Journal of Drug Targeting最新文献

This work aims to assess mechanisms of synthesis of folate-conjugated mesoporous silica nanoparticles (MNPs) for targeted delivery of paclitaxel in cancer treatment. Paaclitaxel, while potent, suffers from poor solubility and severe side effects due to off-target toxicity. The important factors including particle size (140 ± 6 nm), zeta potential (-29.2 ± 1.5 mV), drug loading (11.3 ± 0.8%), and entrapment efficiency (89.5 ± 1.7%) were determined by response surface methodology (RSM) by employing polynomial equations derived from factorial design. In biological fluids, optimised MNPs had good stability, low degree of aggregation (≤5%) and low drug release (≤4%). In vitro cytotoxicity analysis established higher anti-cancer efficacy, the optimised formulation depicted 78.5% tumour cell mortality to contrast with the 58% with free paclitaxel. In vivo, the MNPs containing paclitaxel enhanced the tumour targeting effect with the 87% of tumours observed with the treatment, while Taxol^® was effective in only 65% of the cases, and free paclitaxel in 58%. These results highlight the promise of folate-decorated MNPs as an advanced nanocarrier for safer and more effective paclitaxel chemotherapy, with significantly reduced systemic toxicity compared to commercial Taxol^®. However, further studies assessing drug penetration in larger tumour volumes and addressing scalability for clinical are warranted.

Skin cancer is the most prevalent malignancy, with rising incidence and morbidity, particularly among the white population. This study aims to develop a dual drug-loaded nanoemulsion (NE) gel incorporating 5-fluorouracil (5-FU) and lepidine (LPD) to enhance drug deposition in the stratum corneum and dermal layer for improved skin cancer therapy. Oil-in-water (o/w) NEs were prepared using peppermint oil, Tween 80 and PEG-400 via aqueous phase titration method and optimised through pseudo-ternary phase diagrams. The optimised dual drug-loaded NE showed particle size of 131.7 ± 3.21 nm, PDI of 0.21 ± 0.005 and zeta potential of -26.24 ± 1.532 mV. This NE was then dispersed into a 1% carbopol 934 gel for topical application. In vitro and ex vivo studies demonstrated significantly enhanced drug deposition and prolonged release (**p < .001) compared to a conventional gel. Furthermore, dermatokinetic and CLSM studies confirmed enhanced skin permeation and deeper drug distribution. Skin irritation studies indicated that the NE gel was safe and non-irritant. It is concluded that the developed 5-FU and LPD co-loaded NE gel enhances topical drug delivery against skin cancer by improving drug absorption and distribution between the epidermis and dermis in rodent skin model, which could represent promising strategy for the management of skin cancer.

Background: Glycemic memory contributes to the progression of diabetic nephropathy (DN) despite glycemic control. This study investigates γ-aminobutyric acid (GABA), a natural compound with 82.5% structural similarity to metformin, for its potential in mitigating glycemic memory and DN.

Methods: Structural similarity and molecular docking identified GABA as a SIRT1-targeting metformin analog (binding affinity: 5.8 kcal/mol), supported by ADME profiling. In vitro assays assessed antioxidant activity (DPPH IC₅₀: 141.09 µg/mL), cytotoxicity (MTT assay), oxidative stress markers, and histone H3 acetylation. In vivo, high-fat diet-fed Sprague-Dawley rats underwent dietary reversal and GABA treatment (100/200 mg/kg) to evaluate metabolic, renal, hepatic, oxidative, and epigenetic effects.

Results: GABA maintained >90% cell viability at 5 µM, with no cytotoxicity up to 150 µM. It reduced oxidative markers and restored histone acetylation in vitro. In vivo, 200 mg/kg GABA treatment significantly reduced cholesterol (44.44%), triglycerides (28.64%), and LDL (40.80%), while increasing HDL by 103.65%. At 100 mg/kg, GABA lowered blood urea (30.43%), creatinine (4.65%), uric acid (75.00%), bilirubin (53.57%), SGOT (54.24%), SGPT (39.52%), and ALP (60.58%), with histopathological improvements in renal tissues.

Conclusion: GABA exhibits antioxidant, hepatoprotective, and renoprotective properties, highlighting its potential as a therapeutic agent for glycemic memory-associated DN.

This review critically evaluates the emerging role of lactoferrin, an iron-chelating glycoprotein, as a macromolecular ligand in precision cancer therapy. Lactoferrin exhibits potent anti-tumour, anti-inflammatory, and immunomodulatory properties and targets cancer cells via high-affinity binding to transferrin and LDL receptor-related proteins, enhancing selectivity and minimizing off-target toxicity. It modulates key oncogenic pathways such as PI3K/Akt and MAPK to suppress tumour growth and metastasis. Nanoformulations-like liposomes and polymeric nanoparticles-improve pharmacokinetics, enable targeted drug delivery, and enhance therapeutic efficacy. Lactoferrin's ability to cross biological barriers, including the blood-brain barrier via receptor-mediated transcytosis, offers promise for treating difficult cancers such as glioblastoma. Additionally, it enhances anti-tumour immunity by activating NK cells and polarizing macrophages to the M1 phenotype. Importantly, lactoferrin helps overcome multidrug resistance by modulating efflux pumps like P-glycoprotein. Integrating molecular insights with preclinical and clinical evidence, this review underscores lactoferrin's transformative potential in precision oncology through advanced nanoformulations and synergistic immunomodulatory mechanisms.

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.