Drug Delivery and Translational Research最新文献

Sustained release of drugs by devices such as dexamethasone implant placed in vitreous humor can reduce the frequency of intravitreal injections. The duration over which the device provides therapeutic drug exposure is a critical parameter and so models for predicting ocular pharmacokinetics after placing the device in vitreous humor are valuable. This study developed a model using parameters from literature to predict concentrations in aqueous humor, vitreous humor, retina and sclera-choroid after placing Ozurdex in vitreous humor and validated the model using data reported in literature for rabbits and Cynomolgus monkeys. The model is based on ordinary differential equations representing mass balances in vitreous humor, retina, aqueous humor and sclera-choroid. Additionally, a partial differential equation representing mass balance in the lens is included. The model can be simplified to yield explicit expressions for concentration in all tissues. The results are in reasonable agreement with concentrations reported in literature, particularly considering the in vivo data variability and lack of dependence on fitting parameters in the model. The simulation results suggest that the duration of therapeutic concentration in the retina is longer than the drug release duration from the implant because drug diffuses into the lens, creating a depot. The drug depot in the lens eventually releases the drug back into vitreous humor, which increases the total duration over which the concentrations are efficacious. The model can be applied to other sustained release devices placed in vitreous humor or elsewhere in the eye.

Multidrug nanosystems emerged as an innovation in anticancer therapy, addressing key limitations of conventional mono- and combination therapies, such as poor tumor selectivity, systemic toxicity, low stability and drug resistance. Following the clinical approval of Vyxeos® in 2018, growing therapeutic interest and advances in nanomedicine have paved the way for a new wave of promising next-generation multidrug nanoparticle candidates. These nanosystems offer the unique ability to co-deliver multiple therapeutic agents, aligning pharmacokinetics, improving tumor targeting, and enabling controlled drug release. By incorporating small molecules, genetic material, peptides, and proteins, multidrug nanosystems can achieve potent anticancer effects that significantly enhance therapeutic outcomes. In glioblastoma context these can play a particularly important role, as treatment is limited by tumor cells resistance, as much as low blood-brain barrier penetration. Here, the design principles underlying anticancer multidrug nanosystems are explored, including concurrent and sequential drug delivery strategies, and highlighting recently proposed advances in drug loading, active targeting, and stimuli-responsive mechanisms. A special focus is placed on how these platforms have been designed to improve or bypass blood-brain barrier penetration, and overcome other glioblastoma resistance mechanism challenges. Besides their therapeutic potential, current challenges, including the need for rational therapeutic combination selection, ensuring biosafety, and balancing potency with cost-effectiveness for clinical translation, are discussed. By summarizing recent advances and addressing the remaining hurdles, this review underscores the transformative potential of multidrug nanosystems in cancer therapy, particularly for the hard-to-treat glioblastoma, and outlines the steps needed to accelerate their path to clinical application.

Aberrant Hedgehog (HH) signaling pathway is responsible of tumorigenesis of medulloblastoma (MB) and basal cell carcinoma (BCC), two aggressive malignancies with limited therapeutic options. Targeting Gli1, the final and powerful effector of HH signaling, emerged as a valuable strategy for the treatment of HH-dependent tumors. Among Gli1 inhibitors, Glabrescione B (GlaB), is a small molecule that directly inhibits Gli1/DNA interaction, which showed promising pre-clinical results. However, poor solubility limits its clinical translation. To overcome this issue, here we develop a liposomal formulation of GlaB (Lipo/GlaB) with optimized composition to enhance drug loading, controlled release, storage stability and pharmacokinetic performance. Among various formulations, liposomes composed of EPC and cholesterol (95:5 mol/mol%) achieves high GlaB loading efficiency and stability upon lyophilization. Lipo/GlaB inhibits Gli1 transcriptional activity more potently than free GlaB and significantly reduces the expression of HH target genes. Notably, Lipo/GlaB remarkably reduces the tumor growth in HH-driven MB and BCC in in vitro and in vivo models, correlating with decreased HH signaling. Further, pharmacokinetic studies in mice revealed improved plasma disposition, higher AUC, and slower elimination for Lipo/GlaB compared to the free drug. These findings support the therapeutic value of Lipo/GlaB as a selective and potent strategy for targeting HH-dependent cancers, offering improved biopharmaceutical properties and in vivo efficacy compared to non-formulated GlaB.

