Journal of Drug Targeting最新文献

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.

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.

Purpose: This study aimed to develop sustainable synthetic routes for novel enaminonitrile pyridine derivatives and evaluate a lead compound's potential as a dual-action theranostic agent for oncology, combining targeted therapy and diagnostic imaging.

Methods: Two green chemistry techniques were utilised: microwave-assisted and solvent-free mechanochemical grinding. The lead compound 7 was assessed for in vitro anticancer activity against MCF-7 cells. It was radiolabeled with iodine-131, optimising parameters like substrate amount and pH. Finally, in vivo biodistribution and tumour targeting were studied in tumour-bearing mice.

Results: The green synthesis was highly efficient. Compound 7 showed superior anticancer activity (IC₅₀ = 3.77 ± 0.43 µM) versus cisplatin. Radiolabeling achieved high radiochemical purity (95.74 ± 1.44%). Biodistribution studies confirmed excellent, selective tumour uptake (9.07% ID/g at 1 h) with sustained retention (7.91% ID/g at 24 h) and high target-to-background ratios.

Conclusions: This work successfully establishes efficient green synthesis routes. Compound 7 is a potent and selective sustainable theranostic agent, effectively merging green chemistry principles with precision oncology applications for both therapy and diagnosis.

Colorectal cancer (CRC) remains a major therapeutic challenge due to systemic toxicity and poor tumour selectivity of conventional treatments. Thymoquinone (TQ), a natural anticancer compound, faces limited clinical utility because of poor solubility and bioavailability. To overcome these challenges, a fucoidan (FC)-coated methoxy poly(ethylene glycol)-poly(lactic acid) (mPEG-PLA) nanoparticle system was developed for targeted TQ delivery. The optimised FC-coated TQ nanoparticles (∼105 nm) exhibited high encapsulation efficiency (82.3 ± 0.77%) and low polydispersity (<0.2), enabling passive tumour targeting via the enhanced permeability and retention (EPR) effect. The formulation showed sustained, pH-responsive release and enhanced cytotoxicity in HCT-116 cells (IC₅₀ = 68.97 ± 1.10 µM) compared to uncoated NPs and free TQ. Confocal microscopy confirmed efficient uptake, while Western blot analysis demonstrated a concentration-dependent increase in cleaved caspase-3 in HCT-116 and HT-29 cells, indicating apoptosis induction. In vivo, FC-coated TQ-NPs induced significant tumour regression (75.26 ± 2.24%) and prolonged median survival (49 days) in C26 tumour-bearing mice versus free TQ (22 days). Biochemical analysis showed normal hepatic (alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and renal (blood urea nitrogen (BUN), creatinine) profiles, and cardiac histology remained intact, confirming biosafety. Thus, FC-coated mPEG-PLA-TQ nanoparticles enhance efficacy and safety, offering a promising nanoplatform for targeted CRC therapy.

Corticosteroid-induced osteoporosis leads to accelerated bone loss with associated oxidative stress, necessitating novel targeted therapeutic approaches. This work evaluates the protective efficacy of amorphous calcium phosphate-tagged benzimidazole derivative MR10 (ACP-MR10) nanoconjugate (NC) for its ability to counteract dexamethasone (DEX)-induced skeletal deterioration in zebrafish. ACP-MR10 NCs effectively mitigated ROS accumulation, restored antioxidant defences and preserved skeletal integrity and locomotor function, showing the strongest protective effect. ACP-MR10 significantly preserved DEX-induced mandibular bone deterioration. ACP-MR10's osteoprotective ability visualised through micro-CT also showed enhanced bone mineralisation, with improved trabecular architecture and vertebral alignment. ACP-MR10 treatment restored calcium and phosphorus levels, supporting robust skeletal regeneration. Molecular analysis showed suppressed rankl and runx2b expression while upregulating opg and alp, promoting balanced bone remodelling. Overall, these results point out ACP-MR10 as a credible candidate for its ability to provide a protective effect for bones capable of countering corticosteroid-induced osteoporosis by redox regulation, increased mineralisation, as well as structural retention of the skeleton.

Melanoma is an aggressive cutaneous malignancy characterized by high metastatic potential and poor prognosis. Oxidative stress plays a pivotal role in melanoma pathogenesis, as tumor cells exploit reactive oxygen species (ROS) to promote survival, drive progression, and regulate critical signaling pathways-including the expression of programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule that facilitates immune evasion. This study aimed to investigate whether venlafaxine, a compound with known biological activities, could modulate oxidative stress to suppress PD-L1 expression and enhance anti-tumor immune responses in melanoma. In vitro experiments demonstrated that venlafaxine significantly inhibited melanoma cell proliferation and migration, accompanied by a marked reduction in intracellular ROS production and altered expression of PD-L1-related proteins. In a murine melanoma model, venlafaxine administration effectively retarded tumor growth, downregulated PD-L1 levels in tumor tissues, promoted the infiltration of T lymphocytes into the tumor microenvironment, and increased the proportion of T lymphocytes in the spleen. Collectively, these findings indicate that venlafaxine exerts anti-melanoma effects by mitigating ROS release and potentiating anti-tumor immune responses, thereby highlighting its potential as a therapeutic candidate for melanoma treatment.

