Molecular Pharmaceutics最新文献

{"title":"Mechanical Extrusion of the Plasma Membrane to Generate Ectosome-Mimetic Nanovesicles for Lung Targeting.","authors":"Yahui Liu, Yuelei Ling, Wanyi Tai","doi":"10.1021/acs.molpharmaceut.4c00927","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00927","url":null,"abstract":"<p><p>Extracellular vehicles (EVs) are naturally occurring nanocarriers that participate in the transportation of biologics between cells. Despite their potential in drug delivery, their optimal use in therapy remains a challenge, which comes from the difficulty in preparation scale-up and cargo loading efficiency. As a membrane-enclosed nanoscale system, EVs are reluctant to be transfected with cargos and purified by conventional methods. In the present study, we proposed an EV-mimetic nanovesicle system to overcome the challenges. Using the easy-culture mammalian cells as raw materials, we isolated the plasma membrane sheets and vesiculated them into membrane-enclosed nanovesicles as an EV mimic by the mechanical extrusion through porous membranes. In order to controllably load the cargos in the lumen of vesicles, the endogenous actin filament was chosen as an anchor to capture the cargos (fused with an anti-actin nanobody) in the inner leaflet of plasma membrane sheets and vesiculated inside after extrusion. By loading the bioluminescent tracer nano-luciferase (Nluc) and tracking biodistribution in mice, we unclosed the lung-tropic nature of these nanovesicles. Furthermore, we demonstrated that nanovesicles can be genetically engineered with chimeric antigen receptors to achieve the active targeting of lung cancer cells. In conclusion, our study indicated that plasma membrane extrusion might be an applicable approach to generate EV mimics for drug delivery, especially to the lung tissue.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Drug-Polymer Compatibility in Amorphous Solid Dispersions by MD Simulation: On the Trap of Solvation Free Energies.","authors":"T Higginbotham, K Meier, J Ramírez, A Garaizar","doi":"10.1021/acs.molpharmaceut.4c00810","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00810","url":null,"abstract":"<p><p>Amorphous solid dispersions (ASDs) are a prevalent method for increasing the bioavailability and apparent solubility of poorly soluble drugs. Consequently, extensive research, encompassing both experimental and computational approaches, has been dedicated to developing methods for assessing the key factors influencing their stability, notably drug-polymer interactions. A common computational approach to rank the compatibility of a drug with a set of solvents or polymers is to compare thermodynamic observables, such as solvation free energies at infinite dilution. However, the impact of the molecular weight of the polymer excipient on these interactions remains underexplored. This study delves into this impact through atomistic simulations of Indomethacin in PVP(-VA) and HPMC, and through simulations using a coarse-grained model, emphasizing its critical importance. First, we demonstrate that the molecular weight of the polymer plays a pivotal role in determining the solvation free energy of the drug, at times exerting a more significant influence than the specific chemical identity of the polymer. Additionally, our simulations suggest that higher molecular weight polymers lead to lower solvation free energies and, thus, suggest better compatibility with the drug. Yet, the lower free energy of solvation of the drug in longer polymers does not translate into a higher solubility. This work highlights the subtle role polymer molecular weight plays when measuring thermodynamic observables in amorphous solid dispersions, a role which must be considered when optimizing pharmaceutical formulations.