Pharmaceutics最新文献

Background: Phototherapy utilizes targeted irradiation to inactivate bacteria or treat various medical conditions. Depending on the therapeutic goal, wavelengths from violet to infrared (IR) are applied. Within the visible and near-IR spectrum, photodynamic therapy (PDT) combines light with photosensitizers that generate reactive oxygen species (ROS), leading to bacterial inactivation. Optimizing photodynamic efficacy can involve either enhancing ROS formation through specific topical agents that modulate ROS generation or employing dual-wavelength light irradiation (DWLR) to achieve synergistic excitation. Established DWLR protocols typically combine blue and red light or IR to activate distinct photosensitizers. Materials and Methods: This study investigates whether a similar synergistic effect can be achieved within the green spectral range by simultaneously exciting a single photosensitizer-coproporphyrin III (CP III)-at 496 nm and 547 nm. Results: Convolution analysis and in vitro bacterial reduction experiments with Cutibacterium acnes subsp. elongatum revealed that cyan irradiation (496 nm) achieved the strongest photoreduction (2.31 log steps at 1620 J/cm²), whereas PC-lime irradiation (547 nm) produced a smaller effect (0.74 log steps). DWLR protocols (simultaneous and sequential irradiation) resulted in intermediate reductions (1.64 and 1.73 log steps, respectively), exceeding PC-lime but not surpassing cyan irradiation alone. Conclusions: These findings demonstrate that excitation efficiency at the local absorption maximum of CP III is the primary determinant of ROS generation, while spectral broadening through DWLR does not enhance bacterial inactivation within this wavelength range and in vitro setup.

Background/Objectives: Discriminating bacterial from mammalian membranes remains a central challenge in antibiotic design. Bacterial membranes are enriched in phosphatidylethanolamine (PE), a lipid normally absent from the outer leaflet of mammalian cells, providing a signature for selective molecular engagement. We report a compact covalent ligand, 6-dimethylamino-4-ketohexanoic acid (DMAX), which targets PE via Schiff base formation, leveraging its tertiary amine to facilitate the reaction and strengthen ionic binding with the phosphate group. Methods: The reactivity of DMAX and PE was evaluated by computational simulations, and their interaction was examined by spectroscopic analyses (NMR and FT-IR) and an artificial membrane assay. The targeting ability of DMAX for live bacteria was determined by microscopy study, and its applicability to therapeutic system was tested in vitro under washed conditions that mimic rapid in vivo clearance. Results: Spectrometric analyses revealed the selective covalent interaction of DMAX and PE, consistent with the simulated results. Fluorescently labeled DMAX selectively binds PE-enriched model membranes and efficiently recognizes Gram-negative bacteria while sparing mammalian cells. Conjugation of DMAX to Gemifloxacin (Gem) significantly enhanced antibiotic efficacy by 10-fold compared with free Gem, even after rapid drug clearance, while maintaining safety in mammalian cells. Conclusions: These results identify DMAX as an efficient and versatile PE-targeting platform, enabling selective membrane anchoring to advance precision antibiotic strategies.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, chronic neuroinflammation, and synaptic loss, leading to cognitive decline. Extracellular vesicles (EVs)-lipid bilayer nanoparticles secreted by nearly all cell types-have emerged as critical mediators of intercellular communication, playing a complex dual role in both the pathogenesis and potential treatment of AD. This review generally delineates two opposite roles of EVs in pathogenesis and potential treatment of AD. On one hand, EVs derived from neurons, astrocytes, microglia and oligodendrocytes can propagate toxic proteins (Aβ, tau) and inflammatory signals, thereby accelerating disease progression. On the other hand, EVs-especially those from mesenchymal stem cells (MSCs)-exert neuroprotective effects by facilitating toxic protein clearance, modulating immune responses, preserving synaptic integrity, and alleviating oxidative stress. The cargo-carrying function of EVs gives them considerable diagnostic value. The associated cargos such as proteins and microRNAs (miRNAs) in the EVs may serve as minimally invasive biomarkers for early detection and monitoring of AD. Therapeutically, engineered EVs, including those incorporating CRISPR/Cas9-based genetic modification, are being developed as sophisticated delivery platforms for targeting core AD pathologies. Furthermore, this review highlights emerging technologies such as microfluidic chips and focused ultrasound (FUS), discussing their potential to enhance the translational prospects of EV-based early diagnostic and treatment for AD.

