Molecular Pharmaceutics最新文献

{"title":"Preclinical Evaluation of an Al¹⁸F-Radiolabeled Bicyclic Peptide Targeting Nectin-4.","authors":"Xiaojiang Duan, Zhuochen Zhang, Hongchuang Xu, Jingming Zhang, Yue Yan, Xing Yang","doi":"10.1021/acs.molpharmaceut.4c00858","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00858","url":null,"abstract":"<p><p>Precisely assessing nectin-4 expression in tumors is important in identifying patients who may benefit from nectin-4-targeted therapies. In our previous work, we developed a bicyclic peptide-based nectin-4-targeting radiotracer ⁶⁸Ga-N188 and validated its nectin-4 detection efficacy. However, the relatively short half-life and low positron emission rate of ⁶⁸Ga limit its further application. In this study, we constructed three novel nectin-4-targeting ligands N230-232 based on a bicyclic peptide structure and labeled with radionuclide ¹⁸F, which has a longer half-life and a higher positron emission rate, for PET imaging. Micro-PET/CT imaging-based screening showed that Al¹⁸F-N231 had the best imaging contrast with a tumor-to-muscle ratio of 10.97 ± 2.39. Further characterization demonstrated that ligand N231 had a high affinity to nectin-4 with a <i>K</i>_d of 4.29 nM, and Al¹⁸F-N231 had a good stability and safety profile <i><i>in vivo</i></i>. Biodistribution studies validated the specific binding of Al¹⁸F-N231 to nectin-4 <i>in vivo</i>, with tumor uptake in the nectin-4⁺ SW780 tumor group being 1.45- and 3.75-fold higher than that in the nectin-4^- 5637 tumor group and blocking group, respectively. Based on the results of this work, Al¹⁸F-N231 has promising capability for noninvasive nectin-4 detection <i>in vivo</i>.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798734","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":"FormulationBCS: A Machine Learning Platform Based on Diverse Molecular Representations for Biopharmaceutical Classification System (BCS) Class Prediction.","authors":"Zheng Wu, Nannan Wang, Zhuyifan Ye, Huanle Xu, Ging Chan, Defang Ouyang","doi":"10.1021/acs.molpharmaceut.4c00946","DOIUrl":"10.1021/acs.molpharmaceut.4c00946","url":null,"abstract":"<p><p>The Biopharmaceutics Classification System (BCS) has facilitated biowaivers and played a significant role in enhancing drug regulation and development efficiency. However, the productivity of measuring the key discriminative properties of BCS, solubility and permeability, still requires improvement, limiting high-throughput applications of BCS, which is essential for evaluating drug candidate developability and guiding formulation decisions in the early stages of drug development. In recent years, advancements in machine learning (ML) and molecular characterization have revealed the potential of quantitative structure-performance relationships (QSPR) for rapid and accurate <i>in silico</i> BCS classification. The present study aims to develop a web platform for high-throughput BCS classification based on high-performance ML models. Initially, four data sets of BCS-related molecular properties: log <i>S</i>, log <i>P</i>, log <i>D</i>, and log <i>P</i>_app were curated. Subsequently, 6 ML algorithms or deep learning frameworks were employed to construct models, with diverse molecular representations ranging from one-dimensional molecular fingerprints, descriptors, and molecular graphs to three-dimensional molecular spatial coordinates. By comparing different combinations of molecular representations and learning algorithms, LightGBM exhibited excellent performance in solubility prediction, with an <i>R</i>² of 0.84; AttentiveFP outperformed others in permeability prediction, with <i>R</i>² values of 0.96 and 0.76 for log <i>P</i> and log <i>D</i>, respectively; and XGBoost was the most accurate for log <i>P</i>_app prediction, with an <i>R</i>² of 0.71. When externally validated on a marketed drug BCS category data set, the best-performing models achieved classification accuracies of over 77 and 73% for solubility and permeability, respectively. Finally, the well-trained models were embedded into the first ML-based BCS class prediction web platform (x f), enabling pharmaceutical scientists to quickly determine the BCS category of candidate drugs, which will aid in the high-throughput BCS assessment for candidate drugs during the preformulation stage, thereby promoting reduced risk and enhanced efficiency in drug development and regulation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794048","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":"Novel Use of Manganese Gluconate as a Marker for Visualization of Tablet Dissolution in the Fed Human Stomach Using Magnetic Resonance Imaging.","authors":"Tejal Akbar, Pavel Gershkovich, Konstantinos Stamatopoulos, Penny A Gowland, Snow Stolnik, James Butler, Luca Marciani","doi":"10.1021/acs.molpharmaceut.4c00854","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00854","url":null,"abstract":"<p><p>Magnetic resonance imaging (MRI) of dry or solid materials in the gastrointestinal (GI) tract requires the use of contrast agents to enhance visualization of the dosage forms. In this study, we explore the novel use of manganese gluconate added to tablets. Manganese was released during tablet dissolution, generating a bright \"halo\" effect around the tablets, consistent with shortening of the longitudinal relaxation time of the bulk water surrounding the tablet. This is the first study to use MRI to directly image tablet dissolution in the fed stomach using a manganese gluconate contrast agent as dissolution marker.