time sit-to-stand test, and 15-meter walking time] were assessed before and after treatment. Clinical efficacy was also evaluated.

Results: Post-treatment, both groups showed decreased serum MMP-3, TNF-α, and IL-6 levels, with significantly greater reductions in Group B (p < 0.001). Group B had lower symptom scores (p < 0.05), greater ROM and Lysholm improvements (p < 0.001), and better functional performance (p < 0.001). The effective rate was higher in Group B (100.00%) than in Group A (86.67%) (p = 0.038).

Conclusion: GAH combined with eperisone and exercise therapy is more effective than GAH alone in patients with KOA. It significantly reduces inflammatory markers and symptoms, and enhances knee joint function.

Chitosan-based materials have gained significant attention in drug delivery owing to their exceptional properties, including biocompatibility, biodegradability, mucoadhesiveness, and tuneable physicochemical characteristics. Their structural versatility allows formulation into various delivery tools, such as nanoparticles, microparticles, hydrogels, micelles, and conjugates. These attributes make chitosan an ideal biopolymeric candidate as a drug carrier with engineered characteristics, facilitating active and passive targeting. Chitosan nanoparticles contribute to passive targeting via enhanced permeation and retention (EPR) effect and actively participate in receptor-mediated targeting when functionalized with ligands such as small molecules, peptides, polymers, aptamers, and antibodies. This dual-targeting capability makes chitosan-based drug delivery systems highly advantageous for cancer therapy and other site-specific treatments. This review compiles recent advancements in the synthesis of various types of chitosan-based materials and their study in cancer-targeting efficacy. It explores passive targeting mechanisms through modified chitosan nanoparticles and discusses active targeting strategies achieved via conjugation with cancer cell-specific ligands. Special emphasis is placed on formulation strategies, targeting efficiency, and evaluating therapeutic outcomes through cell viability assays and cellular uptake studies.

Harnessing the immune system through cancer vaccines offers a promising strategy to overcome tumour heterogeneity, which remains one of the most significant challenges in achieving effective treatment for colorectal cancer (CRC). In this study, we designed and validated a novel multi-epitope vaccine against CRC using integrated computational and experimental approaches. The final construct was developed through in silico prediction and optimisation, followed by recombinant expression and in vivo testing in a CRC mouse model. Mice receiving the multi-dose vaccine exhibited a mean tumour volume approximately 80% lower than that of the untreated cancer group. Additionally, IL-4 levels were significantly elevated (p < 0.0001), consistent with activation of humoral immune responses. Histopathological assessment showed largely preserved tissue architecture in the spleen, kidney, and liver. The multi-dose vaccine group achieved 100% survival, compared with 60% survival in the untreated cancer group. These results suggest the vaccine can suppress tumour progression, enhance immune responses, and provide systemic protection, supporting further preclinical development.

Methotrexate (MTX) is widely used in treating cancers and inflammatory conditions like psoriasis and rheumatoid arthritis (RA), however is associated with side effects. Nanoemulsions (NEs) offer enhanced stability, protection and improved permeation via various delivery routes. MTX-loaded oil-in-water NEs (O/W NEs) were formulated to improve entrapment efficiency, permeation ability and efficacy in CFA-induced arthritis model. The area of NEs was identified by pseudoternary phase diagrams, optimisation of MTX-NEs was performed using I-optimal mixture design, and characterised for %entrapment efficiency, droplet size, polydispersity index, zeta potential, morphology and %transmittance. The MTX-NE gel was evaluated for rheology, in vitro drug release, ex vivo permeation and efficacy in a CFA-induced arthritic rats. The MTX-NEs were prepared using S_mix ratio of 3:1 with 0.2 N sodium hydroxide as aqueous phase. It showed >90% entrapment efficiency, size of 161.4 ± 13.5 nm, and 94 ± 1.8% of %transmittance. MTX-NE gel showed sustained release of 86 ± 1.8% MTX, and cumulative permeation of 77.6 ± 1.4% with a flux of 0.184 µg/cm²·h. Efficacy studies in a CFA-induced rat model resulted in significant reduction of paw oedema, radiographic, histopathological and inflammatory biomarkers. The optimised MTX-NE gel showed enhanced delivery, sustained release and significant anti-arthritic effects, supporting its potential as an effective for RA therapy.

This study investigates the topical delivery of Fisetin (FIS) to counteract UVB-induced skin photoaging. Due to FIS's poor solubility and high lipophilicity, it was encapsulated in D-limonene-modified phospholipid carriers, limosomes (LIMOs), co-formulated with Ascorbyl Palmitate (AP) and Hyaluronan (HYA) to improve FIS's solubility, skin penetration, and photoprotective efficacy. FIS-AP-HYA-LIMOs exhibited small size (81.50 ± 0.98 nm), high entrapment (98.93 ± 0.13%), and sustained release over 24 h. FT-IR and DSC confirmed the successful formation of FIS-AP-HYA-LIMOs. The ex vivo permeation study showed high flux (10.54 ± 0.40 µg.cm^-2.h^-1), reflecting evident skin penetration. Confocal microscopy proved the ability of FIS-AP-HYA-LIMOs to deposit FIS to a skin depth of 128 µm with a strong FIS fluorescence in skin layers. FIS-AP-HYA-LIMOs showed potent in vitro antioxidant activity, high biocompatibility, and remained stable for 6 months. In vivo studies revealed the downregulation of MMP9, TNFα, and NF-κB, accompanied by increased SOD and CAT levels, indicating superior anti-ageing, anti-inflammatory, and antioxidant effects compared to FIS suspension. FIS-AP-HYA-LIMOs decreased JNK expression, preserved the integrity of skin layers, and reduced collagen degradation. This is the first report on FIS-loaded limosomes, modified with AP and HYA to synergistically prevent UVB-induced photoaging.

In lung adenocarcinoma (LUAD), dysfunctional CD8⁺ T-cells and an immunosuppressive tumour microenvironment (TME) are major barriers to effective immunotherapy, yet the molecular regulators coordinating T cell exhaustion and macrophage polarisation remain undefined. To address this, we integrated single-cell RNA sequencing, TCGA transcriptome and methylation data, co-culture assays, chromatin profiling, functional assays, and xenograft models to investigate the role of DNAJA1 in immune regulation and tumour progression. Our results demonstrated that DNAJA1 was upregulated in exhausted CD8⁺ T-cells in lung cancer tissues and correlated positively with exhaustion markers including PD-1, TIM-3, and LAG-3. Notably, exhausted CD8⁺ T-cells exhibited DNAJA1 promoter hypomethylation and enrichment of activating histone modifications H3K4me3 and H3K27ac, while inhibiting the activation of H3K4me3 and H3K27ac reduced DNAJA1 expression. Additionally, DNAJA1 overexpression upregulated M2-associated genes (CD206 and IL-10), while its knockdown enhanced the expression of M1-associated genes (CD86 and IL-12). Furthermore, DNAJA1 promoted tumour cell proliferation, and its expression level showed a moderate positive correlation with PD-L1. Collectively, these findings establish DNAJA1 as an epigenetically activated regulator that drives CD8⁺ T-cell exhaustion and protumor macrophage polarisation, highlighting its dual role as a functional immunomodulator and potential biomarker for stratifying LUAD patients with immune-dysregulated TME.