Drug Delivery最新文献

Inflammatory bowel disease (IBD) comprises chronic autoimmune disorders with significant morbidity, highlighting the need for advanced, noninvasive, targeted therapies. Protein-based nanoparticle drug delivery systems (PNP-DDSs) have emerged as promising platforms to overcome limitations of conventional IBD therapies by improving drug stability and bioavailability while enabling colon-specific delivery. This review systematically classifies PNP-DDSs derived from natural proteins (albumin, gelatin, silk fibroin, and plant-derived proteins) and discusses their design principles along with strategies for intestinal targeting, including particle size and surface charge modulation, stimuli-responsive release (triggered by pH, reactive oxygen species, or enzymes), and active targeting. It highlights recent preclinical advances with oral PNP-DDSs delivering curcumin, resveratrol, 5-aminosalicylic acid, quercetin, and other anti-inflammatory agents, which demonstrate the therapeutic potential of these nanoplatforms in IBD models. Despite promising preclinical outcomes, clinical translation of PNP-DDSs remains challenging due to patient heterogeneity, manufacturing scale-up difficulties, and safety concerns. Future progress will require interdisciplinary innovation and optimization of multi‑stimuli-responsive designs for precise and safe clinical application of PNP-DDSs in IBD management.

Topical therapy with imiquimod in a cream [5% w/w imiquimod cream (Aldara™)] for the treatment of nodular basal cell carcinoma (BCC) currently results in low cure rates, attributed to low imiquimod permeation. Herein we have developed novel microneedle array patches (MAPs), to maximize imiquimod intradermal delivery and retention in the skin, with potential as an efficacious treatment for BCC. Enhanced delivery of imiquimod in pig skin and ex vivo BCC tissue was found with the obelisk poly N-acryloylmorpholine (pNAM) MAPs as compared to the 5% w/w imiquimod cream and MAPS manufactured from a commercially available polymer (PVPVA). Additionally, the increased retention in ex vivo BCC tissue was found with the obelisk pNAM MAPs as compared to the 5% w/w imiquimod cream. In addition, detailed characterization of single needles and mechanistic studies of MAPs in tissue using mass spectrometry imaging confirmed the imiquimod homogeneity in the needles. Most importantly, the in vivo tumor efficacy study showed that pNAM obelisk MAPs could deliver imiquimod into the tumor, retarding tumor growth. This study suggests that the drug loaded obelisk pNAM MAPs manufactured here may be of clinical utility for localized intradermal delivery of imiquimod.

Effective topical drug delivery is crucial for glaucoma treatment, necessitating more convenient methods to enhance patient compliance. This study evaluates the efficacy and safety of using freeze-dried hyaluronic acid (HA) as a carrier for a novel conjunctival-contact drug delivery system. We developed HA tablets loaded with latanoprost (HA-latanoprost) and verified the concentration using high-performance liquid chromatography. Twenty mice (C57BL6) were divided into four groups (n = 5 per group): normal saline (group 1), control HA tablet (group 2), Xalatan™ (group 3), and HA-latanoprost tablet (group 4). Treatments were administered to the right eyes, with the left eyes serving as no-treatment controls. Intraocular pressure (IOP) and irritation (measured by scratching motions) were monitored for 10 days. On day 10, we quantified gene expression of inflammatory cytokines and IOP-affecting proteins using polymerase chain reaction, and performed histological and immunohistochemical analyses. Results showed that IOP was significantly lower in groups 3 and 4 compared to the other groups, with group 4 exhibiting the greatest reduction by day 10. Group 4 also experienced less irritation. Additionally, group 4 had lower expression of inflammatory cytokine genes and higher expression of IOP-lowering protein genes compared to group 3. No significant side effects were observed in any group. Overall, HA-latanoprost effectively lowered IOP and reduced ocular irritation more than latanoprost eyedrops in mice. However, these results are based on animal testing, so further development is needed for clinical use.

The clinical treatment of rheumatoid arthritis (RA) with first-line therapeutic drugs is hindered by the poor solubility, low bioavailability, off-target toxicity, and insufficient accumulation in inflamed joints. Liposomes have been shown to mitigate some of these limitations in drug delivery systems. However, the use of cholesterol to stabilize liposomal structures remains controversial due to its potential association with cardiovascular diseases. Here, we developed a novel liposome based on ginsenoside compound K (CK), which not only serves as an effective therapeutic agent for RA but also replaces cholesterol as a membrane stabilizer to address these challenges. Compared with conventional liposomes, ginsenoside CK Liposomes (CK@Lipo) are excellent nanoparticles, with CK stabilizing the liposomal structure and providing targeting functionality toward inflamed joints. When encapsulated with dexamethasone (Dex), CK@Lipo exhibits a synergistic anti-inflammatory effect, slowing the progression of RA. This study provides a theoretical basis for the future development of multifunctional novel ginsenoside CK@Lipo.

