Search Results (4,656)

Small-molecule kinase inhibitors offer a compelling therapeutic strategy for glioblastoma, yet their clinical efficacy remains severely limited by blood–brain barrier penetration and active efflux transporter extrusion. This review evaluates current medicinal chemistry approaches and translational paradigms to overcome these drug delivery and biological constraints. A critical analysis of the literature reveals that direct structural optimization faces a multidimensional balancing act; next-generation design must prioritize macrocyclization, structural rigidification, and bioisosteric capping to lower polar surface area and evade P-glycoprotein and BCRP efflux. Furthermore, carrier-mediated prodrugs targeting the LAT1 transporter provide a viable rescue strategy for highly potent scaffolds. Reviewing recent clinical failures, such as paxalisib and osimertinib, underscores that single-node monotherapies fail due to compensatory pathway hyperactivation and clonal heterogeneity, whereas multi-targeted agents or rational dual-node combinations prevent rapid tumor adaptation. Additionally, combining kinase inhibitors with DNA damage repair inhibitors, immune checkpoint modulation, or MR-guided focused ultrasound could provide powerful synergistic networks. Finally, bridging the translational gap requires complementing conventional serum-cultured cell lines with patient-derived glioma stem cells and orthotopic xenografts to better recapitulate the cellular architecture of the disease. Ultimately, overcoming the therapeutic challenges in glioblastoma demands a fundamental pivot toward rigorous neuro-pharmacological design and multi-lineage network oncology. Full article

Background/Objectives: Corneal neovascularization (CNV) is a leading cause of vision loss, but current treatments are limited by poor ocular drug penetration and rapid tear clearance. Luteolin (LUT) is a poorly water-soluble natural anti-angiogenic agent. To address this limitation, we develop an ion- and pH-responsive in situ gel system (LUT-NLC-ISG) by incorporating LUT-loaded nanostructured lipid carriers (LUT-NLC) into a gellan gum/Carbopol matrix, aiming to enhance ocular bioavailability and therapeutic efficacy against CNV. Methods: LUT-NLC-ISG was optimized using a central composite design-response surface methodology (CCD-RSM) and characterized by physicochemical properties (particle size, viscosity, gelation behavior). Ocular pharmacokinetics and biodistribution were evaluated in rabbits after a single topical administration. Biocompatibility was assessed via Hen’s egg test–chorioallantoic membrane assay (HET-CAM), Draize tests, and cytotoxicity studies. Therapeutic efficacy and mechanism were investigated in a murine model of alkali burn-induced CNV. Results: The optimized LUT-NLC-ISG had a particle size of 25.27 ± 0.23 nm and exhibited a 45-fold viscosity increase upon simulated tear fluid (STF) exposure. In rabbits, LUT-NLC-ISG significantly increased the bioavailability of LUT in ocular tissues compared with LUT-NLC alone, with 2.57-, 1.83-, and 10.59-fold higher area under the concentration–time curve (AUC) in the cornea, conjunctiva, and tears, respectively and exhibited excellent ocular biocompatibility. In the CNV mouse model, 0.1% (w/v) LUT-NLC-ISG effectively inhibited corneal neovascularization, comparable to 0.025% dexamethasone, and downregulated VEGF-A and MMP-9 expression. Conclusions: LUT-NLC-ISG synergistically combines NLC technology and dual-sensitive in situ gelation to significantly improve LUT ocular bioavailability, offering a promising non-invasive candidate for CNV management. Full article

Emodin (EO) is a naturally occurring anthraquinone with promising anticancer activity; however, its clinical application is limited by poor aqueous solubility and low bioavailability. Herein, we demonstrate that surface engineering of fluorescent SBA-15 nanocarriers governs the intracellular fate of EO by modulating drug confinement, release behavior, intracellular trafficking, and apoptotic responses. SBA-15 was functionalized with aminopropyl groups and a fluorescent moiety to generate traceable nanocarriers with distinct drug–carrier interactions. Physicochemical characterization (SAXS, BET, SEM/TEM, TGA, UV–Vis, and fluorescence spectroscopy) confirmed the preservation of the ordered mesoporous structure and efficient EO encapsulation (~35%). In PC3 prostate cancer cells, the functionalized system (SBA-15–M|EO) exhibited enhanced cytotoxicity (IC₅₀ = 18.2 µM) compared to free EO and the non-functionalized carrier. Time-lapse fluorescence microscopy demonstrated efficient cellular uptake, perinuclear accumulation, and sustained intracellular release, whereas flow cytometry revealed distinct apoptotic responses. SBA-15|EO promoted rapid intracellular EO accumulation and extensive late apoptosis, while SBA-15–M|EO induced gradual intracellular accumulation accompanied by delayed but sustained apoptosis. Molecular docking further revealed favorable interactions of EO with the anti-apoptotic proteins BCL-2 and BCL-xL (ΔG_bind ≈ −6.5 kcal mol⁻¹). These findings establish a direct relationship between nanocarrier surface chemistry, intracellular trafficking, and apoptotic fate, highlighting surface engineering as a strategy for controlling cellular responses beyond conventional drug delivery. Full article

