Molecular Pharmaceutics最新文献_第10页

Therapeutic Immunomodulation of Tumor-Lymphatic Crosstalk via Intratumoral Immunotherapy. 通过瘤内免疫疗法对肿瘤-淋巴串联进行治疗性免疫调节

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-10-31 DOI: 10.1021/acs.molpharmaceut.4c00692

Samuel N Lucas, Susan N Thomas

引用次数: 0

Trop2-Targeted Molecular Imaging in Solid Tumors: Current Advances and Future Outlook. 实体瘤中的 Trop2 靶向分子成像：当前进展与未来展望》。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-11-13 DOI: 10.1021/acs.molpharmaceut.4c00848

Yongshun Liu, Wenpeng Huang, Rachel J Saladin, Jessica C Hsu, Weibo Cai, Lei Kang

{"title":"Trop2-Targeted Molecular Imaging in Solid Tumors: Current Advances and Future Outlook.","authors":"Yongshun Liu, Wenpeng Huang, Rachel J Saladin, Jessica C Hsu, Weibo Cai, Lei Kang","doi":"10.1021/acs.molpharmaceut.4c00848","DOIUrl":"10.1021/acs.molpharmaceut.4c00848","url":null,"abstract":"Trophoblast cell surface antigen 2 (Trop2), a transmembrane glycoprotein, plays a dual role in physiological and pathological processes. In healthy tissues, Trop2 facilitates development and orchestrates intracellular calcium signaling. However, its overexpression in numerous solid tumors shifts its function toward driving cell proliferation and metastasis, thus leading to a poor prognosis. The clinical relevance of Trop2 is underscored by its utility as both a biomarker for diagnostic imaging and a target for therapy. Notably, the U.S. Food and Drug Administration (FDA) has approved sacituzumab govitecan (SG), a novel Trop2-targeted agent, for treating triple-negative breast cancer (TNBC) and refractory urothelial cancer, highlighting the significance of Trop2 in clinical oncology. Molecular imaging, a powerful tool for visualizing and quantifying biological phenomena at the molecular and cellular levels, has emerged as a critical technique for studying Trop2. This approach encompasses various modalities, including optical imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and targeted antibodies labeled with radioactive isotopes. Incorporating Trop2-targeted molecular imaging into clinical practice is vital for the early detection, prognostic assessment, and treatment planning of a broad spectrum of solid tumors. Our review captures the latest progress in Trop2-targeted molecular imaging, focusing on both diagnostic and therapeutic applications across diverse tumor types, including lung, breast, gastric, pancreatic, prostate, and cervical cancers, as well as salivary gland carcinomas. We critically evaluate the current state by examining the relevant applications, diagnostic accuracy, therapeutic efficacy, and inherent limitations. Finally, we analyze the challenges impeding widespread clinical application and offer insights into strategies for advancing the field, thereby guiding future research endeavors.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"5909-5928"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612771","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}

引用次数: 0

Microneedles as an Emerging Platform for Transdermal Delivery of Phytochemicals. 微针作为植物化学物质透皮给药的新兴平台。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-10-29 DOI: 10.1021/acs.molpharmaceut.4c00894

B H Jaswanth Gowda, Mohammed Gulzar Ahmed, Raghu Raj Singh Thakur, Ryan F Donnelly, Lalitkumar K Vora

{"title":"Microneedles as an Emerging Platform for Transdermal Delivery of Phytochemicals.","authors":"B H Jaswanth Gowda, Mohammed Gulzar Ahmed, Raghu Raj Singh Thakur, Ryan F Donnelly, Lalitkumar K Vora","doi":"10.1021/acs.molpharmaceut.4c00894","DOIUrl":"10.1021/acs.molpharmaceut.4c00894","url":null,"abstract":"Phytochemicals, which are predominantly found in plants, hold substantial medicinal value. Despite their potential, challenges such as poor oral bioavailability and instability in the gastrointestinal tract have limited their therapeutic use. Traditional intra/transdermal drug delivery systems offer some advantages over oral administration but still suffer from issues such as limited penetration depth, slow drug release rates, and inconsistent drug absorption. In contrast, microneedles (MNs) represent a significant advancement in intra/transdermal drug delivery by providing precise control over phytochemical delivery and enhanced penetration capabilities. By circumventing skin barriers, MNs directly access dermal layers rich in blood vessels and lymphatics, thus facilitating efficient phytochemical delivery. This review extensively discusses the obstacles of traditional oral delivery and the benefits of intra/transdermal delivery routes with a particular focus on the transformative potential of MNs for phytochemical delivery. This review explores the complexities of delivering phytochemicals through intra/transdermal routes, the development and types of MNs as innovative delivery tools, and the optimal design and properties of MNs for effective phytochemical delivery. Additionally, this review examines the versatile applications of MN-mediated phytochemical delivery, including its role in administering phytophotosensitizers for photodynamic therapy, and concludes with insights into relevant patents and future perspectives.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6007-6033"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of a Novel MET-Targeting Camelid-Derived Antibody in Head and Neck Cancer. 评估一种新型 MET 靶向驼科动物抗体在头颈癌中的应用