Vyxeos, a liposomal combination of cytarabine and daunorubicin, has improved survival outcomes for patients with high-risk acute myeloid leukemia (AML). However, its safety profile in real-world settings requires comprehensive evaluation. This study aims to assess the adverse event profiles associated with Vyxeos using data from the U.S. FDA's Adverse Event Reporting System (FAERS). A retrospective analysis of adverse event reports from the FAERS database was conducted for Vyxeos from January 2017 to June 2024. Reports were analyzed to assess patient demographics, system organ classes (SOCs), and preferred terms (PTs). Signal detection analysis was performed using disproportionality metrics, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). A total of 1,036 reports were analyzed. The most frequently reported adverse events were hematologic (37.73%), infectious (28.42%), and cardiac disorders (13.22%). Febrile neutropenia, neutropenic sepsis, and pneumonia fungal were the most commonly reported events, with febrile neutropenia showing a strong association (ROR = 92.18). Males had a higher frequency of infectious events, while females reported more cardiac events. Most adverse events occurred within 30 days of treatment initiation, and 16.92% of reports involved hospitalization, while 18.33% reported death. Vyxeos is associated with significant hematologic, infectious, and cardiac adverse events. Close monitoring, infection prophylaxis, and cardiac assessments are recommended for patients receiving Vyxeos. Further research is needed to validate these findings and explore the mechanisms underlying the observed toxicities.

The mitochondrial potassium channel Kv1.3 is a critical therapeutic target, as its blockade induces cancer cell apoptosis, highlighting its therapeutic potential. PAP-1, a potent and selective membrane-permeant Kv1.3 inhibitor, faces solubility challenges affecting its bioavailability and antitumor efficacy. To circumvent these challenges, we developed a tumor-targeting drug delivery system by encapsulating PAP-1 within pH-responsive mPEG-PAE polymeric micelles. These self-assembled micelles exhibited high entrapment efficiency (91.35%) and drug loading level (8.30%). As pH decreased, the micelles exhibited a significant increase in particle size and zeta potential, accompanied by a surge in PAP-1 release. Molecular simulations revealed that PAE's tertiary amine protonation affected the self-assembly process, modifying hydrophobicity and resulting in larger, loosely packed particles. Furthermore, compared to free PAP-1 or PAP-1 combined with MDR inhibitors, PAP-1-loaded micelles significantly enhanced cytotoxicity and apoptosis induction in Jurkat and B16F10 cells, through mechanisms involving decreased mitochondrial membrane potential and elevated caspase-3 activity. In vivo, while free PAP-1 failed to reduce tumor size in a B16F10 melanoma mouse model, PAP-1-loaded micelles substantially suppressed tumors, reducing volume by up to 94.26%. Fluorescent-marked micelles effectively accumulated in mouse tumors, confirming their targeting efficiency. This strategy holds promise for significantly improving PAP-1's antitumor efficacy in tumor therapy.

Regulating inflammatory microglia presents a promising strategy for treating neurodegenerative and autoimmune disorders, yet effective therapeutic agents delivery to these cells remains a challenge. This study investigates modified lipid nanoparticles (LNP) for mRNA delivery to hyperactivated microglia, particularly those with pro-inflammatory characteristics, utilizing supervised machine learning (ML) classifiers. We developed and screened a library of 216 LNP formulations with varying lipid compositions, N/P ratios, and hyaluronic acid (HA) modifications. The transfection efficiency of eGFP mRNA was assessed in the BV-2 murine microglia cell line under different immunological states, including resting and activated conditions (LPS-activated and IL4/IL13-activated). ML-guided morphometric analysis tracked the phenotypes of various microglia subtypes before and after transfection. Four supervised ML classifiers were investigated to predict transfection efficiency and phenotypic changes based on LNP design parameters. The Multi-Layer Perceptron (MLP) neural network emerged as the best-performing model, achieving weighted F1-scores ≥0.8. While it accurately predicted responses from LPS-activated and resting cells, it struggled with IL4/IL13-activated cells. The MLP model was validated by predicting the performance of four unseen LNP formulations delivering eGFP mRNA to LPS-activated BV2 cells. HA-LNP2 emerged as optimal formulation for delivering target IL10 mRNA, effectively suppressing inflammatory phenotypes, evidenced by shifts in cell morphology, increased IL10 expression, and reduced TNF-α levels. We also evaluated HA-LNP2 on LPS-activated human iPSC-derived microglia, confirming its efficacy in modulating inflammatory responses. This study highlights the potential of tailored LNP design and ML techniques to enhance mRNA therapy for neuroinflammatory disorders by leveraging carrier's immunogenic properties to modulate microglial responses.