Chronic wounds remain a significant clinical challenge due to persistent inflammation and impaired tissue repair. Anti-inflammatory agents play a pivotal role in wound management by reducing excessive inflammation, preventing further tissue damage, and creating a microenvironment conducive to healing. Among them, Ketoprofen, a non-steroidal anti-inflammatory drug, is effective in modulating inflammation. However, its systemic administration is associated with adverse effects, highlighting the need for localized and controlled delivery systems. Gelatin-based carriers provide important advantages, including biocompatibility, biodegradability, low immunogenicity, cost-effectiveness, and the ease of chemical modification to tailor drug release profiles. In this pioneering study, gelatin-based microspheres crosslinked with tannic acid were developed to achieve sustained topical release of Ketoprofen. The microparticle system was produced through the single water-in-oil emulsification process and optimized by varying homogenization speed, crosslinking time, and molar ratio. Morphological, physicochemical, functional, and biological characterizations were conducted. The optimized formulation yielded spherical microspheres (5–35 µm) with high crosslinking efficiency and a controlled drug release profile over time. COX inhibition assays provided preliminary evidence that released Ketoprofen-retained inhibitory activity under the assay conditions, while cytocompatibility tests supported the short-term compatibility of the system within the tested concentration range. A qualitative wound-model test provided preliminary evidence of powder hydration, film formation, and macroscopic retention. Overall, tannic acid-crosslinked gelatin microspheres represent a biocompatible and promising platform for localized drug delivery of non-steroidal anti-inflammatory in wound management. Full article

While anti-tumor drugs markedly improve patient survival, dose-limiting toxicities remain major constraints on clinical efficacy and quality of life. Conventional management strategies lack timeliness and precision. Traditional Chinese medicine (TCM) and its active ingredients offer unique potential for mitigating anti-tumor drug toxicities through multi-component and multi-target regulation. However, the transformation of TCM is hampered by poor bioavailability and targeting. This review summarizes and evaluates an integrated strategy combining TCM with nanotechnology to develop novel nanomedicines. It elucidates the distinct toxicity mechanisms of chemotherapy drugs, targeted drugs, and immunotherapy drugs, revealing toxicopathological transitions from non-specific killing to microenvironment disruption and immune imbalance. Subsequently, it discusses the intervention mechanisms and research progress of TCM and its active ingredients targeting different categories of anti-tumor drug toxicity. To overcome delivery challenges, this review explores construction strategies for diverse nanodelivery systems, including carrier-free self-assembled nanomedicines, physically loaded nanomedicines, and chemically coupled nanomedicines, highlighting their value in organ-specific accumulation and controlled release. Finally, it objectively analyzes challenges in the clinical translation of these nanomedicines, encompassing safety and industrialization, while prospecting future trends, aiming to contribute to a new therapeutic paradigm focused on “toxicity attenuation and efficacy potentiation” and steer cancer treatment toward greater precision and intelligence. Full article

Periodontal diseases are highly prevalent conditions characterized by chronic inflammation, which leads to progressive destruction of tooth-supporting tissues. Conventional therapies, including scaling and root planing, grafting, and surgical procedures, are effective in controlling infection but show limited regenerative capacity. In this context, hydrogels—three-dimensional, highly hydrated polymeric biomaterials that mimic the extracellular matrix—have emerged as promising tools in periodontal regeneration. These materials can be engineered to modulate mechanical properties, porosity, and the delivery of bioactive molecules. Hydrogels can function as barrier membranes for guided tissue regeneration, scaffolds for stem cell support, and carriers for antimicrobial, anti-inflammatory, and osteogenic agents, enabling sustained and localized drug release. Recent studies have demonstrated their potential to inhibit bacterial biofilms, enhance osteogenic differentiation, and reduce inflammation in preclinical models. However, challenges remain regarding mechanical stability in the oral environment, controlled and sequential release of therapeutic agents, biocompatibility, and cost-effectiveness. Overall, hydrogels represent a promising adjunct in regenerative periodontal therapy, although further research is required to support their translation into routine clinical practice. Full article

