Journal of Drug Targeting最新文献

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), represents a significant challenge to global health. The management of the disease requires an extended course of antibiotic therapy, spanning a duration of 6 to 9 months. The complexity and duration of these regimens frequently lead to significant adverse effects, gastrointestinal issues, and the development of drug resistance. To address these challenges, the nanoparticulate based inhalable drug delivery system was designed as such by synthesising mannosylated chitosan decorated PLGA nanoparticles loaded with isoniazid (MC-PLGA-INH-PNPs) for targeted pulmonary delivery. Hence, nanoparticle based drug delivery system offers the potential to target and deliver the loaded drug directly into the M.tb infected cells. The prepared and optimised nano-formulation had a particle size of 154.9 ± 21 nm, zeta potential -23.2 ± 0.52 mV and entrapment efficiency of 79.8% ± 0.45. Additionally, the MC-PLGA-INH-PNPs exhibited a sustained drug release profile at physiological pH 7.4 for a period of 24 hr. An in vivo study of the MC-PLGA-INH-PNPs was performed on a mouse model utilising lipopolysaccharide as an inducer. The data obtained from the in vivo studies showed substantial improvements in lung tissues architecture and reduced inflammation. The group of animals treated with the MC-PLGA-INH-PNPs showed significant improvement in restoration of the disease when compared to pure drug treated group. These findings further indicate that these inhalable MC-PLGA-INH-PNPs hold a promising strategy for the treatment of tuberculosis and considerably improves pulmonary drug delivery to the target site. However, detailed investigations and testing of this nano-formulation on other relevant animal models will be essential to successfully translate this concept from laboratory to clinical practice.

Arthritis is a chronic inflammatory disorder that impairs joint function and necessitates efficient localised treatment. This research aimed to formulate and optimise leflunomide-loaded nanostructured lipid carriers (NLCs) for topical delivery via a systematic Quality by Design technique. Dynasan 114 and corn oil were used as the solid and liquid lipids, respectively, and NLCs were formulated using high-speed homogenisation followed by probe sonication to achieve uniform particle size and stability. A dual experimental design approach was employed, using Plackett-Burman screening to identify critical formulation parameters, followed by Box-Behnken for formulation optimisation. This strategy resulted in optimised NLCs with a particle size of 125.5nm, a PDI of 0.188, a zeta potential of -15.5mV, and an entrapment efficiency of 92.20 ± 1.28%.% FT-IR, DSC, P-XRD, and TEM validated the amorphous dispersion of leflunomide within the lipid matrix and the spherical morphology of the NLCs. The optimised NLCs were integrated into a Carbopol 980 NF (0.75%) gel base, demonstrating appropriate rheological properties such as extrudability (176 g), adhesiveness (-112 g), and pH (6.92). The gel formulation demonstrated prolonged drug release (96% over 24 hours) and increased ex-vivo permeation with flux of 0.3632mg/cm²/hour, hence validating enhanced diffusion through the skin barrier. The in-vivo pharmacodynamic study using a carrageenan-induced paw edema model exhibited an 89.40% reduction in inflammation, exceeding the efficacy of the marketed leflunomide formulation. These findings suggest that the leflunomide-loaded NLC-based gel offers a promising platform for dermal drug distribution and enhanced anti-inflammatory activity.

Epigallocatechin gallate (EGCG) exhibits remarkable bioactivities, notably enhancing wound healing via keratinocyte activation and re-epithelialization. However, its susceptibility to oxidation restricts its efficient application. To address this, this study aims to improve its stability and bioavailability by integrating EGCG liposomes (ELS) with N-isopropylacrylamide (NIPAM)-modified chitosan (CS) hydrogel (TSCN). Specifically, the TSCN2/5 hydrogel with a mass ratio of CS/NIPAM of 2/5 is injectable and can undergo a reversible phase transition around 30.4 °C, which also exhibits a good adhesive strength of 36.73 kPa. The ELS1 liposomes (the mass ratio of lecithin/cholesterol/EGCG is 40/10/3) demonstrate good stability and encapsulation efficiency, with a particle size of about 110 nm and an encapsulation efficiency of about 85%. Cellular experiments reveal that ELS1 and TSCN2/5 are non-toxic to cells, and the ELSCN hydrogel (composite of ELS1 and TSCN2/5) can increase the expression of PPAR-α protein in skin repair. Animal experiments demonstrate that ELSCN with a high concentration of EGCG can promote wound healing by reducing skin inflammation, boosting collagen synthesis, facilitating epidermal repair, and promoting granulation tissue formation. Consequently, this composite hydrogel will be used as a coating for efficient skin wound repair.

