Molecular Pharmaceutics最新文献

Supramolecular deep eutectic solvents (SUPRADESs) as novel biomaterials are attracting increasing attention. However, their application to transdermal drug delivery has not yet been fully explored. This study aimed to investigate the internal mechanism and applicability. First, SUPRADESs composed of six cyclodextrins (CDs) and levulinic acid (Lev) were prepared and characterized. Resveratrol (RES) was used as a model drug. A series of experiments combined with molecular dynamics simulations indicated that SUPRADES remarkably enhanced the solubility of RES compared to only CD and Lev, whose solubilizing ability was contrary to the initial binding strength of the host–guest. The thermodynamic parameters and intermolecular interactions confirmed that the complexation formation in SUPRADES was driven by a favorable enthalpy decrease and a larger unfavorable entropy reduction. When the initial entropy contribution of the host–guest binding was smaller (the weak binding strength), the Gibbs free energy change became smaller in SUPRADES, and the solubilization ability of SUPRADES on drug was further increased. Skin penetration studies showed that, compared to RES/CD complexes, SUPRADES significantly enhanced the penetration and retention of RES in the skin. Thermodynamic calculations and molecular interactions studies revealed that the penetration enhancement was related to the improved skin wettability, the denaturation of the α-helix structure of keratin, and the increased skin hydration. Additionally, SUPRADES enhanced the stability and bioactivity of RES and exhibited low cytotoxicity and skin irritation. Overall, our study reveals the molecular mechanisms of SUPRADES-mediated solubility and permeation enhancement, guides the design of drug-SUPRADES formulations, and extends their pharmaceutical applications.

The high intracellular glutathione (GSH) level, naturally hypoxic conditions within the tumor microenvironment, and limited reactive oxygen species (ROS) generation pose significant obstacles to the effectiveness of sonodynamic therapy (SDT). Overcoming these barriers through depletion of GSH and relieving hypoxia offer a promising strategy to enhance SDT effectiveness. Herein, we developed a dendritic tetra-sulfide-bridged mesoporous silica (DTSMO) that encapsulated both chlorin e6 (Ce6) and cerium via channel-limited in situ coordination and is subsequently cloaked with the macrophage cell membrane (MCM) to facilitate efficient reactive oxygen species (ROS)-based therapy via multispecies enzymatic activities. First, this nanosystem exhibited Ce(IV) ions to mimic catalase (CAT)-like activity, converting H₂O₂ into O₂, thereby effectively alleviating tumor hypoxia. Meanwhile, the nanosystem possessed Ce (III)-based peroxidase (POD)-like activity, enabling the conversion of H₂O₂ into hydroxyl radicals (^•OH) while simultaneously depleting GSH. Both in vitro and in vivo experiments demonstrated that GSH depletion exerted a powerful supplementary effect on CDT and SDT, achieving a tumor inhibition rate of up to 96%, without affecting normal tissues during treatment.

Liver fibrosis, driven by hepatic stellate cells (HSCs) activation and pathological extracellular matrix (ECM) remodeling, involves dynamic crosstalk among macrophages, hepatocytes, liver sinusoidal endothelial cells (LSECs), and the fibrotic niche. In this perspective, we discuss the complex interactions among macrophages, hepatocytes, LSECs, ECM, and HSCs within the hepatic microenvironment, highlighting their role in liver fibrosis. Emerging nanomedicine strategies offer a promising solution through precision targeting, functionalization, and delivery optimization. This perspective highlights the pharmacological challenges of conventional therapies and underscores how nanomedicine overcomes biological barriers through enhanced biodistribution, reduced off-target effects, and combinatorial payload delivery. Future directions emphasize the need for patient stratification based on fibrosis etiology, the development of biomarker-guided smart nanosystems, and the clinical translation of microenvironment-remodeling approaches. By bridging mechanistic insights with cutting-edge drug delivery technologies, this work provides a roadmap for next-generation antifibrotic therapeutics.

The arrival of novel, more effective antiobesity medications has resulted in a surge in their use in the treatment of metabolic disorders including type 2 diabetes and weight-related comorbidities. Rapid growth in product demand has been witnessed in the United States and around the world. Ensuring that patients can access such life-saving medicines is vital to public health. One notable advancement in this field is the development of multiple-dose formulations containing antimicrobial preservatives. By enabling multiple doses from a single device or container, these products reduce the overall cost per dose and ease the supply chain bottleneck that causes product shortage, making medications more affordable and accessible. Interactions between a peptide and the preservative may induce structural perturbations and, as a result, impact the stability of the product. In the current study, we introduce a computational framework to investigate the interactions between a model therapeutic incretin peptide and antimicrobial preservatives, namely, benzyl alcohol and phenol. By integrating MD simulations with NMR data, we aim to elucidate how preservatives influence the stability of the peptide in the formulations. Our findings reveal that phenol displayed a significantly higher interaction frequency with the peptide compared to benzyl alcohol, particularly at the Trp cage and hydrophobic regions along the N- and C-termini. These interactions disrupt key stabilizing hydrogen bonds and increase the level of hydrophobic surface exposure, collectively heightening the stability risk of the peptide. Furthermore, phenol exhibited higher contact frequencies for residues such as Asp15, Ile17, Leu26, and Ile27, potentially explaining the differences in chemical stability observed with phenol-rich formulations. More importantly, the insights gained from simulations were independently corroborated by experimental results. This framework offers a strategy for developing robust multiple-dose preserved peptide formulations with the desired product stability throughout the shelf life.

