Journal of Drug Targeting最新文献

PD-1/PD-L1 blockade therapy shows good efficacy in melanoma treatment. Yet, most patients still exhibit poor responses. Exploring more effective drugs remains worthwhile. In contrast to developing new drugs which entails a lengthy process, high costs and uncertainties, repurposing old drugs is regarded as a promising and safe method, attracting greater attention. In this study, we evaluated the anti-melanoma effect of buspirone hydrochloride, a novel anti-anxiety drug. The results demonstrated that buspirone hydrochloride effectively restrained cell proliferation and migration and decreased the expression of related proteins p-STAT3, cyclin D1 and MMP2. Significantly, we discovered that buspirone hydrochloride efficiently enhanced the degradation of PD-L1. Further investigations in a melanoma-bearing mouse model showed that buspirone hydrochloride delayed the growth of tumours in tumour-bearing mice, increased apoptosis of tumour cells and inhibited cell proliferation. We found that buspirone hydrochloride treatment increased the ratio of T lymphocytes in the spleen of mice and the infiltration of T lymphocytes in tumour tissues. These findings suggest that buspirone hydrochloride not only plays an anti-melanoma role by directly inhibiting cell proliferation and promoting apoptosis but also enhances the anti-tumour immune response by suppressing PD-L1 expression, thus providing a new alternative for the development of melanoma treatment drugs.

Colorectal cancer liver metastasis (CCLM) remains a major therapeutic challenge due to chemoresistance and dose-limiting toxicities of conventional therapies. This study developed a copper-doped mesoporous silica nanoparticle (DSF@Cu-MSNs-BSA) for co-delivering disulphiram (DSF) and doxycycline (DOX) to synergistically target CCLM. The nanocomposite was synthesised via Sol-gel co-condensation, surface amination, and albumin adsorption, achieving a high DSF loading capacity (12.69 ± 2.47% w/w) with sustained release. Physicochemical characterisation confirmed uniform spherical morphology (160.8 ± 20.7 nm), Cu²⁺ incorporation (4.74% atomic ratio), and exceptional colloidal stability (>24 h). In vitro studies demonstrated synergistic cytotoxicity in CT26.WT cells, with combination therapy reducing IC₅₀ by 2.5-fold versus monotherapes (p < 0.01), mediated by ROS overproduction (6.7-fold vs control) and mitochondrial depolarisation. Pharmacological ROS quenching attenuated cytotoxicity by 46.5%, validating redox-driven mechanisms. In an orthotopic CCLM model, DSF@Cu-MSNs-BSA/DOX combination suppressed hepatic metastasis by 72-75%, extending median survival by 51% versus control (p < 0.01), comparable to capecitabine (p > 0.05). Histopathology revealed minimal metastatic burden and reduced hepatotoxicity in combinatorial groups. The Goldie-Coldman synergy index (q = 1.18) confirmed supra-additive efficacy. This nanoplatform addresses DSF's pharmacokinetic limitations while leveraging DOX's mitochondrial targeting, offering a promising strategy for metastatic CRC management with favourable safety profiles.

Mitochondrial dysfunction is closely associated with the onset and progression of various major diseases, including cancer and neurodegenerative disorders. The design of smart nanomaterial-natural product composite systems offers an innovative strategy for multifunctional nanocarriers. These smart carriers not only enable precise, controlled release of active components at specific mitochondrial targets but also provide novel technical support for natural products to overcome various barriers encountered during in vivo administration, thereby enhancing bioavailability. This review systematically summarises the latest research advances in mitochondria-targeted nano-drug delivery systems based on smart responsive principles for delivering natural products. It focuses on exploring the design principles, mechanisms of action, and representative applications of various responsive systems (including pH-, enzyme-, redox-, temperature-, light-, magnetic-, and ultrasound-responsive systems). Furthermore, existing challenges and unexplored therapeutic opportunities through interdisciplinary strategies integrating AI technology, CRISPR gene editing, and biomimetic materials are also highlighted and discussed to inspire the next generation of mitochondrial-targeted nanotherapeutics.

Cancer remains a leading cause of mortality worldwide, with treatment failure and disease recurrence often driven by cancer stem cells (CSCs), which constitute a resilient subpopulation within tumours characterised by self-renewal, differentiation capacity and resistance to conventional therapies. Extracellular vesicles (EVs), including exosomes and microvesicles, are secreted by CSCs and play pivotal roles in tumour progression, immune evasion and therapeutic resistance by transporting bioactive molecules such as heat shock proteins and regulatory RNAs. These vesicles reflect the molecular signature of their parent cells and offer unique opportunities for non-invasive diagnostics and targeted therapy. The theranostic paradigm, which integrates diagnostic and therapeutic functions, leverages EVs for CSC-specific biomarker detection, drug delivery and real-time monitoring of treatment response. Advances in nanotechnology and molecular engineering have enabled the functionalization of EVs with imaging agents and therapeutic payloads, increasing their specificity and efficacy in preclinical and early clinical settings. This narrative review synthesises current knowledge on CSC biology, EV biogenesis and the evolving landscape of EV-based theranostics, highlighting translational progress, technical challenges and future directions. Theranostic EVs represent a promising frontier in precision oncology, offering transformative potential for the management of CSC-driven tumorigenesis and relapse.

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.

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.

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.

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.

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.