Drug Delivery and Translational Research最新文献

Bisphosphonates (BPs) are widely used in treating bone-related conditions, with emerging evidence supporting their potential in treating both skeletal and extra-skeletal diseases. However, their clinical utility is limited by high cytotoxicity, particularly toward macrophages, leading to immune system disruption upon frequent use. This limitation highlights the need for an effective drug delivery system. While nanoparticle formulations improve pharmacokinetics and biodistribution, they often suffer from limited drug loading capacity, poor sustained-release ability, and increased cytotoxicity due to their rapid and excessive intracellular uptake.Here, we present a multifunctional formulation, composed of calcium-zoledronic acid nanoparticles (CaZol NP) encapsulated within polymeric microparticles (CaZol NiM), designed to address many challenges associated with therapeutic use of zoledronic acid (Zol). CaZol NiM improves cellular uptake of Zol, facilitates pH sensitive sustained release of Zol and allows ligand mediated uptake by macrophages. The controlled release of Zol from CaZol NiM effectively reduces Zol's cytotoxic effects on macrophages, enabling their immune modulation by suppressing NF-κB and reactive oxygen species (ROS) activity, while promoting macrophage repolarization from their pro-inflammatory M1 state.Altogether, these findings highlight the potential of CaZol NiM in minimizing off-target effect and expand the clinical applications of Zol in managing both skeletal and extra-skeletal inflammatory disorders.

Wound healing for various diseases and wounds such as diabetes and burns remains a major biomedical challenge. Conventional monotherapy is ineffective, and the efficacy of drug delivery is limited by the depth of drug penetration. In this study, we develop a novel, multifunctional, dissolvable hyaluronic acid (HA) microneedle patch (MN-LTT). Microneedling is biocompatible and delivers the drug in a painless and non-invasive manner. Lidocaine and thrombin are mixed with HA hydrogel and loaded onto the needle tips of the MN-LTT, which facilitates wound repair by continuously delivering the drug deep into the dermis for rapid analgesia and hemostasis. In addition, the backing layer of the MN-LTT is composed of tetracycline hydrochloride and HA hydrogel, and its excellent antimicrobial properties further accelerate wound healing. In a mouse full-thickness skin wound model, MN-LTT accelerated cell proliferation and granulation tissue growth, reduced inflammatory-factor levels, and restored collagen deposition, resulting in complete wound healing within seven days. Thus, the proposed microneedle delivery system achieved rapid hemostatic, analgesic, and bactericidal effects, providing a safer and more effective strategy for wound healing. These features make the multifunctional HA microneedle patch potentially valuable for clinical applications.

Breast cancer is the most common cancer among women, with approximately 2.3 million new cases globally. Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression, making it unresponsive to traditional therapies. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is overexpressed in TNBC, promoting cell survival by inhibiting apoptosis through phosphorylation of eEF2. Recently, eEF2K has been targeted for cancer therapy, and siRNA-based gene therapy has emerged as an effective approach to silence overexpressed genes. However, siRNA delivery is challenging due to its instability and susceptibility to degradation. In this study, we developed a novel hybrid nanoparticle (HNP) using a Layer-by-Layer (LbL) method for siRNA delivery targeting eEF2K in TNBC. The HNPs consist of a silver nanoparticle (AgNP) core, coated with poly (allylamine hydrochloride) (PAH) and poly(styrene sulfonate) (PSS), and loaded with eEF2K-siRNA and quercetin (QU), a chemotherapeutic agent, in separate layers. The nanoparticles also incorporated 4-ATP molecules for Raman traceability. In vitro experiments on TNBC cell lines (MDA-MB-231, BT-549, 4T1) showed that the combination therapy of eEF2K-siRNA and QU reduced cell viability, inhibited colony formation, and suppressed cell migration. At high 120 nM of siRNA concentration, 3D spheroid disintegration, activation of apoptotic pathways, and eventual necrotic cell death were observed. The results demonstrate that the developed HNPs are non-toxic, effective, and offer potential as a theranostic platform for TNBC treatment.

Ulcerative colitis (UC) is a chronic, immune-mediated disorder with limited treatment efficacy due to drug resistance. As key immune effectors, Macrophages drive UC pathogenesis: The M1 polarization promoted through P-selectin/PSGL-1 binding between platelets and macrophages exacerbates inflammation. Rutin-PEG-PLGA nanoparticles (P@Rut) were engineered by encapsulating rutin in PEG-PLGA cores. Biomimetic platelet membrane nanoparticles (PP@Rut) were synthesized by extracting platelet membranes and coating P@Rut. The blockade of platelet-macrophage interactions by PP@Rut was assessed in vitro and in vivo. The inhibition of macrophage polarization and JNK/STAT1 pathway was evaluated via immunofluorescence (CD86/CD206) and RT-qPCR (IL-1β, TNF-α, TGF-β). Apoptosis was quantified using flow cytometry and TUNEL staining, complemented by Western blot analysis of apoptosis-related proteins(Bcl-xl, Bak, and cleaved-caspase3). Additionally, intestinal barrier integrity was assessed through tight junction protein expression (Occludin, Claudin-1, ZO-1), while therapeutic efficacy was determined via colon length, body weight, disease activity index (DAI) scores, and H&E staining histopathological analysis. PP@Rut significantly shifted macrophage polarization from M1 to M2 through the JNK/STAT1 pathway, suppressed inflammatory response, reduced mucosal epithelial cells apoptosis, and improved intestinal barrier integrity. In DSS-induced mice, PP@Rut demonstrated higher accumulation in inflamed colon versus P@Rut, ameliorating body weight loss, DAI scores, colon shortening, and histopathological injury, including the reduction in inflammatory infiltration and crypt damage. PP@Rut represents a synergistic nanotherapeutic strategy that competitively inhibits platelet-macrophage binding to reprogram polarization, suppress inflammation, and restore barrier function in UC.

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.