Background/Objectives: Chagas disease remains a major unmet medical need due to the limited efficacy and safety of current therapies. Here, we investigated sixteen thiosemicarbazone (TSC) derivatives as cruzain inhibitors using an integrated in silico/in vitro workflow. Methods: Docking against cruzain (PDB 3KKU) guided hit prioritization and correlated with enzyme inhibition; validation by redocking supported the protocol's reliability. Results: The top compounds-H7, H10 and H11-showed potent cruzain inhibition (IC₅₀ = 0.306, 0.512 and 0.412 µM, respectively) and low-micromolar trypanocidal activity, with negligible cytotoxicity in human fibroblasts (CC₅₀ > 64 µM) and favorable selectivity. Structure-activity insights highlighted the role of expanded aromatic systems and electron-donating groups in enhancing binding within S2/S1' subsites, while nitro substituents were associated with higher cytotoxicity. In silico ADMET parameters supported oral drug-likeness and acceptable metabolic liabilities. Conclusions: Overall, these data position TSCs as promising anti-T. cruzi leads and underscore the value of rational design against cruzain.

Background/Objectives: Docetaxel is a widely used chemotherapeutic agent for several malignancies and is an established treatment for castration-resistant prostate cancer. However, its poor aqueous solubility, systemic toxicity, and the emergence of drug resistance limit its clinical benefit. Zein, a prolamin, forms micelles that enhance the solubility and delivery of hydrophobic drugs. As PEG length and ligand presentation govern micelle behavior, we investigated transferrin-functionalized PEGylated zein micelles as docetaxel nanocarriers and examined how PEG chain length (5 K vs. 10 K) and transferrin-mediated targeting affect delivery to prostate cancer cells. Methods: Docetaxel-loaded zein micelles bearing 5 K or 10 K PEG chains were prepared and conjugated to transferrin. Formulations were characterized for size, charge, morphology, critical micelle concentration, colloidal stability, drug loading and transferrin density. Cellular uptake and mechanisms were assessed in PC-3-Luc, DU145 and LNCaP cells by confocal microscopy, flow cytometry and pharmacological inhibition. Anti-proliferative activity was determined by MTT assays. Results: Both PEG5K and PEG10K micelles formed micellar dispersions with low polydispersity and high encapsulation efficiency. PEG5K micelles achieved higher transferrin conjugation and drug loading. Transferrin-functionalized PEG5K micelles showed enhanced uptake in DU145 and LNCaP cells but lower internalization in PC-3-Luc cells. Inhibitor studies indicated receptor-dependent uptake via clathrin- and caveolae-mediated endocytosis. Free docetaxel remained the most potent. However, among nanocarriers, transferrin-targeted PEG5K micelles showed the greatest anti-proliferative efficacy relative to their non-targeted counterparts, whereas transferrin-targeted PEG10K micelles were less potent than the non-targeted PEG10K micelles across all three cell lines. Conclusions: PEG chain length and ligand presentation are key determinants of uptake and cytotoxicity of docetaxel-loaded zein micelles. Shorter PEG chains favor effective transferrin display and receptor engagement, whereas longer PEG likely induces steric hindrance and reduces targeting, supporting transferrin-conjugated PEG5K zein micelles (the lead formulation in this study) as a targeted delivery platform that improves performance relative to matched non-targeted micelles in vitro, while free docetaxel remains more potent in 2D monolayer assays.

Background/Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) exhibit neuroprotective properties in preclinical models of Alzheimer's disease (AD), reducing amyloid accumulation, neuroinflammation, and insulin resistance within the brain. However, clinical evidence regarding their cognitive effects in AD and mild cognitive impairment (MCI) remains inconclusive. To evaluate the effects of GLP-1 RAs on cognitive outcomes in patients with AD or MCI due to AD. Methods: A systematic review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD420251143171). Although the original registry was broad, the identification of a small set of homogeneous randomized controlled trials (RCTs) during screening, prior to data extraction, allowed for a random-effects meta-analysis of cognitive outcomes. RCTs enrolling adults with clinically or biomarker-confirmed AD or MCI were included. Interventions comprised liraglutide or exenatide compared with placebo. Standardized mean differences (SMD) in global cognitive scores were pooled using a random-effects model (restricted maximum likelihood [REML] estimator with Hartung-Knapp adjustment). Results: Three randomized trials (n = 278 participants; 51% women; mean age 68 ± 7 years) met inclusion criteria. Treatment duration ranged from 26 weeks to 18 months. Pooled analysis revealed no significant effect of GLP-1 RAs on global cognition compared with placebo -0.21 (95% CI -0.81 to 0.38; I² = 47%; τ² = 3.77). Sensitivity analyses restricted to liraglutide or studies ≥ 12 months yielded similar results. Conclusions: Current randomized evidence does not support cognitive improvement with GLP-1 RAs in AD or MCI.