Plasma proteins are becoming more and more popular among researchers due to their minimal toxicity and immunogenicity. The largest percentage of plasma proteins is human serum albumin (HSA). HSA is widely used as a drug carrier due to its biocompatibility and specific affinity to cancer cells. 10H-3,6-diazaphenothiazine (DAPT) is a newly synthesized phenothiazine derivative with promising anticancer activity. The main aim of this study was to encapsulate the DAPT into human serum albumin nanoparticles (DAPT-HSA-NPs) as well as to study DAPT interaction with HSA based on spectroscopic, microscopic, and calorimetric techniques. HSA nanoparticles with DAPT (DAPT-HSA-NPs) were prepared using the desolvation method, and this reaction was accompanied by a thermal transition. High encapsulation efficiency of DAPT into the HSA-NPs (DAPT-HSA-NPs) was obtained (~100%) and its release kinetics from the DAPT-HSA-NP system followed the zero-order kinetic model. Both nanoparticle preparation (HSA-NPs) and HSA interaction with DAPT (DAPT-HSA) resulted in changes in the HSA secondary structure. Moreover, the process of DAPT binding to HSA was exothermic (ΔH [kcal·mol⁻¹] < 0), and DAPT probably formed a static complex with HSA (kq [L·mol⁻¹·s⁻¹] > 10¹²) with moderate affinity (K_a [L·mol⁻¹] of the order of 10⁴). Despite reports on human serum albumin nanoparticles (HSA-NPs) and 10H-3,6-diazaphenothiazine (DAPT), no studies on DAPT encapsulation into HSA-NPs have been published. Therefore, HSA-NPs as a 3,6-diazaphenothiazine delivery system, including preparation methods and interaction analysis, have been evaluated. Full article

Conventional antibiotics exhibit limited ability to penetrate host cell membranes, making intracellular bacterial infections difficult to eradicate completely. As naturally derived nanoscale membrane structures, bacterial extracellular vesicles (EVs) possess excellent biocompatibility and intrinsic transmembrane transport capability, thereby demonstrating unique advantages for in vivo drug delivery. The present study investigated the feasibility of using EVs derived from the avirulent Streptococcus suis T15 as novel carriers for ciprofloxacin delivery. We also comprehensively evaluated the biosafety and anti-infective efficacy of this nanodrug delivery system in vitro and in vivo. Cytotoxicity assays, live/dead cell staining, and hemolysis analyses demonstrated that T15-derived EVs at concentrations below 50 μg/mL did not cause significant cellular damage or hemolysis. Serum biochemical analyses in mice further confirmed the absence of obvious organ toxicity, indicating favorable biosafety within the tested concentration range. Ciprofloxacin was successfully loaded into EVs using a combination of ultrasonication and electroporation, achieving a drug concentration of 438.6 μg/mL and a loading efficiency of 10.96%. The ciprofloxacin-loaded EVs (EV-CIP) exhibited significantly greater antibacterial activity than free ciprofloxacin against both intracellular bacteria and fluoroquinolone-resistant strains exhibiting efflux pump activity. Evaluation in animal infection models showed that EV-CIP markedly reduced mortality in infected Galleria mellonella larvae. It also decreased bacterial burdens in multiple mouse organs and significantly alleviated histopathological damage. These results collectively suggest that EVs derived from the avirulent S. suis T15 were safe and effective within the tested concentration range and experimental conditions. The EV-based ciprofloxacin delivery system substantially enhanced the clearance of intracellular pathogens and fluoroquinolone efflux pump-positive bacteria, suggesting its potential application in the treatment of difficult-to-treat bacterial infections. This study provides a theoretical and experimental basis for the further development of novel EV-based anti-infective drug delivery strategies for livestock and poultry. Full article

