Drug Delivery and Translational Research最新文献

Fetal growth restriction (FGR) affects 5% to 10% of all pregnancies in developed countries and is the second most leading cause of perinatal mortality and morbidity. Life-long consequences of FGR range from learning and behavioral issues to cerebral palsy. To support the newborn brain following FGR, timely and accessible neuroprotection strategies are needed. Curcumin-loaded polymeric nanoparticles, which have been widely explored for the treatment of cancer, neurological disorders, and bacterial infections, have the potential to prevent and mitigate pathogenic inflammatory processes in the FGR brain. Curcumin is a hydrophobic molecule with poor aqueous solubility and therefore has been incorporated into nanoparticles to improve solubility and delivery. However, curcumin loading in many nanoparticles can be limited to 10% by weight or lower. Here, we first optimize the formulation process of curcumin-loaded polymeric nanoparticles to find a tunable, reproducible, and stable formulation with high curcumin loading and encapsulation efficiency. We establish a curcumin formulation with 39% curcumin loading and > 95% curcumin encapsulation efficiency. Using this formulation, we assessed the biodistribution of polymeric nanoparticles in FGR piglets and normally grown (NG) piglets following different administration routes and evaluated brain cellular uptake. We show a significant amount of nanoparticle accumulation in the brain parenchyma of neonatal piglets as early as 4 h after intranasal administration. Nanoparticles colocalized in microglia, a therapeutic target of interest in FGR brain injury. This study demonstrates the potential of curcumin-loaded nanoparticles to treat neuroinflammation associated with FGR in the newborn.

Neurodegenerative conditions, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's disease, represent a critical medical challenge due to their increasing prevalence, severe consequences, and absence of curative treatments. Beyond the need for a deeper understanding of the fundamental mechanisms underlying neurodegeneration, the development of effective treatments is hindered by the blood-brain barrier, which poses a major obstacle to delivering therapeutic agents to the central nervous system. This review provides a comprehensive analysis of the current landscape of nanoparticle-based strategies to overcome the blood-brain barrier and enhance drug delivery for the treatment of neurodegenerative diseases. The nanocarriers reviewed in this work encompass a diverse array of nanoparticles, including polymeric nanoparticles (e.g. micelles and dendrimers), inorganic nanoparticles (e.g. superparamagentic iron oxide nanoparticles, mesoporous silica nanoparticles, gold nanoparticles, selenium and cerium oxide nanoparticles), lipid nanoparticles (e.g. liposomes, solid lipid nanoparticles, nanoemulsions), as well as quantum dots, protein nanoparticles, and hybrid nanocarriers. By examining recent advancements and highlighting future research directions, we aim to shed light on the promising role of nanomedicine in addressing the unmet therapeutic needs of these diseases.

Although nucleotide-based therapeutics hold promise for a variety of diseases, their clinical application is limited because of low stability and poor bioavailability. Among non-viral gene delivery vectors, poly(β-aminoester)s (pBAEs) stand out because of their low cytotoxicity, high transfection capacity, and adequate biodegradation profile. Oligopeptide end-Modified pBAEs (OM-pBAEs) enable enhanced polynucleotide encapsulation, cellular internalization, and transfection. Despite the outstanding properties of OM-pBAEs as non-viral gene delivery vectors, traditional OM-pBAE formulations have low cell selectivity and require formulation with two or more polymers. In this study, we first develop a simplified OM-pBAE formulation with a single polymer (pBAE-CRHR) and then add a zwitterionic moiety as part of the end-capping process (pBAE-CRHR-Zw) to decrease unspecific transfection. Subsequently, we recover transfection capacity for target cancer cells in two ways: (i) by addition of a photo-cleavable moiety between the pBAE and the zwitterion, and (ii) by functionalization of pBAEs with BrainBike-4, a bicyclic peptidomimetic targeting the transferrin receptor 1. Finally, we show that derivatization of pBAE-CRHR-Zw with BrainBike-4 enhances transmigration of the gene delivery system across a tight monolayer of human endothelial cells mimicking the BBB.

Osteoarthritis (OA) is a heterogeneous and multifactorial disorder that affects the entire joint organ. It is a major global public health concern, impacting more than 500 million individuals worldwide. The onset and progression of OA are driven by a complex interplay of factors and modifiable risks such as obesity and joint injury. Consequently, OA imposes a substantial burden on patients' quality of life and on society, owing to increased healthcare expenditures and reduced work productivity. The purpose of this study is to assess the therapeutic efficacy of transdermal patches loaded with etoricoxib nanocrystals (ETX-NCs, previously prepared and evaluated) in the treatment and reduction of osteoarthritis exacerbation. ETX-NCs patches of various polymers were prepared using solvent evaporation technique. The prepared patches were evaluated for drug content, thickness, moisture uptake, folding endurance, in vitro drug release, and skin permeation properties. The prepared patches based on HPMC, CMC Na, and PVA demonstrated uniformity, flexibility, smooth surface morphology and high drug content, along with acceptable physicochemical properties. Among these, the CMC Na based nanocrystal patches exhibited the most prolonged drug release (73.76 ± 2.38%). HPMC and CMC Na based patches showed promising skin penetration of 79.64 ± 1.20 μg/cm² and 44.06 ± 2.72 μg/cm², with corresponding flux values of 16.13 ± 0.21 μg/cm²/h and 8.08 ± 0.47 μg/cm²/h, respectively. Based on in vivo findings, the prepared ETX-NCs patches found to successfully alleviate OA symptoms within short duration (5 days), also protecting against disease progression.