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear Molecular Imaging for Evaluating T Cell Exhaustion.","authors":"Huimin Zhou, Guangfa Bao, Jun Zhao, Xiaohua Zhu","doi":"10.1021/acs.molpharmaceut.4c00970","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00970","url":null,"abstract":"<p><p>T cells are indispensable for the therapeutic efficacy of cancer immunotherapies, including immune checkpoint blockade. However, prolonged antigen exposure also drives T cells into exhaustion, which is characterized by upregulated inhibitory molecules, impaired effector functions, reduced cytotoxicity, altered metabolism, etc. Noninvasive monitoring of T cell exhaustion allows a timely identification of cancer patients that are most likely to benefit from immunotherapies. In this Review, we briefly explain the biological cascades underlying the modulation of inhibitory molecules, present a concise update on the nuclear molecular imaging tracers of T cell exhaustion, and then discuss the potential opportunities for future development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Novel Prosthetic Click-Linker for Radioiodination of Antibody-Based Radiopharmaceuticals with High Stability and Specificity.","authors":"Changkeun Im, Jae Hun Ahn, Hwisoo Lim, Dohyeon Kim, Yong Jin Lee, Chi Soo Kang, Choong Mo Kang","doi":"10.1021/acs.molpharmaceut.4c00897","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00897","url":null,"abstract":"<p><p>Radioiodine has been exploited in nuclear medicine for diagnostic and therapeutic purposes in various diseases. There are two radioiodination methods for biomolecules, that is, (1) direct radioiodination of tyrosine or histidine residue in a biomolecule and (2) indirect radioiodination by using a prosthetic group, which bridges radioiodine and the biomolecule. While directly radioiodinated biomolecules suffer from deiodination <i>in vivo</i>, the most commonly used indirect labeling method based on <i>N</i>-succinimidyl-3-[*I]iodobenzoate has a problem of inconvenience due to an high-performance liquid chromatography (HPLC) purification process. To tackle both issues, a novel prosthetic click-linker-antibody conjugate (3-[^123/125I]iodobenzoyl-PEG₄-tetrazine-TCO-PEG₄-trastuzumab (3-[^123/125I]IBTTT)) with favorable radiochemical yield (>57%) and purity (>99%) was developed using a fluorous tin-based organotin precursor with streamlined purification process utilizing fluorous solid-phase extraction (FSPE) cartridge and spin column. <i>In vitro</i> binding studies demonstrated that 3-[¹²⁵I]IBTTT maintained its biological activity with a <i>K</i>_D value (5.606 nM) comparable to that of unmodified trastuzumab (5.0 nM). <i>In vivo</i> imaging of 3-[¹²³I]IBTTT in a human epidermal growth factor receptor 2 (HER2)-expressing gastric cancer mouse model revealed favorable tumor accumulation and negligible thyroid uptake compared to directly radioiodinated trastuzumab ([¹²³I]trastuzumab). It was also confirmed, by blocking experiments and a biodistribution study, that the tumor accumulation of 3-[¹²³I]IBTTT was attributed to HER2-specific binding. In summary, we developed a novel radioiodinated prosthetic click-linker agent (3-[^123/125I]IBTTT) with favorable radiochemical yield, purity, stability, and <i>in vivo</i> behavior, providing a highly promising tool for targeted imaging and potential therapy of HER2-positive cancers.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Cyclic Peptide Targets Glioblastoma by Binding to Aberrantly Exposed SNAP25.","authors":"Alberto G Arias, Laura Tovar-Martinez, Eliana K Asciutto, Aman Mann, Kristina Põšnograjeva, Lorena Simón Gracia, Miriam Royo, Maarja Haugas, Tambet Teesalu, Cristian Smulski, Erkki Ruoslahti, Pablo Scodeller","doi":"10.1021/acs.molpharmaceut.4c00958","DOIUrl":"10.1021/acs.molpharmaceut.4c00958","url":null,"abstract":"<p><p>Disease-specific changes in tumors and other diseased tissues are an important target of research because they provide clues about the pathophysiology of the disease as well as uncover potentially useful markers for diagnosis and treatment. Here, we report a new cyclic peptide, CESPLLSEC (CES), that specifically accumulated (homed) in intracranial U87MG and the WT-GBM model of glioblastoma (GBM) from intravenous (IV) injection, and associated with the vasculature. Affinity chromatography of U87MG tumor extracts on insolubilized CES peptide identified Synaptosomal Associated Protein 25 (SNAP25) as a candidate target molecule (receptor) for CES. Several results supported the identification of SNAP25 as the CES receptor. IV-injected FAM-CES colocalized with SNAP25 in the tumors, and direct binding studies showed