Topical anesthesia offers a painless alternative to injections but is limited by the low skin permeability of local anesthetics through the stratum corneum, leading to a slow onset. In this study, we introduce a novel spicule-assisted topical delivery system using Sponge Haliclona sp. spicules (SHS) combined with Carbomer gel to enhance the transdermal absorption of lidocaine hydrochloride (LH). SHS act as dispersed microneedles, creating numerous microchannels that significantly improve skin permeability. In vitro, SHS increased total skin absorption of LH nearly tenfold (78.45 ± 6.96%) and accelerated drug penetration into deeper skin layers (97.5% in dermis and receptor compartments). In vivo, SHS-LH treatment achieved a maximum anesthetic effect within 10 min, markedly faster and stronger than conventional topical application. A pilot clinical trial confirmed that the SHS-Carbomer gel system halved the onset time of lidocaine and significantly prolonged its anesthetic effect. These findings demonstrate that the SHS-based dispersed microneedle system provides a rapid, safe, and needle-free alternative for local anesthesia, offering a substantial improvement over conventional topical formulations.

Osteoarthritis (OA) is a chronic degenerative joint disease that lacks effective therapies to halt its progression. While endogenous purinergic signaling-particularly via adenosine-shows promise for reducing inflammation, it is limited by short half-life and off-target effects. To address these limitations, we developed an optimal anti-inflammatory adenosine-guanosine-based oligonucleotide encapsulated in poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NanoOligo) to enhance in vivo stability and investigated its impact on surgically induced OA models and the underlying mechanisms responsible for its anabolic effects. A large oligonucleotide library (482 unique 10- to 20-mer sequences) was screened in RAW264.7 macrophages under LPS-induced inflammation to identify the most potent candidate, which was then encapsulated into PLGA nanoparticles using a microfluidic system. NanoOligo significantly protected against cartilage degeneration and alleviated pain behaviors in the rat ACLT + pMx model following intra-articular administration. In IL-1β-treated chondrocytes, it markedly suppressed inflammatory cytokines (TNFα, IL-6) and catabolic proteases (MMP-3, MMP-13, ADAMTS5). Mechanistically, NanoOligo's anti-catabolic effects were dependent on A1R and A2AR, leading to activation of the PKA-CREB axis and suppression of p38 MAPK signaling, which in turn reduced oxidative stress and cellular senescence via upregulation of the Sirt1-Nrf2-HO-1 antioxidant pathway. Collectively, these findings support joint-localized purinergic modulation as a potential therapeutic target for OA treatment, aligning structural protection with improvements in pain-related behaviors.

Bydureon^® is a once-weekly injection of poly(lactide-co-glycolide) (PLGA) microspheres containing exenatide acetate, a synthetic analog of the GLP-1 receptor agonist exendin-4. These microspheres are formulated by coacervation (i.e., phase separation), using a single-emulsion method. There remains a knowledge gap between how formulation variables affect product attributes and performance. We aimed to bridge this gap by evaluating the effect of formulation variables on encapsulating exenatide in PLGA microspheres at similar compositions to Bydureon^®. We first screened process variables without peptide to establish stability windows during coacervation, i.e., conditions that produced high yields of well-formed microspheres. We introduced exenatide during coacervation as a function of PLGA concentration, DCM (dichloromethane): water and DCM: Si oil (polydimethylsiloxane) volume ratios, hold time between Si oil addition and heptane bath immersion, and other manufacturing conditions. We evaluated the formulation yield, residual solvent content, encapsulation efficiency, and 24-h release. A PLGA concentration of 6% w/w was selected because of its wide range of stable formulations with varying DCM: Si oil phase volume ratios. The hold time between Si oil addition and heptane immersion was set at 1 min, although microspheres were stable between a range of 10 s to 2 min. The resultant formulations displayed elevated yields of > 50%, and a low in-vitro 24-h burst release of 2-6%. These formulations exhibited continuous release profiles of predominantly parent and glycolic acid acylated peptide for over 56 days in vitro, as expected by the commercial product. The framework of conditions and their effects on the formulations was established for loading exenatide in PLGA microspheres with desirable release characteristics. These results are useful for both microencapsulation of generic and new peptides in PLGA microspheres by coacervation.

