Journal of Drug Targeting最新文献

This study presents the development of dissolving levonorgestrel-loaded microneedles (LMNs) incorporating a chitosan-β-glycerophosphate thermogelling system for sustained transdermal delivery of levonorgestrel (LNG) as a contraceptive. Polyvinylpyrrolidone K90 and Dextran 40 were included to enhance mechanical strength and controlled drug release. LMNs fabricated using poly dimethyl siloxane moulds exhibited uniform, sharp structures as confirmed by scanning electron microscopy. Fourier transform infra-red and X-ray diffraction analyses demonstrated chemical compatibility and physical stability of LNG within the matrix. The optimised LMNs showed significant mechanical strength (p < 0.05) and high insertion efficiency (F = 17.83, p = 3.03 × 10^-8) across Parafilm^® layers and fully dissolved within 30 min in porcine skin. Ex vivo studies revealed sustained LNG release (70.86% ± 0.42%) over 48 h, outperforming a topical gel (42.33% ± 0.91%). Drug release followed first-order kinetics (R² = 0.996) and non-Fickian diffusion (n = 0.79), indicating a combined diffusion-erosion mechanism. In vivo evaluation in Wistar rats showed significant contraceptive efficacy, with reduced implantation sites (0.5 ± 0.55) and uterine thickness (3.66 ± 0.51 mm; p < 0.0001), comparable to oral LNG. These results highlight LMNs as a promising, minimally invasive platform for long-acting transdermal contraception, offering improved bioavailability, patient compliance and therapeutic effectiveness.

Polycystic ovarian syndrome is a highly prevalent, multifaceted endocrinopathy among reproductive women. Current therapies have limited therapeutic success and compliance owing to multiple complications. Here, we developed MPPs-Gel formulation for efficient targeted intravaginal delivery that addresses the complementary mechanism of insulin resistance and other associated disorders. The MPPs size was observed to be 194.1 ± 3.54 nm with the zeta potential of -6.45 mV, depicting the acceptable value providing enhanced penetration across the vaginal delivery. The study investigated the effects of the MPPs-Gel formulation on insulin resistance and reproductive health in a PCOS rat model. The oestrous cycle of rats revealed that the MPPs-Gel efficiently regulated, as validated by the presence of all the phases. Ultrasonographic study, the MPPs-Gel group demonstrated an approximately 50% reduction in ovarian size (4.8 ± 0.78 mm) in comparison to the PC group (9.2 ± 0.84 mm). Results demonstrated significant improvement in insulin sensitivity, with a notable recovery observed in the MPPs-Gel group. The findings revealed a marked reduction in serum androgen concentrations, alongside notable improvements in other endocrine hormones with enhanced regulation of the reproductive cycle and oocyte quality. Thus, our findings validated that MPPs-Gel could be a promising holistic treatment approach for the associated disorders in PCOS.

Objective: Sildenafil citrate (SC) could promote uterine lining development, leading to successful embryo implantation. Due to the low oral bioavailability of the first-pass elimination of SC, it is necessary to develop a gel for vaginal administration to improve the efficacy.

Methods: A vaginal gel was prepared using the cold method to increase the retention of SC in the uterus, which allows for prolonged contact between SC and the vaginal mucosa. A poloxamer-based thermosensitive in situ gel containing SC (SC-Tsgel) and an HPMC-based standard gel containing SC (SC-Cogel) were prepared. The rheological properties, in vitro drug release, and in vivo retention in the uterus of SC-Tsgel and SC-Cogel were compared.

Results: The gel formulations significantly prolonged the time it took for drugs to be released following a release study. SC-Tsgel and SC-Cogel administered vaginally increased the duration of drug administration compared to SC solutions injected through the tail vein. Nevertheless, compared with tail vein injection of SC solutions or vaginal administration of the SC-Cogel, the retention of SC in the uterus was increased significantly after vaginal administration of the SC-Tsgel.

Conclusions: Novel formulations of SC prepared with poloxamer 407 show promise as vaginal medication preparations for the management of a thin endometrium.