The round window membrane (RWM) presents a major barrier to local drug delivery into the inner ear. Although magnetically guided superparamagnetic iron oxide nanoparticles (SPIONs) have shown promise for enhancing transport across the RWM, the effectiveness of magnetic-field-driven delivery decreases rapidly with distance from the magnet, limiting clinical applicability. In this study, PEGylated SPIONs were investigated as externally actuated carriers for enhanced transport across membrane barriers using magnetic, photothermal, ultrasonic, and vibrational stimulation. Nanoparticle transport was evaluated using a custom dual-chamber benchtop platform containing porcine small intestinal submucosa (SIS) membranes as a model transport barrier. Transport studies demonstrated that magnetic-field-assisted delivery significantly increased magnetic nanoparticle (MNP) transport rates relative to passive diffusion; however, transport enhancement decreased sharply with increasing magnet-to-membrane distance. To overcome this limitation, alternative external actuation strategies were explored. Laser-induced photothermal heating, ultrasonication, and mechanical vibration all significantly enhanced MNP transport, even in the absence of magnetic fields. Among the conditions examined, combined magnetic and photothermal stimulation produced the highest transport rates, indicating synergistic enhancement. These results show that MNP transport can be effectively enhanced through magnetic, thermal, and mechanical mechanisms. The findings establish a multimodal transport-engineering framework for improving drug delivery across the RWM and suggest clinically translatable alternatives to magnetic-field-only approaches for inner-ear therapy. Full article

Background/Objectives: Diclofenac (DCF) and other nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain and inflammation management; however, their clinical significance is limited by poor aqueous solubility, short biological half-life, and dose-dependent gastrointestinal, renal, and cardiovascular adverse effects. Nanocarrier-based delivery systems have been extensively explored because they can enhance the apparent solubility of poorly water-soluble NSAIDs, provide controlled and sustained drug release, prolong systemic circulation, and improve drug localization at the site of action. By reducing peak plasma concentrations and off-target exposure, these systems may decrease dose-dependent gastrointestinal and systemic adverse effects while maintaining therapeutic efficacy. Most studies focus on optimizing formulation composition, while the manufacturing process is often treated as a secondary parameter. The research critically evaluates conventional and emerging fabrication methods for NSAID nanocarriers, using DCF as the principal reference compound, with emphasis on their impact on physicochemical characteristics, reproducibility, scalability, and translational potential. Methods: A structured literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science (2015–2026, with emphasis on 2022–2026) for DCF and NSAID-loaded submicron delivery systems reporting quantitative formulation data and clearly defined fabrication methods, resulting in a narrative review of approximately 375–395 eligible studies, comprising 75 DCF-specific studies and approximately 300–320 studies involving other NSAIDs that were included as representative surrogate systems when DCF-specific evidence was unavailable for particular fabrication approaches. The review followed Scale for the Assessment of Narrative Review Articles (SANRA) recommendations. Studies were analyzed using a standardized seven-parameter framework including encapsulation efficiency, release profile, particle size control, polydispersity, scalability, reproducibility, and process complexity. Results: Batch-based techniques, such as thin-film hydration for chitosan-coated liposomal systems, consistently provide high encapsulation efficiency, sustained drug release, and good biocompatibility. However, these methods are often associated with batch-to-batch variability, operator dependence, and limited scalability. In contrast, continuous manufacturing approaches, including microfluidic mixing, nanostructured lipid carriers, and Quality-by-Design (QbD)–guided processes, demonstrate improved control over particle size distribution and polydispersity, enhanced reproducibility, and better scalability potential. Conclusions: Manufacturing methodology is an important determinant of DCF and NSAID nanocarrier performance alongside formulation composition. Continuous manufacturing approaches offer promising improvements in reproducibility, process control, and scalability, but current evidence remains uneven across different nanocarrier classes. Further standardized comparative studies are needed to support their broader translation into clinical applications. Full article

Background/Objectives: Natural clinoptilolite–amoxicillin hybrids (CNZ@AMOX) were incorporated into alginate microcapsules via ionic gelation to develop a hybrid mineral–polymer delivery system for the controlled release of amoxicillin. Methods: A face-centered central composite design combined with response surface methodology (FCCD-RSM) was utilized to assess the effects of the zeolite/sodium alginate ratio, alginate concentration, calcium chloride concentration and curing time on the encapsulation efficiency (EE), sphericity factor (SF), and roundness (Rn). Results: The EE ranged from 5.9% to 91.3%, depending on the formulation composition. Numerical optimization identified the optimal conditions as 70.962% EE, 0.05 SF and 1.00 Rn, with a desirability score of 0.873. The incorporation of natural clinoptilolite improved microcapsule structural integrity and reduced the initial burst release by modulating diffusion pathways within the hybrid matrix. The optimized CNZ@AMOX exhibited pH-dependent release behavior, with minimal drug release in simulated gastric fluid (SGF) and diffusion-controlled release in simulated intestinal fluid (SIF), which was best described by the Korsmeyer–Peppas model. Conclusions: These findings demonstrate that zeolite–alginate hybrid microcapsules represent promising inorganic–organic composite carriers for the pH-responsive and controlled delivery of AMOX. Full article