Silicosis represents a formidable occupational lung pathology precipitated by the pulmonary assimilation of respirable crystalline silica particulates. This condition engenders a cascade of cellular oxidative stress via the activation of bioavailable silica, culminating in the generation of reactive oxygen species (ROS). Such oxidative mechanisms lead to irrevocable pulmonary impairment. Contemporary scholarly examinations have underscored the substantial antioxidative efficacy of platinum nanoparticles (PtNPs), postulating their utility as an adjunct therapeutic modality in silicosis management. The physicochemical interaction between PtNPs and silica demonstrates a propensity for adsorption, thereby facilitating the amelioration and subsequent pulmonary clearance of silica aggregates. In addition to their detoxifying attributes, PtNPs exhibit pronounced anti-inflammatory and antioxidative activities, which can neutralize ROS and inhibit macrophage-mediated inflammatory processes. Such attributes are instrumental in attenuating inflammatory responses and forestalling subsequent lung tissue damage. This discourse delineates the interplay between ROS and PtNPs, the pathogenesis of silicosis and its progression to pulmonary fibrosis, and critically evaluates the potential adjunct role of PtNPs in the therapeutic landscape of silicosis, alongside a contemplation of the inherent limitations associated with PtNPs application in this context.

Extracellular vesicles (EVs) are emerging as versatile nanocarriers for targeted drug delivery and immune modulation. However, strategies that can induce antigen-specific immune tolerance remain limited, highlighting an unmet need for more precise and effective approaches. To address this challenge, we aimed to develop a modular EV-based system capable of inducing antigen-specific regulatory T cells (Tregs). In this study, we developed engineered antigen-presenting EVs (AP-EVs) that co-display peptide-major histocompatibility complex class II complexes (pMHCII), interleukin-2 (IL-2), and transforming growth factor-β (TGF-β) on their surface. These immunomodulatory molecules were anchored to the EV membrane via CD81 or milk fat globule-EGF factor 8 (MFG-E8) scaffolds to ensure stable and multivalent presentation. AP-EVs induced the differentiation of antigen-specific Tregs from naïve CD4⁺ T cells in vitro, and promoted their proliferation and expression of canonical regulatory markers, including CD25, CTLA-4, PD-L1, and LAG-3. In vivo, the combination of AP-EVs and mTOR inhibition with rapamycin significantly enhanced the generation of Foxp3⁺ Tregs in antigen-specific adoptive transfer models. The Tregs induced by AP-EVs in vitro exhibited suppressive function, highlighting the therapeutic potential of this system. Our findings establish a modular, cell-free EV platform for antigen-specific immune tolerance, with potential applications in the treatment of autoimmune and allergic diseases through targeted immune regulation.

Multivalency can drive high-avidity binding of ligand-functionalized nanoparticles to cells with high target receptor expression, but it can also contribute to off-target binding to low-expression non-target cells. We explored how ligand affinity and liposome valency shape the resulting binding performance index (BPI), defined as the product of the proportion of liposome-bound target cells and that of non-bound non-target cells. Designed ankyrin repeat proteins (DARPins) spanning a wide range of HER2-binding affinities were tethered onto PEGylated liposomes at varying concentrations. BPI was initially evaluated in mixed-cell suspensions of HER2^high SKBR3 (target) cells and HER2^low T47D (non-target) cells, with the highest BPI (> 0.8) observed for high-valency liposomes displaying high-affinity DARPins. To further map the BPI landscape, we measured particle binding to HEK293T cells transiently transfected with HER2-EGFP, leveraging the inherent transfection heterogeneity to generate continuous binding response curves as a function of HER2 expression. HER2^high (target) and HER2^low (non-target) populations were defined by a HER2 threshold, which was varied across the range of HER2 expression to determine maximum BPI values (> 0.85) and corresponding HER2 threshold optima (HER2_OPT). BPI generally tracks with traditional binding selectivity, but BPI is more sensitive to off-target effects or poor on-target binding and thus may better assess particle performance. We further demonstrate that HER2_OPT can be rationally increased or decreased by adjusting DARPin valency and affinity (separately or synergistically) to lower or higher values, respectively. The approach outlined here enables rapid testing and optimization of ligand parameters for nanoparticle binding toward a given therapeutic target.