Oral mucositis (OM) is a debilitating condition that typically results from chemotherapy or radiotherapy, causing painful ulceration and inflammation in the oral cavity. This work optimised and tested a dual-action mucoadhesive buccal film containing curcumin (CUR) with lidocaine (LID) for the localised targeting treatment of OM to develope an anti-inflammatory and analgesic effects and mucosal healing. Mucoadhesive buccal films were formulated using a solvent casting technique based on nanoemulsion. Buccal films were produced combining plasticisers (PEG 400), hydrophilic polymers (PVA, HPMC, PVP), and permeation enhancers (Tween 80, Transcutol). The optimised formula have high folding endurance (>300 folds), uniform thickness (1.0 ± 0.01 mm), pH compatibility (6.7), and excellent drug content homogeneity (∼97% for LID and ∼96% for CUR). In vitro, the film released 95% of LID and 90% of CUR within 13 min. Ex vivo studies showed higher permeation of LID (95 µg/cm²) compared to CUR (80 µg/cm²). In vivo, the CUR-LID film significantly enhanced ulcer healing (∼95-100% by day 5), with complete mucosal regeneration and normalisation of inflammatory biomarkers to baseline levels. This work supports the CUR-LID buccal film as a prospective non-invasive platform for managing oral mucositis with better therapeutic outcomes, effective drug delivery, and prolonged mucosal contact.

Mesenchymal stem cells (MSC)-derived exosomes have been identified as highly potential, cell-free therapeutic agents that play pivotal roles in immune-based modulation in conjunction with regenerative medicine. These extracellular vesicles are mostly isolated using ultracentrifugation, size-exclusion chromatography, or immunoaffinity capture and carry a wide range of bioactive molecules (lipids, nucleic acids, and proteins). MSC-derived exosomes have strong immunomodulatory properties, such as inhibition of pro-inflammatory cytokines, expansion of regulatory T cells, and induction of an anti-inflammatory microenvironment. Therapeutically, they are influential in various disease models, some of which include autoimmune disorders, cardiovascular disease, etc. Engineered MSC-derived exosomes present an exciting potential as a drug delivery vehicle in the field of oncology as a means of addressing chemoresistance and improving drug bioavailability. Exosomes have several advantages over MSC-based therapies. Distinct from previous reviews that have examined immunomodulation or regenerative indications in isolation, this article specifically integrates cargo-defined immune rewiring by MSC-derived exosomes with organ-specific regenerative outcomes across inflammatory, autoimmune, oncologic, and neurodegenerative disorders, and links these mechanisms to emerging drug-sensitization strategies and early-phase clinical trials. This narrative review includes the strategies of purifying MSC-derived exosomes and their potential therapeutic importance in diseases, where standardized methods are needed to improve clinical translation.

Melanoma is an aggressive cutaneous malignancy characterised by high metastatic potential and poor prognosis. Oxidative stress plays a pivotal role in melanoma pathogenesis, as tumour cells exploit reactive oxygen species (ROS) to promote survival, drive progression, and regulate critical signalling 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-tumour 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 tumour growth, downregulated PD-L1 levels in tumour tissues, promoted the infiltration of T lymphocytes into the tumour 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-tumour immune responses, thereby highlighting its potential as a therapeutic candidate for melanoma treatment.

The importance of mitochondria in cancer is undeniable, as they serve as a vital centre for energy metabolism and regulating apoptosis. Herein, we engineered cubosomes as a nanocarrier with encapsulation of the chemotherapeutic agent 5-fluorouracil and an antioxidant with reported antitumor activity, lycopene. The formulation was fabricated by utilising glyceryl monooleate, oleic acid, and polaxamer-407, facilitating simultaneous encapsulation of hydrophobic lycopene and hydrophilic 5-fluorouracil. To target mitochondria, the nanoparticle surface was decorated with triphenylphosphine, a lipophilic cation known to gather within the negatively charged mitochondrial membrane. Physicochemical evaluation verified nanoscale particle size (158.7 nm), uniform distribution (0.2482 PDI), and high encapsulation efficiency (79 ± 5.2% for 5-FU and 85 ± 7.1% for lycopene). The synergistic impact of 5-FU-induced DNA synthesis suppression and lycopene-mediated mitochondrial oxidative stress was augmented by TPP-driven mitochondrial accumulation, resulting in significant apoptotic activity in cancer cells, as confirmed in in vitro cytotoxicity assays and in vivo animal studies. These findings highlight the potential of synergism of 5-FU and lycopene in skin cancer and also the potential of TPP-functionalised entrapped dual-drug-loaded cubosomes in mitochondrial targeting of skin cancerous cells.