Adverse drug reactions-including those caused by drug-drug interactions (DDIs)-are a major cause of emergency department visits and subsequent hospitalizations in the United States, with studies estimating that 10-30% of these visits are drug-related [...].

Background/Objectives: Leishmaniasis constitutes one of the most fatal parasitic diseases globally, adversely impacting the health of individuals residing in both intertropical and temperate zones. In these geographical areas, the administration of treatment is often inconsistent and largely ineffective with the available pharmaceuticals, as these exhibit more pronounced side effects than the therapeutic advantages they purport to provide. Methods: Consequently, the current investigation seeks to engage in molecular modeling of novel pharmacological candidates incorporating 1,2,3 disubstituted triazole moieties, coordinated with Cu^II metal centers, in pursuit of promising bioactive properties. Results: Two complexes were prepared and X-ray analysis revealed a comparable structural configuration surrounding the copper (II) atom. The planar square coordination geometry was elucidated through the assessment of the τ4=0 (tau four) parameters. The comprehensive characterization encompasses HRMS-ESI (+), NMR, elemental analyses, mid-infrared, and UV-vis spectroscopic techniques. Time-dependent density functional theory (TD-DFT) analyses will substantiate the findings obtained through UV-vis spectroscopy. Crucially, the biological assays against Leishmania (L.) amazonensis revealed that Complex 1 exhibited outstanding potency against the intracellular amastigote form, demonstrating a half-maximal inhibitory concentration (IC₅₀) of 0.4 µM. This activity was 6-fold higher than that of amphotericin B (IC₅₀ = 2.5 µM) and 33-fold higher than pentamidine (IC₅₀ = 13.3 µM). Furthermore, Complex 1 showed a promising selectivity index (SI = 9.7) against amastigotes, surpassing the reference drugs and meeting the criteria for a lead compound. While less active on promastigotes, both complexes demonstrated high stability in DMSO solution, a prerequisite for biological testing. Conclusions: These results unequivocally identify Complex 1 as a highly promising candidate for the development of new antileishmanial therapies, warranting further in vivo studies.

Cell membrane-coated nanoparticles represent a biomimetic drug delivery approach that integrates biological membrane functions with synthetic nanomaterials. Among the various membrane sources, those derived from blood cells such as red blood cells, platelets, and leukocytes offer distinctive advantages, including immune evasion, prolonged systemic circulation, and selective tissue targeting. These properties collectively enable efficient and biocompatible delivery of therapeutic agents to diseased tissues, minimizing off-target effects and systemic toxicity. This review focuses on blood cell membrane-derived nanocarriers as drug delivery and immune-regenerative platforms, in which membrane-mediated immunomodulation synergizes with therapeutic payloads to address inflammatory or degenerative pathology. We discuss recent advances in blood cell membrane coating technologies, including membrane isolation, nanoparticle core selection, fabrication techniques, and the development of hybrid and engineered membrane systems that enhance therapeutic efficacy through integrated immune regulation and localized drug action. To illustrate these advances, we also compile membrane type-specific nanocarrier systems, summarizing their core nanoparticle designs, coating strategies, therapeutic cargoes, and associated disease models. Challenges related to biological source variability, scalability, safety, and regulatory standardization remain important considerations for clinical translation. In this review we systematically address these issues and discuss emerging solutions and design strategies aimed at advancing blood cell membrane-based nanocarriers toward clinically viable immune-regenerative therapies.

The growing demand for effective skincare products that can effectively target specific dermatological concerns has accelerated the development of advanced delivery technologies. Among them, nanocarrier-based topical delivery systems have gained significant attention for their ability to enhance the performance of skincare formulations. Acting as versatile delivery tools, nanocarriers not only stabilize and protect sensitive cosmetic ingredients but also improve their penetration through the skin barrier and enable controlled, sustained, or targeted release. Therefore, this review focuses on the recent achievements of nanocarrier-based topical delivery technology for skincare applications, which systematically summarizes the design principles, mechanisms and functional characteristics of diverse nano-based delivery platforms, including vesicular nanocarriers, lipid-based nanocarriers, emulsion-based nanocarriers, polymeric nanocarriers, inorganic nanoparticles, and inclusion complexes. Meanwhile, these nanocarriers are discussed according to their relevance to the pathogenesis of prevalent skin disorders, highlighting how tailored nanocarriers can address specific therapeutic or cosmetic needs. Overall, this review emphasizes the emerging trends and future perspectives of nanotechnology-based topical delivery systems in modern cosmetology, offering more opportunities for precise, effective and science-driven cosmetic solutions.