Vascular diseases such as atherosclerosis, aneurysms, and peripheral arterial disease remain leading causes of morbidity and mortality, with current treatments primarily managing symptoms rather than addressing underlying molecular drivers. Gene therapy offers a promising avenue for targeted intervention, and recent advances in multi-omics approaches-including genomics, transcriptomics, and epigenetics-are enhancing the precision and efficacy of these therapies. High-throughput sequencing and integrative omics analyses have facilitated the identification of causal genes, non-coding RNAs, and epigenetic regulators involved in vascular pathology. This review examines how multi-omics frameworks inform gene therapy design, from genomic editing of cardiovascular disease loci to transcriptome-guided RNA therapies and epigenetic modulation of disease states. We highlight emerging applications such as CRISPR-based interventions, RNA therapeutics, and individualised precision medicine strategies. Additionally, we address analytical challenges, implementation hurdles, and ethical considerations in translating multi-omics-driven gene therapies into clinical practice. By integrating systems biology and advanced computational methods, the convergence of multi-omics and gene therapy holds transformative potential for vascular medicine, offering new avenues for disease modification and patient-specific therapeutic solutions.

Purpose: This study investigates the development and evaluation of rosuvastatin-loaded polymeric nanoparticles as a targeted wound-healing therapy. The work aims to overcome solubility and bioavailability limitations and to enhance therapeutic outcomes in cutaneous wound repair.

Methods: Six nanoparticle formulations were prepared via the nanoprecipitation method, varying polymer type and excipient content. Particle size, polydispersity index and zeta potential were measured by dynamic light scattering, while drug-loading efficiency was determined spectrophotometrically. In vitro release study was assessed. A gel incorporated optimised formulation was evaluated in a rat excisional wound model. Wound-area reduction and healing percentages were quantified over 14 days.

Results: The PVP-K90-based formulation exhibited the smallest mean diameter, narrow size distribution and high entrapment efficiency. In vitro, this system achieved higher cumulative rosuvastatin release at 24 h. In vivo, the rosuvastatin hydrogel accelerated the wound-healing cascade, achieving complete closure by day 14, with significantly greater re-epithelialisation and neovascularisation compared to controls (p < .001).

Conclusions: The findings demonstrate that polymeric nanoprecipitation offers a versatile platform to tailor nanoparticle characteristics and release profiles, translating into marked improvements in wound repair. This approach holds promise for the clinical translation of statin-based nanoformulations in both acute and chronic wound management.

Glioblastoma is a devastating disease with a high mortality rate. Gene therapy with anti-microRNA inhibitors has been suggested as a new modality for treatment of glioblastoma. In this study, glioblastoma-targeted extracellular vesicles (EVs) were produced with specific ligands and evaluated as a carrier of anti-microRNA-21 oligonucleotides (AMO21). Angiopep-2 (ANG) and chlorotoxin (CTX) were linked to EVs by DNA recombination techniques. Cholesterol-conjugated AMO21 (AMO21c) was loaded onto the EVs decorated with ANG or CTX (ANG-EV or CTX-EV) by hydrophobic interactions. In vitro cellular uptake assays indicated that CTX-EV had higher delivery efficiency than unmodified EV (Unmod-EV) and ANG-EV. In addition, CTX-EV had higher transcytosis efficiency than the other EVs, suggesting that it effectively passes through the blood-brain barrier. In orthotopic glioblastoma animal models, CTX-EV delivered AMO21c more efficiently than Lipofectamine/AMO21c, Unmod-EV/AMO21c and ANG-EV/AMO21c. As a result, a greater decrease in tumour size with CTX-EV/AMO21c was observed, as compared with Lipofectamine/AMO21c, Unmod-EV/AMO21c and ANG-EV/AMO21c. CTX-EV/AMO21c induced the expression of the phosphatase and tensin homolog (PTEN) and programmed cell death 4 (PDCD4) genes in tumours. In addition, apoptosis levels in tumour tissues were enhanced by CTX-EV/AMO21c, as compared with the other samples. In conclusion, CTX-EV is effective for targeted delivery of AMO21 to glioblastoma and may have potential in glioblastoma gene therapy.

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.