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-11-08 DOI: 10.1021/acs.molpharmaceut.4c00938

Rachel L Minne, Natalie Y Luo, Caroline M Mork, Madalynn R Wopat, Karla Esbona, Saahil Javeri, Kwangok P Nickel, Reinier Hernandez, Aaron M LeBeau, Randall J Kimple, Andrew M Baschnagel

{"title":"Evaluation of a Novel MET-Targeting Camelid-Derived Antibody in Head and Neck Cancer.","authors":"Rachel L Minne, Natalie Y Luo, Caroline M Mork, Madalynn R Wopat, Karla Esbona, Saahil Javeri, Kwangok P Nickel, Reinier Hernandez, Aaron M LeBeau, Randall J Kimple, Andrew M Baschnagel","doi":"10.1021/acs.molpharmaceut.4c00938","DOIUrl":"10.1021/acs.molpharmaceut.4c00938","url":null,"abstract":"In head and neck squamous cell carcinoma (HNSCC), the mesenchymal epithelial transition (MET) receptor drives cancer growth, proliferation, and metastasis. MET is known to be overexpressed in HNSCC and, therefore, is an appealing therapeutic target. In this study, we evaluated MET expression in patients with HNSCC and investigated the potential imaging application of a novel MET-binding single-domain camelid antibody using positron emission tomography/computed tomography (PET/CT) in a preclinical MET-expressing HNSCC model. Multiplex immunostaining for MET protein performed on a tissue microarray from 203 patients with HNSCC found 86% of patients to have MET expression, with 14% having high expression and 53% having low MET expression. Using The Cancer Genome Atlas (TCGA) database, high MET RNA expression was associated with worse progression-free survival and overall survival in patients with HPV-negative HSNCC. Utilizing flow cytometry and immunofluorescence, our novel camelid antibody fused to a human IgG Fc chain (1E7-Fc) showed high binding affinity and specificity to high MET-expressing Detroit 562 cells but not to low MET-expressing HNSCC cells. The efficacy and biodistribution of [89Zr]Zr-1E7-Fc as a PET imaging agent was then investigated in a MET-expressing head and neck xenograft model. [89Zr]Zr-1E7-Fc rapidly localized and showed high tumor uptake in Detroit 562 xenografts (8.4% ID/g at 72 h postinjection), with rapid clearance from the circulatory system (2.7 tumor-to-blood radioactivity ratio at 72 h postinjection). Our preclinical data suggest that the camelid antibody 1E7-Fc could be a potential theranostic agent for HNSCC. Further investigations are warranted to confirm these findings in patients and to evaluate 1E7-Fc as an imaging agent and platform to deliver radionuclide or drug therapy to MET-driven cancers.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6376-6384"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602057","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}

引用次数: 0

Cocrystallization Enables Ensitrelvir to Overcome Anomalous Low Solubility Caused by Strong Intermolecular Interactions between Triazine-Triazole Groups in Stable Crystal Form. 共晶体化使 Ensitrelvir 克服了三嗪-三唑基团间强烈的分子间相互作用导致的异常低溶解度，形成稳定的晶体。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-11-14 DOI: 10.1021/acs.molpharmaceut.4c01108

Tetsuya Miyano, Shigeru Ando, Daiki Nagamatsu, Yui Watanabe, Daichi Sawada, Hiroshi Ueda