Psoriasis is a chronic autoimmune skin disease, which affects the quality of life of patients. Cyclosporine (Cys-A) & Vitamin D (Vit D₃) are crucial drugs used in the treatment of the disease. They are mainly administered via oral dosage forms for the treatment of psoriasis. However, their conventional dosage forms suffer from low oral bioavailability, along with systemic adverse effects. Developing the topical dosage forms of these drugs can be advantageous to overcome the problems associated with conventional therapy. Hence, ethosomes (ETH) were developed for the simultaneous administration of both the drugs. The particle size of the developed ethosomes was found to be 120.8 ± 5.6 nm, zeta potential value was found to be -24.7 ± 1.5 and entrapment efficiency was found to be 74.8 ± 1.52% & 80 ± 1.8% respectively, for Cys-A and Vit D₃. In vitro drug release studies exhibited drug release of about 74% and 78% for Cys-A & Vit D_3, respectively. Skin permeation studies demonstrated significantly higher drug permeation of ETH gel for Cys-A & Vit-D₃ (71.6% and 72.2% respectively) than the conventional gel formulation (52.9% and 54.8% respectively). A cytotoxicity study conducted on the HaCaT cell line showed no cytotoxicity with ≥ 90% of cell viability. The therapeutic efficacy of the formulation tested on the in-vivo antipsoriatic rat model demonstrated comparable efficacy to that of the marketed formulation and the signs of inflammation were reverted within 14 days.

Doxorubicin (DRC) is widely used as a breast cancer treatment. However, its use is limited due to cardio, hepatic, and renal toxicities. Carvedilol (CVL) has emerged as a potential protective agent against DRC-induced toxicity (DIT). Despite this, CVL has a short half-life, resulting in poor efficacy. Therefore, this study aimed to develop a nasal in situ pH-sensitive CVL-transbilosome (IPCT) formulation to enhance the sustainability, targeting, and effectiveness of CVL when administered alongside DRC (DRC-IPCT) to prevent DIT. Various CVL-transbilosomes (CT) were developed using design expert software to identify the optimal formulation. The selected optimal CT formulation was subsequently combined with chitosan and glyceryl monooleate to develop the IPCT formulation. The effectiveness of the DRC-IPCT formulation was evaluated in vivo using a breast cancer model induced by 12-Dimethylbenz(a)anthracene. The IPCT formulation enhanced the sustainability and permeability of CVL by 78.24% and 8.58-fold, respectively, compared to free CVL. The DRC-IPCT formulation reduced tumour volume and the levels of lactate dehydrogenase, creatine kinase, and malondialdehyde by 96.89%, 86.02%, 95.26%, and 68.28%, respectively. Furthermore, DRC-IPCT increased the levels of glutathione, superoxide dismutase, and catalase by 2.03-fold, 1.52-fold, and 1.94-fold, respectively. These findings indicate that the DRC-IPCT formulation is a promising therapy to prevent DIT-associated breast cancer.

Psoriasis is an autoimmune dermal disease characterised by inflammation that results in excessive keratinocyte proliferation. The current topical therapies struggle to penetrate the keratinised layer to reach the targeted area. A combinatorial therapy was employed to reverse inflammatory expression and cellular infiltration. Salicylic acid (SA) provides a keratolytic effect by softening and removing the thickened layer of keratin to facilitate better absorption of the Mupirocin-loaded nanoemulsion (MUP-NE), supplemented by black seed oil, where MUP inhibits tRNA synthetase, aiding in psoriasis management. In our studies, MUP-NE was developed and optimised using central composite design (CCD), resulting in an average globule size of 86.56 nm, PDI of 0.3479 and transmittance of 89.68 ± 0.32%, further incorporated into SA-gel (MUP-SA-NEG). The in-vitro and ex-vivo studies demonstrated targeted delivery of SA to the epithelial layer and deeper penetration of MUP via nanocarriers. Pharmacodynamic studies were subsequently performed using a psoriasis-induced mice model, PASI (Psoriasis Area and Severity Index) assessment on treated mice showed prominent reduction in keratinised scales, inflammation, and epithelial thickness of the skin tissue. Histopathological and immune-histology revealed notable recovery in the MUP-SA-NEG group of mice in comparison with the control and conventional treatment groups. These findings align with promising clinical acceptability.