Neurological disorders (ND) pose a major global health challenge, in large part due to the restrictive nature of the blood-brain barrier (BBB), which prevents most therapeutic agents from reaching the central nervous system (CNS). Intranasal delivery (IN) offers a non-invasive and patient-friendly route to bypass the BBB via the olfactory and trigeminal pathways, but its success requires advanced nanocarrier systems capable of enhancing drug retention, stability, and controlled release. In this study, a Quality by Design (QbD) framework was applied to systematically develop and optimize 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG₂₀₀₀)-functionalized nanostructured lipid carriers (NLCs) using Donepezil (DPZ) as a model drug. Through sequential risk assessment, Plackett-Burman screening design (PBD), and Central Composite Design (CCD) optimization, the Critical Formulation Variables (CFVs) and Critical Process Parameters (CPPs) influencing particle size (PS) and entrapment efficiency (%EE) were identified. The optimized DSPE-PEG₂₀₀₀-NLCs exhibited nanoscale size (133.4 ± 2.91 nm), high %EE (89.5 ± 1.51%), strong mucin binding (84.6 ± 2.68%), and a distinct core-shell morphology. In vitro and ex vivo studies confirmed a biphasic and sustained drug release up to 60 h & 67 h, outperforming uncoated NLCs and conventional formulations. Stability studies demonstrated improved preservation under refrigerated conditions. Beyond DPZ, the QbD-guided strategy presented here provides a generalizable and regulatory-aligned platform for designing IN nanocarriers, paving the way for reproducible, scalable, and translational drug delivery systems targeting a wide range of ND.

Machine learning (ML) is expected to accelerate the developments of three-dimensional (3D) printed medicines. Despite ML's potential, the need for large datasets can hinder progression, as 3D printing remains an emerging pharmaceutical manufacturing technology. This study explores an ML strategy called active learning (AL), which harnesses the benefits of ML whilst applicable with small datasets. AL was tested to predict the printability of three 3D printing datasets: 1437 fused deposition modelling (FDM), 650 vat polymerisation and 297 selective laser sintering (SLS) formulations. The analysis revealed that accuracies of 60% can be achieved when starting with 33 formulations, and subsequent increases in training data size enhances predictive performance. Furthermore, AL was found to achieve 100% predictive accuracy, which is the highest recorded to date for pharmaceutical 3D printing. These initial findings highlight AL's advantages over traditional ML modelling and showcase its potential to accelerate the development of 3D printing medicines. This research also demonstrates the potential of modelling with small datasets, thereby widening ML's application in pharmaceutical research.

Tetramethylpyrazine (TMP), a potent coronary vasodilator, enhances myocardial perfusion and shows promise for treating cardiovascular disorders. Its clinical utility is limited, however, by the short half-life of conventional tablets and injections, which necessitates frequent dosing. To overcome this drawback, we developed a transdermal patch that co-loadsTMP and borneol (BO-TMP). After optimization, patches containing 3% borneol as a permeation enhancer, exhibiting the highest cumulative penetration amount of TMP (6.80 mg·cm^-2 over 24 h) in vitro. Pharmacokinetic profiling revealed that borneol markedly improved TMP exposure. C_max rose from (1.96 ± 0.27) to (2.88 ± 0.72) mg/L, and AUC_0-t expanded from (47.73 ± 6.93) to (73.18 ± 13.86) mg/L*h in plasma; C_max rose from (12.99 ± 2.28) to (15.33 ± 4.24) mg/L, and AUC_0-t expanded from (220.86 ± 53.88) to (374.55 ± 111.84) mg/L*h in skin, C_max rose from (0.87 ± 0.12) to (6.20 ± 0.84) mg/L, and AUC_0-t expanded from (13.08 ± 3.35) to (79.80 ± 16.31) mg/L*h in heart when BO-TMP patches were administrated compared with TMP patches. Tissue distribution studies demonstrated that borneol redirected TMP distribution, shifting the order of tissue abundance from liver > kidney > brain > spleen > heart > lung to liver > kidney > heart > brain > spleen > lung, and thus enriched the drug at its therapeutic site. By selectively heightening cardiac exposure, the BO-TMP patch transform TMP into a cardiovascular-focused therapy, offering a convenient, long-acting dosage from with the potential to enhance efficacy and improve patient outcomes.

In recent years, microneedles (MNs) have drawn significant attention as a new strategy for drug delivery. Especially, dissolving microneedles (DMNs) are the most suitable system for their degradability and low biological hazard. However, MNs will inevitably cause skin irritation, which needs to be improved. The goal of this study is to develop soothing and sustained-release DMNs to reduce skin irritation during drug delivery. The MNs were successfully fabricated using biocompatible sodium hyaluronate, resilient hydroxyethyl cellulose, and γ-polyglutamic acid, which possess skin repair functions. An orthogonal experiment was designed and the performance of different DMNs was characterized to explore the optimal formation, including morphology and mechanical performance. We found that the optimal formulation was 13% HA-Na, 7% HEC and 5% γ-PGA at 30℃ for 3 h. The morphology of the DMNs had structural integrity with sharp tips and a uniform array. They could withstand a force of up to 20 N without fracture, demonstrating sufficient mechanical strength for skin penetration. Subsequently, further characterization of the optimal formulation of DMNs was performed, including skin penetration ability, compression resistance, and in vitro/in vivo dissolution behavior. The DMNs successfully penetrated porcine skin and simulated skin models under a force of 2 N. In vivo dissolution in mouse skin was completed within 1 h, supporting their soothing and sustained-release potential. The skin repair function was validated through a skin irritation experiment; the mice treated by DMNs with 5% γ-PGA had no erythema and edema during the whole process and the pinholes were observed to fully disappear in 5 min, indicating rapid skin repair function. Through these tests, our fabricated DMNs possessed soothing and sustained-release properties and skin repair function. To further realize the drug delivery application of the DMNs, some experiments should be conducted in the future, including drug loading and transdermal release performance.