{"title":"Cocrystallization Enables Ensitrelvir to Overcome Anomalous Low Solubility Caused by Strong Intermolecular Interactions between Triazine-Triazole Groups in Stable Crystal Form.","authors":"Tetsuya Miyano, Shigeru Ando, Daiki Nagamatsu, Yui Watanabe, Daichi Sawada, Hiroshi Ueda","doi":"10.1021/acs.molpharmaceut.4c01108","DOIUrl":"10.1021/acs.molpharmaceut.4c01108","url":null,"abstract":"Ensitrelvir is a nonpeptide 3CL protease inhibitor used for coronavirus disease 2019 treatment. Four crystalline forms of ensitrelvir, metastable (Form I), acetonate (Form II), stable (Form III), and hydrate (Form IV), have been analyzed as pharmaceutical crystals. Their rank order of solubility is Form I > IV > III. Form III is the stable crystal with a significantly lower solubility than that predicted from its log P value of 2.7. Here, single-crystal structural analysis revealed strong intermolecular interactions between the triazine (acidic) and triazole (basic) groups of Form III not Forms I and IV. Multicomponent crystals were also designed to improve the solubility by altering the intermolecular interactions in Form III. Slurry conversion with equal molar ratios of ensitrelvir and fumaric acid successfully induced the formation of a novel cocrystal (Form V). Fumaric acid inhibited the triazine-triazole interactions, and dissolution of Form V was approximately 8- and 13-fold higher than that of Form III in pH 1.2 and 6.8 media, respectively. Furthermore, Form V exhibited an approximately 16-fold higher flux value than that of Form III. Therefore, alterations in intermolecular interactions via cocrystallization significantly enhance the dissolution and permeation of ensitrelvir.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6473-6483"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612756","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}

引用次数: 0

Exploration of a Novel Terpolymer Nanoparticle System for the Prevention of Alcohol-Induced Dose Dumping. 探索新型三元共聚物纳米粒子系统，防止酒精引起的剂量倾倒。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-11-11 DOI: 10.1021/acs.molpharmaceut.4c00706

Kuan Chen, Hao Han R Chang, Jamie Lugtu-Pe, Yuan Gao, Fuh-Ching Liu, Anil Kane, Xiao Yu Wu

{"title":"Exploration of a Novel Terpolymer Nanoparticle System for the Prevention of Alcohol-Induced Dose Dumping.","authors":"Kuan Chen, Hao Han R Chang, Jamie Lugtu-Pe, Yuan Gao, Fuh-Ching Liu, Anil Kane, Xiao Yu Wu","doi":"10.1021/acs.molpharmaceut.4c00706","DOIUrl":"10.1021/acs.molpharmaceut.4c00706","url":null,"abstract":"Alcohol-induced dose dumping (AIDD) remains a serious challenge in the controlled delivery of high potency drugs, such as opioids, which requires extensive investigation and innovative solutions. Current technologies rely on ethanol-insoluble excipients, such as guar gum and sodium alginate, to counteract the increased solubility of hydrophobic polymeric excipients in ethanol. However, these excipients pose several shortcomings, such as high viscosity of coating dispersion, high solution temperature, rapid gelation, and heterogeneity of resulted film. In this work, we explored the application of a cross-linked terpolymer nanoparticle (TPN) as an alcohol-resistant excipient in a water-insoluble controlled release film of ethylcellulose (EC) for the prevention of AIDD. Herein, we optimized the composition of TPN using a central composite design (CCD) to minimize swelling and weight loss of TPN-EC film in the presence of 20% ethanol. The optimized TPN showed a negligible effect on the viscosity of the coating dispersion, while guar gum increased the viscosity by 76-fold. Permeability studies in a pH 1.2 media containing 0% or 40% v/v ethanol revealed that cationic drugs (propranolol HCl, diltiazem HCl, and naloxone HCl (an opioid receptor-binding model drug)) exhibited significantly lower permeability ratios (P40%/P0%) than un-ionized drugs (theophylline and salicylic acid). FTIR analysis indicated an increase in ionic hydrogen bonding between TPN and the cationic drug in the presence of ethanol. These results suggest that drug-polymer-solvent interactions play an important role in alcohol-independent drug permeability through the TPN-EC film. By leveraging the drug permeability altering capability of the TPN-EC system, the release of cationic drugs in hydroethanolic media appeared to be suppressed, suggesting a promising new mechanism of alcohol resistance.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6257-6269"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612764","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}