Antimicrobial peptides (AMPs), such as Temporin-FL, exhibit promising antibacterial activity against Staphylococcus aureus. However, their clinical application is hindered by rapid degradation in wound environments and poor bioavailability. To address these limitations, we developed mesoporous polydopamine nanoparticles (MPDA) for the skin-targeted delivery of Temporin-FL. MPDA was synthesized via a one-pot polymerization method, with structural characterization confirming uniform mesopores (∼10 nm) and high surface area (320 m²/g). Subsequently, Temporin-FL was loaded into MPDA (MPDA@Temporin-FL), achieving a 61.04% encapsulation efficiency. Notably, the nanocomposite demonstrated a pH-responsive drug release, mimicking the acidic microenvironment of infected wounds. The studies in vitro revealed enhanced intracellular bacterial clearance in HaCaT cells, while the in vivo experiments using murine full-thickness wound models showed superior skin penetration and accelerated healing. Importantly, histological analysis highlighted robust granulation tissue formation and collagen deposition in the MPDA@Temporin-FL group, concomitantly with reduced pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). Collectively, these results underscore the dual functionality of MPDA@Temporin-FL: targeted antimicrobial delivery and tissue regenerative modulation. Therefore, this nanoplatform represents a clinically translatable strategy to combat antibiotic-resistant infections while promoting wound repair, addressing critical gaps in current AMP-based therapies.

Bivalent protein degraders, or proteolysis targeting chimeras (PROTACs), are an emerging therapeutic modality that can be used to drug challenging targets and drive differentiated pharmacology. However, the atypical physicochemical and structural properties of PROTACs can contribute to poor biopharmaceutical properties (e.g., solubility), and complicate drug research and development. To date, there are limited publications on modality-specific formulation strategies to mitigate these liabilities. Herein, we use multiple NMR spectroscopy techniques, isothermal titration calorimetry, and quantitative solubility measurements to study solubilization of a VHL-based PROTAC for SMARCA2, A515. In aqueous solution without solubilizing excipients, we found that A515 exists in two distinct and measurable populations that differ in the rotation of the amide group─a trans-proline rotational isomer that comprises a set of relatively open conformations with larger hydrodynamic size, and a cis-proline rotational isomer with relatively condensed conformations with smaller hydrodynamic size. Upon addition of the solubilizing excipient 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) to A515, we show that the efficiency of ternary host–guest complexation (i.e., the mechanism of solubilization) in each population is distinct and modulated by conformation (i.e., the accessibility of the terminal regions of A515 that are involved in complexation). These observations highlight the unreported and important role of stereochemistry and conformation in the rational formulation design for PROTACs (including solubility enhancement), and suggest specific considerations for VHL-based PROTACs.

Teverelix is a short non-natural peptide, which is a gonadotropin releasing hormone antagonist and used as a treatment for prostate cancer. Teverelix is formulated as a trifluoroacetic acid salt, which, at the high concentrations used for parenteral injection, forms a microcrystalline suspension. At low concentrations and immediately after injection, teverelix self-assembles into a fibrillar species thought to be important for the slow-release kinetics and long-acting action of this peptide in vivo. In this paper, we confirmed the amyloid-like identity of teverelix fibrils using X-ray fiber diffraction and transmission electron microscopy. The inter-β-sheet packing distance was found to be larger than that of typical amyloid fibrils and this was attributed to the large non-natural side chains within the peptide. Using data from numerous biophysical experiments, a model of the structure of teverelix within the fibril is proposed. The kinetics of fibril formation were investigated using standard ThT assays, and teverelix found to fibrillate rapidly over a wide range of conditions. The fibrillation rate was shown to depend critically upon pH, peptide, and trifluoroacetic acid concentration. Fibrillation was accompanied by a drop in pH, which we attribute to the fact that the pyridinium side chain must be deprotonated before self-assembly. Based on our results, we propose a nucleation–polymerization mechanism in which dimers of teverelix rapidly self-assemble into amyloid-like fibrils with little change in the secondary structure but burial of some of the aromatic acid side chains. Interestingly, the fibrils can, under certain conditions, align to create a highly ordered array. To the best of our knowledge, this is the first paper studying teverelix in detail from a biophysical perspective, and it is directly relevant to the aggregation of the peptide observed in vivo.

Epigenetic homeostasis is integral to the development of malignant tumors. Combining epigenetic drugs with chemotherapy is a promising strategy to overcome the challenges in treating lung metastasis from melanoma. In this study, we constructed sialic acid-modified ibrutinib–phospholipid complex nanoparticles (SA-IBR-NPs) to actively target and deliver the drug to lung metastasis sites through the mononuclear phagocytic system (MPS) pathway. A highly soluble 5-Carboxy-8-hydroxyquinoline-arginine salt (IOX1-Arg) was also developed to inhibit tumor cells’ intrinsic immune escape mechanisms. The combined administration of IOX1-Arg and SA-IBR-NPs significantly reduced the migration and invasion abilities of B16F10 cells and inhibited lung metastasis. The number of tumor nodules in experimental groups (including single-agent treatment groups, non-SA-modified nanoparticle groups, and non-IOX1-Arg combined groups) was 3.67–28.00 times higher than that of the IOX1-Arg + SA-IBR-NPs. The malignant index of tumor metastasis in single therapy or plain nanoparticle groups was 5.38–1062.29 times higher than that of the IOX1-Arg + SA-IBR-NP treatments, as well. This combination therapy also increased the levels of cytotoxic T cells. The antitumor immune response was effectively restructured by blocking the intrinsic escape mechanism of tumor cells and simultaneously inhibiting the immunosuppressive factors in the microenvironment. This strategy presents a novel approach to enhancing targeted therapy for metastatic tumors.