Fungal keratitis (FK), caused by fungi like Aspergillus, Fusarium, and Candida, accounts for 20-60% of microbial keratitis cases and over 1 million visual impairments annually. Voriconazole (VOR) is effective against FK, but its eye drop formulations suffer from poor bioavailability, while intrastromal injections are invasive and carry risks. This study aimed to address these challenges by formulating a VOR nanosuspension (NS) and fabricating an ocular bilayer dissolving microneedle array patch (dMAP) incorporating the VOR NS for localized drug delivery to the cornea. The VOR NS was prepared using an aqueous media milling method with polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) as stabilizer and cryoprotectant, resulting in stable nanosized particles with a mean size of 270.11 ± 5.82 nm and a PDI of 0.217 ± 0.019. The formulation demonstrated a 1.71-fold increase in saturation solubility and a high drug content (72.5%). Both VOR NS and free VOR were incorporated into the MAP tips using a two-layer casting method. The VOR NS-loaded bilayer dMAP exhibited higher drug content (118.84 ± 20.67 µg) compared to the free VOR-loaded bilayer dMAP (83.08 ± 2.69 µg). Additionally, they demonstrated superior mechanical strength, greater insertion depth (~ 390 μm), and faster tip dissolution in excised porcine corneal tissue (~ 5 min) compared to the free VOR-loaded bilayer dMAP. Ex vivo studies showed that the VOR NS-loaded bilayer dMAP deposited 47.38 ± 8.08 µg of drug into the porcine cornea, 2.31 times more than the free VOR-loaded bilayer dMAP (20.43 ± 6.11 µg), closely approximating the clinical dose used in VOR intrastromal injections (50 µg/0.1 mL). Furthermore, the disc diffusion assay revealed that VOR NS and VOR NS-loaded bilayer dMAP had greater antifungal activity against Candida albicans and Aspergillus fumigatus compared to free VOR and free VOR-loaded bilayer dMAP. Biocompatibility was confirmed through a human corneal epithelial cell viability assay, and ocular irritation potential was evaluated using the HET-CAM assay, revealing a safe and non-irritant profile. Thus, this innovative NS-MAP hybrid system offers efficient drug delivery with minimal invasiveness and could potentially improve therapeutic outcomes in the management of FK.

Buccal and sublingual mucosae offer highly vascularized, patient-acceptable routes for systemic peptide delivery, providing a promising alternative to peptide injections and conventional oral peptide dosage forms that suffer from enzymatic degradation, limited permeability, and hepatic first-pass metabolism. Despite these advantages, achieving consistent peptide bioavailability from oromucosal dosage forms remain challenging due to salivary washout, enzymatic instability, and the compact, lipid-rich epithelial structure. This review provides a comprehensive overview of formulation strategies developed to overcome these barriers, with an emphasis on the use of permeation enhancers (PEs), mucoadhesive polymers, and multilayer film architectures. Advances in nanoparticle-integrated films are highlighted for their potential to improve peptide stability and mucosal permeation. The review concludes by addressing patient compliance, translational potential, and regulatory perspectives that shape the clinical advancement of peptide-loaded oromucosal films.

Breast cancer remains one of the most prevalent causes of cancer-related mortality worldwide. Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that has a poor prognosis and limited therapeutic options. Smart nanocarriers have been developed through significant advancements in nanotechnology over the past few years. To increase therapeutic effectiveness while reducing systemic toxicity, recent developments in nanotechnology have led to the creation of smart nanocarriers-nanosystems designed to carry drugs in a targeted, stimulus-responsive manner. Liposomes, dendrimers, micelles, carbon nanotubes, and polymeric nanoparticles are among the most common types of smart nanocarriers discussed in this study. Their design principles and functional features characterize the many forms of smart nanocarriers. Targeting techniques specific to breast cancer are highlighted, with a particular focus on active targeting via ligands and tumor microenvironment-responsive systems applicable to TNBC. By examining the integration of biodegradable materials, green synthesis methods, and alignment with the global Sustainable Development Goals (SDGs), the study also underscores the crucial role of sustainability in nanomedicine. Significant advancements have been made, but several biological, regulatory, and therapeutic issues still hinder the practical application of nanomedicine in treating TNBC. This review highlights key translational roadblocks and proposes strategic solutions to bridge the gap between the bench and the bedside.