specific binding of the CES peptide to recombinant human SNAP25. A CES peptide-drug conjugate designed for photodynamic therapy showed selective cytotoxicity to SNAP25⁺ glioblastoma cell lines. Specific accumulation of systemically injected anti-SNAP25 antibody in U87MG glioblastoma and labeling of intact U87MG cells with anti-SNAP in flow cytometry showed that SNAP25 is available from the circulation but not in normal tissues and that it is present at the cell surface. Using an array of ECM proteins and surface plasmon resonance revealed that SNAP25 binds moderately to collagen V and strongly to collagen VI. Modeling studies suggested that CES and collagen VI compete for the same binding site on SNAP25. Our results introduce CES as a valuable targeting peptide for drug delivery and its receptor SNAP25 as a possible molecular marker of interest for glioblastoma.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxygen/Nitric Oxide Dual-Releasing Nanozyme for Augmenting TMZ-Mediated Apoptosis and Necrosis.","authors":"Jun Ma, Jingjing Qiu, Gus A Wright, Shiren Wang","doi":"10.1021/acs.molpharmaceut.4c00817","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00817","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor, with a poor prognosis. Temozolomide (TMZ) represents the standard chemotherapy for GBM but has limited efficacy due to poor targeting and a hypoxic tumor microenvironment (TME). To address these challenges, we developed a dual-gas-releasing, cancer-cell-membrane-camouflaged nanoparticle to deliver TMZ. This nanoceria, camouflaged with a cancer cell membrane (CCM-CeO₂), targets explicitly GBM cells and accumulates in lysosomes, triggering the rapid release of TMZ. Additionally, CCM-CeO₂ could release oxygen (O₂) and nitric oxide (NO) in response to the TME. Synthesized using d-arginine, catalytic nanoceria could decompose excessive hydrogen peroxide (H₂O₂) in the TME to produce O₂, while d-arginine could nonenzymatically react with H₂O₂ to generate NO. CCM-CeO₂ could penetrate GBM spheroids to a depth of 148.3 ± 31 μm, with the O₂ and NO produced, reducing HIF-1α protein expression. When loaded with TMZ, CCM-CeO₂ could increase the intracellular ROS produced by TMZ, leading to lysosome membrane permeabilization and notably augmented apoptosis and necrosis in GBM cells. An in vitro antitumor assay using spheroids showed that CCM-CeO₂ reduced the IC₅₀ value of TMZ from 174.5 to 42.6 μg/mL, likely due to the catalase-like activity of nanoceria. These results suggest that alleviating hypoxia and increasing ROS produced by chemotherapeutics could be an effective therapeutic strategy for treating GBM.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Matchmakers: Bioconjugation Techniques Enhance Prodrug Potency for Immunotherapy.","authors":"Yinuo Chen, Natalie Clay, Nathan Phan, Elijah Lothrop, Courtney Culkins, Blaise Robinson, Ariana Stubblefield, Alani Ferguson, Blaise R Kimmel","doi":"10.1021/acs.molpharmaceut.4c00867","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00867","url":null,"abstract":"<p><p>Cancer patients suffer greatly from the severe off-target side effects of small molecule drugs, chemotherapy, and radiotherapy─therapies that offer little protection following remission. Engineered immunotherapies─including cytokines, immune checkpoint blockade, monoclonal antibodies, and CAR-T cells─provide better targeting and future tumor growth prevention. Still, issues such as ineffective activation, immunogenicity, and off-target effects remain primary concerns. \"Prodrug\" therapies─classified as therapies administered as inactive and then selectively activated to control the time and area of release─hold significant promise in overcoming these concerns. Bioconjugation techniques (e.g., natural linker conjugation, bioorthogonal reactions, and noncanonical amino acid incorporation) enable the rapid and homogeneous synthesis of prodrugs and offer selective loading of immunotherapeutic agents to carrier molecules and protecting groups to prevent off-target effects after administration. Several prodrug activation mechanisms have been highlighted for cancer therapeutics, including endogenous activation by hypoxic or acidic conditions common in tumors, exogenous activation by targeted bioorthogonal cleavage, or stimuli-responsive light activation, and dual-stimuli activation, which adds specificity by combining these mechanisms. This review will explore modern prodrug conjugation and activation options, focusing on how these strategies can enhance immunotherapy responses and improve patient outcomes. We will also discuss the implications of computational methodology for therapy design and recommend procedures to determine how and where to conjugate carrier systems and \"prodrug\" groups onto therapeutic agents to enhance the safety and control of these delivery platforms.