引用次数: 0

Single-Step Extrusion Process for Formulation Development of Self-Emulsifying Granules for Oral Delivery of a BCS Class IV Drug. 用于口服 BCS IV 类药物的自乳化颗粒配方开发的单步挤压工艺。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-10-08 DOI: 10.1021/acs.molpharmaceut.4c00199

Vineet R Kulkarni, Santosh Bashyal, Varsha V Nair, Ishaan Duggal, Mohammed Maniruzzaman

{"title":"Single-Step Extrusion Process for Formulation Development of Self-Emulsifying Granules for Oral Delivery of a BCS Class IV Drug.","authors":"Vineet R Kulkarni, Santosh Bashyal, Varsha V Nair, Ishaan Duggal, Mohammed Maniruzzaman","doi":"10.1021/acs.molpharmaceut.4c00199","DOIUrl":"10.1021/acs.molpharmaceut.4c00199","url":null,"abstract":"This study aimed to develop and optimize formulations containinga BCS Class IV drug by improving its solubility and permeability. Herein development of self-emulsifying solid lipid matrices was investigated as carrier systems for a BCS Class IV model drug. Self-emulsifying drug delivery systems (SEDDS) have been extensively investigated for formulating drugs with poor water solubility. However, manufacturing SEDDS is challenging. These systems usually have low drug-loading capacities, and the incorporated drugs tend to recrystallize during storage, which severely impacts the storage stability in vitro and performance in vivo. Moreover, they require greater amounts (>80%) of lipid carriers, cosolvents, surfactants, and other excipients to keep them from recrystallizing. This in turn is again challenging for high-dose drugs as it affects the size of the final drug product (tablets and capsules). Also, the final liquid nature of the formulation affects the handling and processability of the formulation, which poses challenges during the manufacturing and packaging steps. In this work, we have studied the feasibility of a single-step extrusion process to formulate and optimize solid self-emulsifying granules with a relatively higher drug loading of Ritonavir (RTV), a BCS Class IV drug. Further, we have compared the performance of using these granules as the feedstock for direct powder extrusion-based 3D printing as opposed to the use of physical blends. The stability and solubility-permeability advantage of these granules was also evaluated where SEDDS showed about 27 and 20 fold increase in apparent solublity and permeability compared to bulk drug, respectively. Combining the capabilities of HME to form drug-loaded homogeneous granules as a continuous process along with application of direct printing extruiosn (DPE) 3D printing improves the drug delivery prospects for such candidates.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6123-6136"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386421","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}

引用次数: 0

Assessing the Manufacturability and Critical Quality Attribute Profiles of Anti-IL-8 Immunoglobulin G Mutant Variants. 评估抗 IL-8 免疫球蛋白 G 突变体的可制造性和关键质量属性特征。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-11-07 DOI: 10.1021/acs.molpharmaceut.4c01010

Georgina Bethany Armstrong, Glenn A Burley, William Lewis, Zahra Rattray

{"title":"Assessing the Manufacturability and Critical Quality Attribute Profiles of Anti-IL-8 Immunoglobulin G Mutant Variants.","authors":"Georgina Bethany Armstrong, Glenn A Burley, William Lewis, Zahra Rattray","doi":"10.1021/acs.molpharmaceut.4c01010","DOIUrl":"10.1021/acs.molpharmaceut.4c01010","url":null,"abstract":"Early-phase manufacturability assessment of high-concentration therapeutic monoclonal antibodies (mAbs) involves screening of process-related risks impacting their translation into the clinic. Manufacturing a mAb at scale relies on cost-effective and robust approaches to derisk manufacturability parameters, such as viscosity, conformational stability, aggregation, and process-related impurities. Using a panel of model anti-IL-8 IgG1 mutants, we investigate upstream and downstream processability, phase behavior, and process-related impurities. We correlate trends in the biophysical properties of mAbs with their cell growth, expression, filtration flux, solubility, and post-translational modifications. We find significant trends in increased relative free light chain expression with heavy chain mutants and detect a requirement for adjusted operation pH for cation exchange polishing steps with charge-altering variants. Moreover, trends between phase stability and high-concentration viscosity were observed. We also investigated unique correlations between increased glycosylation and biophysical behavior. Further in-depth analysis and modeling are required to elucidate the impact of the mAb sequence on the metabolism of the expression system, solubility limits, and alternative gelation models as future directions.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6423-6432"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PEGylation of New Thrombin Inhibitor Peptide Ultravariegin for Prolonged In Vivo Circulation and Enhanced Antithrombotic Effects. 对新型凝血酶抑制肽 Ultravariegin 进行聚乙二醇化处理，延长其体内循环时间并增强其抗血栓作用。