A novel intra-articular (IA) nanocarrier system for leflunomide (LEF) was developed using modified proposomes to enhance therapeutic efficacy in rheumatoid arthritis (RA). LEF was efficiently encapsulated within propylene glycol-based proposomes, which were sequentially functionalised with chitosan (CS) and hyaluronic acid (HA) to improve stability, bioadhesion and targeted delivery. The optimised nanoparticles exhibited a uniform nanoscale size, a zeta potential of -50.46 ± 6.4 mV, and a high entrapment efficiency of 94.12 ± 1.7%. In vitro release studies revealed a sustained LEF release profile from LEF-HA-proposomes over 84 h. In a Complete Freund's adjuvant (CFA)-induced RA rat model, IA administration of LEF-HA-proposomes resulted in marked therapeutic improvements (P˂0.05), including a 39.24% reduction in paw edoema, a 3.26-fold decrease in rheumatoid factor, a 3.47-fold reduction in TNF-α, and a 4.75-fold decline in IL-1β levels, accompanied by a 2.73-fold elevation in Nrf2 expression. Histopathological evaluation confirmed significant preservation of joint architecture and attenuation of synovial inflammation in the LEF-HA-proposomes group. Collectively, these findings highlight LEF-HA-proposomes as a promising IA nanocarrier platform for targeted RA therapy, offering prolonged drug retention, enhanced local anti-inflammatory efficacy, and minimised systemic toxicity compared with conventional oral treatments.

Mitochondria-targeted antioxidants can selectively accumulate within mitochondria at low doses, thereby significantly enhancing therapeutic efficiency while minimising potential side effects. SKQ1, a novel mitochondria-targeted antioxidant, operates through a well-defined mechanism: a lipophilic cation enables mitochondrial targeting, while plastoquinone exerts antioxidant activity. SKQ1 primarily exerts its potent antioxidative effects by directly neutralising reactive oxygen species (ROS), thereby protecting mitochondrial function. Numerous studies have explored the biological functions of SKQ1, identifying its significant potential in anti-ageing, immune regulation, and antimicrobial activity. In this review, we summarise all available therapeutic evidence of SKQ1. We propose that SKQ1 represents a promising candidate for treating mitochondrial dysfunction-related diseases; however, its safety profile warrants further investigation.

Cancer remains a major global health challenge, with existing diagnostic and therapeutic strategies often limited by poor selectivity, systemic toxicity and resistance. Nanomedicine - a convergence of nanotechnology and molecular medicine - offers promising solutions to these limitations by enabling more precise cancer diagnosis and effective treatment. Engineered nanoparticles (NPs) such as liposomes, polymeric micelles, dendrimers and metallic NPs have been widely studied for their ability to deliver therapeutic agents or genetic materials directly to tumours. NPs can exploit the enhanced permeability and retention (EPR) effect for passive targeting and can be further functionalised with ligands for active targeting of tumour-specific markers such as EGFR, HER2 or folate receptors. In diagnostics, nanoprobes and nanobiosensors enable high-resolution imaging modalities including MRI, PET and optical imaging, allowing early tumour detection and real-time monitoring. Moreover, multifunctional theranostic NPs integrate both therapeutic and diagnostic functions in a single platform. Recent innovations also include nanocarriers for RNA interference, CRISPR-Cas9 delivery and stimuli-responsive drug release. Additionally, NPs are being explored for photothermal therapy (PTT) and radio-sensitisation to further enhance treatment outcomes. This review summarises recent progress in nanomedicine applications across multiple cancer types - lung, breast, brain, liver and gastrointestinal - and correlates these developments with tumour biology and microenvironmental factors.