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A New Analytical Method for Quantifying Acid-End-Cap PLGA in Sub-Milligram Quantities.","authors":"John Garner, Sarah Skidmore, Gary Overdorf, Justin Hadar, Haesun Park, Kinam Park, Yan Wang, Young Kuk Jhon, William C Smith, Deyi Zhang, Yuan Zou","doi":"10.1021/acs.molpharmaceut.4c01057","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01057","url":null,"abstract":"<p><p>Characterization of PLGA polymers used in FDA-approved drug products is critical for quality control and qualitative/quantitative (Q1/Q2) evaluation of potential generic formulations. Various techniques have been developed and used to characterize the molecular properties of PLGA polymers, such as molecular weight, molecular composition, and molecular structure. Commonly used techniques include gel permeation chromatography (GPC), nuclear magnetic resonance (NMR), semisolvent methods, and GPC-based intrinsic viscosity measurement. It is noted that the existing analytical methods may not be able to separate and quantify PLGA polymers when used as a mixture in a drug product (e.g., Durysta and Ozurdex). In particular, one assay method still lacking is quantitating the PLGA polymer with acid-end-cap (PLGA-A) in the mixture containing PLGA with ester-end-cap (PLGA-E), especially when the sample quantity is below the submilligram level. The total PLGA quantities available in Durysta and Ozurdex formulations are too small (<1 mg) to use existing assay methods to quantify the PLGA-A content. A new assay method was developed to quantitate PLGA-A in the mixture with PLGA-E. The acid end-cap was modified with pyrene methylamine (a UV dye) to enhance the signal and compared with the total PLGA quantity measured with the refractive index (RI) after a sample was run through a GPC. This GPC-UV/RI approach is based on measuring the total acid number (TAN) of PLGA-A and converting it to the PLGA-A quantity to compare with the total PLGA. Unlike conventional methods of measuring TAN, the GPC-UV/RI methods enables TAN measurements of submilligram PLGA quantities. Application of this method to Ozurdex-similar samples showed the expected acid:ester ratio of PLGAs. This new approach provides another powerful tool for characterizing PLGA polymers in FDA-approved drug products. This is especially significant considering that the PLGAs of commercial products are likely to have molecular properties different from those of the raw PLGAs before going through the manufacturing process.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"“The More, the Better?”: The Impact of Sugar-to-Protein Molar Ratio in Freeze-Dried Monoclonal Antibody Formulations on Protein Stability","authors":"Ken Lo Presti,&nbsp;Mathilde Jégo and Wolfgang Frieß*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0117410.1021/acs.molpharmaceut.4c01174","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01174https://doi.org/10.1021/acs.molpharmaceut.4c01174","url":null,"abstract":"<p >Lyophilization is widely used to ensure the stability of protein drugs by minimizing chemical and physical degradation in the dry solid state. To this end, proteins are typically formulated with sugars that form an amorphous immobilizing matrix and stabilize hydrogen bonds replacing water molecules. The optimal amount of sugar required and protein stability at low excipient-to-protein molar ratios are not well understood. We investigated this by focusing on the physical stability of formulations, reflecting highly concentrated monoclonal antibody (mAb) lyophilizates at low sucrose to mAb ratios between 25:1 and 