In this study, taking NdCl₃ and 2-amino-1,4-benzenedicarboxylic acid (H₂ATA) as raw materials, a novel lanthanide metal–organic framework, Nd(ATA), was synthesized by the coprecipitation method. After loading antibiotic levofloxacin (LEV), Nd(ATA) was combined with GelMA hydrogel to prepare a drug-loaded composite hydrogel, LEV@Nd(ATA)-Gel, which can emit near-infrared fluorescence under excitation at 808 nm and possesses improved mechanical properties compared to pure GelMA hydrogel. LEV@Nd(ATA)-Gel exhibited high bactericidal activity and low cytotoxicity, with cell viability increased by 35% compared to the control group. The release rate of the loaded LEV was found increasing with the pH decreasing from 7 to 3, and demonstrated a potential responsiveness to wound microenvironment. Furthermore, drug delivery studies revealed a significant correlation with the fluorescence intensity of the composite hydrogel and the drug release behavior, and the extent of drug release was quantitatively captured by an in vitro imaging technology. This study successfully integrated the drug release with fluorescent signal of carrier, providing a highly sensitive and visualizable strategy for the development of internal wound adhesive. Full article

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, characterized by poor prognosis and a median survival of 12–18 months despite standard therapies such as surgery, radiation, and temozolomide chemotherapy. Its high cellular heterogeneity, along with complex mechanisms of therapy resistance, presents significant challenges for effective treatment. Conventional systemic chemotherapy is limited by the blood–brain barrier (BBB), systemic toxicity, and insufficient drug penetration into the tumor microenvironment. Emerging therapeutic strategies aim to overcome these barriers through novel chemotherapeutic agents, targeted therapies, immunotherapies, and smart drug delivery systems. Endovascular drug delivery, particularly super-selective intra-arterial cerebral infusion (SSIACI), offers a minimally invasive approach to directly target the tumor vasculature, potentially increasing drug concentration at the tumor site while reducing systemic exposure. Complementary techniques, such as MR-guided focused ultrasound, hyperosmotic disruption, and nanoparticle-based carriers, are being explored to enhance BBB penetration and retention of therapeutics within the tumor. Ongoing clinical trials and translational studies provide insights into optimizing these approaches, with future directions focused on precision medicine, biomarker-driven patient selection, and combination therapies. Integrating endovascular strategies with innovative chemotherapies and immunotherapies may transform GBM management, but further research is required to establish their efficacy and safety in clinical practice. Full article

Wet age-related macular degeneration (wAMD) is characterized by choroidal neovascularization (CNV) and remains a major cause of severe vision loss in older adults. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the current standard of care for wAMD. However, repeated injections are associated with poor adherence, procedure-related complications, and a substantial cumulative treatment burden. Topical nanocarrier-based systems have therefore attracted increasing attention as needle-free approaches for improving posterior segment drug exposure. Complementing broader reviews of ocular nanomedicine, this review specifically examines topical nanocarrier-mediated posterior segment delivery for wAMD, with a focus on three representative platforms: liposomes, polymeric nanoparticles, and polymeric micelles. These systems are engineered through the optimization of particle size, surface properties, drug-loading strategies, and functional modifications to improve payload stability, ocular surface residence, tissue penetration, and lesion-relevant delivery. By integrating formulation design, ocular barrier transport, ocular posterior segment bioavailability, and translational feasibility in the context of wAMD, this review provides a disease-focused and application-oriented perspective that complements existing broader reviews of ocular nanocarriers and ophthalmic nanomedicine. We summarize current evidence from preclinical and translational studies and discuss major barriers limiting clinical application, including insufficient posterior segment drug exposure, dose–safety trade-offs, pharmacokinetic instability, limited targeting efficiency, and challenges in delivering macromolecular biologics, such as anti-VEGF antibodies and fusion proteins. At present, topical nanocarrier-based strategies remain investigational, but they hold potential for development as therapeutic approaches for wAMD. Key priorities for future development include quantitative posterior segment pharmacokinetic/pharmacodynamic evaluation, long-term safety assessment, payload-specific carrier design, scalable manufacturing, and clinically relevant efficacy endpoints. This review provides a focused framework for the rational design and translational assessment of nanocarrier-based topical strategies for wAMD management. Full article