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-10-16 DOI: 10.1021/acs.molpharmaceut.4c00769

Xia Song, Yuting Wen, Aaron Wei Liang Li, Jingling Zhu, Cho Yeow Koh, R Manjunatha Kini, Mark Yan Yee Chan, Jun Li

{"title":"PEGylation of New Thrombin Inhibitor Peptide Ultravariegin for Prolonged In Vivo Circulation and Enhanced Antithrombotic Effects.","authors":"Xia Song, Yuting Wen, Aaron Wei Liang Li, Jingling Zhu, Cho Yeow Koh, R Manjunatha Kini, Mark Yan Yee Chan, Jun Li","doi":"10.1021/acs.molpharmaceut.4c00769","DOIUrl":"10.1021/acs.molpharmaceut.4c00769","url":null,"abstract":"Anticoagulant therapy is commonly used to prevent and treat arterial and venous blood clots in patients with cardiovascular disease, cerebrovascular disease, and cancer. Venous blood clots are the third leading cause of cardiovascular death following acute coronary artery disease and stroke. There is a significant need for effective anticoagulant therapy with minimal risk of bleeding. Variegin and its variants are a new type of antithrombin peptide that has shown promising results in preclinical studies. Variegin and its best variant, ultravariegin (UV), can more effectively inhibit blood clot formation while causing less bleeding than traditional medications such as heparin and bivalirudin. However, the short lifespan of UV remains a limitation for its use in clinical settings. PEGylation, a method of conjugating poly(ethylene glycol) (PEG) chains to peptides or drugs, may help improve the effectiveness of UV by extending its circulation time in the body. In this study, UV was PEGylated using maleimide-PEG5k and 10k. The impact of PEGylation on the antithrombin activity of UV was assessed in vitro and ex vivo in rat and rabbit plasma, showing minimal effects on the efficacy. In vivo studies in rats and rabbits revealed that PEGylated UV had a longer half-life and greater anticoagulant effects than unmodified UV did, especially when it was administered subcutaneously. PEGylation significantly extended the half-life of UV in rabbits, resulting in sustained anticoagulant effects for up to 4 days. This demonstrated that increasing the size of UV and shielding it with PEG could reduce clearance by the kidneys and prolong its circulation time. The improved half-life and antithrombin activity of PEGylated UV make it a more favorable choice for anticoagulant therapy.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6302-6310"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453465","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}

引用次数: 0

Transdermal Delivery of Tofacitinib Citrate via Mannose-Decorated Transferosomes Loaded with Tofacitinib Citrate in Arthritic Joints. 通过负载有枸橼酸托法替尼的甘露糖蜕变转移体在关节炎关节中透皮给药

IF 4.5 2区医学

Molecular Pharmaceutics Pub Date : 2024-12-02 Epub Date: 2024-11-20 DOI: 10.1021/acs.molpharmaceut.4c00496

Alaa Mahmoud, Mai Rady, Mohammad Abdel-Halim, Basma M El-Shenawy, Samar Mansour

{"title":"Transdermal Delivery of Tofacitinib Citrate via Mannose-Decorated Transferosomes Loaded with Tofacitinib Citrate in Arthritic Joints.","authors":"Alaa Mahmoud, Mai Rady, Mohammad Abdel-Halim, Basma M El-Shenawy, Samar Mansour","doi":"10.1021/acs.molpharmaceut.4c00496","DOIUrl":"10.1021/acs.molpharmaceut.4c00496","url":null,"abstract":"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 in vivo 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 (P < 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.","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6458-6472"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674441","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}

引用次数: 0