360:1. Additionally, the impact of different excipient types, buffer concentrations, and polysorbates was studied. The mAb stability was evaluated over up to three months at 25 and 40 °C. We investigated the “the more, the better” approach regarding excipient usage in protein formulation and the existence of a potential stabilizing threshold. Our findings show efficient monomeric content preservation even at low molar ratios, which could be explained based on the water replacement theory. We identified an exponential correlation between the sucrose to protein molar ratio and aggregate formation and found that there is no molar ratio threshold to achieve minimum stabilization. Sucrose demonstrated the best stabilization effect. Both mannitol, used as a cryoprotectant at low concentrations, and arginine reduced aggregation compared to the pure mAb formulation. The higher ionic strength of 5 mM histidine buffer enhanced protein stability compared to that of 0.1 mM histidine buffer, which was more pronounced at lower molar ratios. The addition of polysorbate 20 contributed an additional interfacial stabilizing effect, complementing the cryoprotective and lyoprotective properties of sucrose. Overall, a model could be developed to optimize the quantity of sugar required for protein stabilization and facilitate a more rational design of protein lyophilizates. The molar ratio of sugar to protein for high-concentration mAb products is limited by the acceptable tonicity, but we showed that sufficient stabilization can be achieved even at low molar ratios.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"6484–6490 6484–6490"},"PeriodicalIF":4.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transdermal Delivery of Tofacitinib Citrate via Mannose-Decorated Transferosomes Loaded with Tofacitinib Citrate in Arthritic Joints","authors":"Alaa Mahmoud,&nbsp;Mai Rady*,&nbsp;Mohammad Abdel-Halim,&nbsp;Basma M. El-Shenawy and Samar Mansour*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0049610.1021/acs.molpharmaceut.4c00496","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00496https://doi.org/10.1021/acs.molpharmaceut.4c00496","url":null,"abstract":"<p >Transdermal drug delivery systems are a promising option for the treatment of rheumatoid arthritis (RA) because they can lower systemic adverse effects of immunosuppressants. Janus kinase (JAK) inhibitors were found to be effective for the treatment of RA by inhibiting the JAK-STAT pathway and preventing autoimmune joint destruction. The aim of this study is to deliver tofacitinib (a JAK 1 and 3 inhibitor) through mannose-decorated transferosomes (MDTs) directly to inflamed joints. Transferosomes are composed of phospholipids, Cremophor A25, PEG400, Labrafac lipophile, and oleic acid to enhance the permeation of tofacitinib and control nanovesicle size (∼70–200 nm). Permeation through rat skin was evaluated, where the skin permeation of MDTs (Q24: 38.8 ± 9.82 μg/cm²) and flux (0.5311 ± 0.072 μg/cm²/h) were significantly greater than those of the uncoated transferosomes (Q24 of T1: 1.522 ± 0.329 μg/cm², Q24 of T2: 3.5002 ± 0.998 μg/cm², and Q24 of T3: 18.226 ± 5.25 μg/cm²). In addition, MDTs seem to permeate the skin intact, as shown by the transmission electron microscopy (TEM) images of the recipient buffer removed from the Franz diffusion cell. A histopathology assay was performed during the <i>in vivo</i> evaluation of MDTs in an arthritic rat model, in which, significantly less inflammation was observed when MDTs were applied directly to the joint compared to when applied to the dorsal skin and untreated arthritic joints. Furthermore, significantly lower tumor necrosis factor-α (TNFα), IL-6, and IL-1β levels (<i>P</i> &lt; 0.05) were detected by enzyme-linked immunosorbent assay (ELISA) in homogenates of the joints treated with MDTs than in untreated arthritic joints. In conclusion, this study proposed effective MDTs that could deliver tofacitinib directly to inflamed joints possibly by targeting the macrophages circulating in the proximity of the site of inflammation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"21 12","pages":"6458–6472 6458–6472"},"PeriodicalIF":4.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}