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783349","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":"Comment on \"Photodynamic Therapy Induced Mitochondrial Targeting Strategies for Cancer Treatment: Emerging Trends and Insights\".","authors":"David Kessel","doi":"10.1021/acs.molpharmaceut.4c00385","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00385","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783347","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":"Reply to \"Comment on 'Photodynamic Therapy Induced Mitochondrial Targeting Strategies for Cancer Treatment: Emerging Trends and Insights'\".","authors":"Vaibhavi Meghraj Desai, Mahima Choudhary, Rajdeep Chowdhury, Gautam Singhvi","doi":"10.1021/acs.molpharmaceut.4c01100","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01100","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783351","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":"Comparison of C-type Nanoantibody Produced in Different Expression Systems Implying Potential Clinical Applications.","authors":"Moxuan Li, Yancheng Zhan, Bihao Wu, Ye Qin, Jiazhao Gao, Lan Liu, Rui Gong","doi":"10.1021/acs.molpharmaceut.4c00980","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00980","url":null,"abstract":"<p><p>In the pharmaceutical industry, the Chinese hamster ovary cell, a type of mammalian cell, is extensively employed for the production of conventional full-length monoclonal antibodies. Nanobody is one of the most attractive directions for the development of next-generation antibody drugs. However, a suitable expression system for its manufacture has not yet been comprehensively evaluated. Previously, we proposed that the immunoglobulin constant CH2 domain could be a promising scaffold for developing C-type nanoantibodies (C-Nabs) as candidate therapeutics. Here, we used an antiviral C-Nab, which we identified previously (under review), as a model for investigation. We expressed C-Nabs without a tag in different systems, including a bacterium (C-Nab_bac), yeast (C-Nab_yeast), and mammalian cell (C-Nab_mam). After purification, the binding and neutralizing activities of C-Nabs from different expression systems are similar. Their secondary structures are rich in β-strand. The melting temperatures of C-Nab_bac (71.5 °C) and C-Nab_mam (70.2 °C) are similar, which are slightly higher than that of C-Nab_yeast (65.6 °C), while C-Nab_yeast and C-Nab_mam are more resistant to urea-induced unfolding than C-Nab_bac. C-Nab_yeast and C-Nab_mam demonstrate higher resistance to aggregation compared to C-Nab_bac. C-Nab_yeast exhibits greater resistance to enzyme digestion compared to C-Nab_bac and C-Nab_mam. Notably, when administered via intraperitoneal injection in mice, C-Nab_yeast shows superior pharmacokinetics. Overall, after comparing C-Nab proteins from various expression systems, we determined that yeast is the most suitable host for producing C-Nabs. This finding is beneficial for the production of nanobodies as potential drug candidates.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764817","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":"Impact of Polymers on the Kinetics of the Solid-State Phase Transition of Piracetam Polymorphs.","authors":"Fanfan Fan, Yi Lu, Shuyuan Xu, Minshan Guo, Ting Cai","doi":"10.1021/acs.molpharmaceut.4c01119","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01119","url":null,"abstract":"<p><p>Metastable polymorphs of active pharmaceutical ingredients can occasionally be used to enhance bioavailability or make processing more convenient. However, the thermodynamic instability of metastable polymorphs poses a severe threat to the quality and performance of the drug products. In this study, we used hot-stage microscopy and powder X-ray diffraction to quantitatively analyze the kinetics of the solid-solid phase transition of piracetam (PCM) polymorphs in the absence and presence of several polymeric excipients. The Forms I and II of PCM are enantiotropically related polymorphs, and the transition point is 75 °C. We found that 1 wt % polymer can strongly affect the transformation rate of Form II to Form I of PCM above 75 °C. PVP K30 has the highest <i>T</i>_g and the strongest inhibitory effect on the transition, whereas PEG has the lowest <i>T</i>_g and the weakest effect on the transition. Below 75 °C, the addition of 1 wt % PEG can decrease the transformation rate from Form I to Form II of PCM by a few orders of magnitude, whereas no phase transition occurs in the presence of the other investigated polymers. The inhibitory effects of the same concentration of polymers on the kinetics of the solid-solid phase transition of piracetam polymorphs are considerably greater than those on the crystallization of PCM from the amorphous phase, especially at low temperatures. We propose that the low segmental mobility of polymers enriched between the crystalline phases can considerably inhibit the nucleation and growth of the stable form at the interface during the phase transition. Our findings deepen the current understanding of the mechanisms underlying the solid-state phase transition of polymorphic drugs in the presence of polymeric excipients, providing a promising formulation approach for stabilizing the metastable pharmaceutical polymorphs.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778734","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":"Using Oscillation to Improve the Insertion Depth and Consistency of Hollow Microneedles for Transdermal Insulin Delivery with Mechanistic Insights.","authors":"Fiona Smith, Anna M Kotowska, Benjamin Fiedler, Edward Cerny, Karmen Cheung, Catrin S Rutland, Faz Chowdhury, Joel Segal, Frankie J Rawson, Maria Marlow","doi":"10.1021/acs.molpharmaceut.4c00942","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00942","url":null,"abstract":"<p><p>Microneedles (MNs) offer the potential for discrete and painless transdermal drug delivery, yet poor insertion and dosing consistency have hindered their clinical translation. Specifically, hollow MNs are appropriate for the administration of liquid modalities, including insulin, which could prove to be beneficial for patients with type 1 diabetes mellitus. This work aimed to design and manufacture a hollow MN with an improved insertion and delivery profile suitable for insulin administration. <i>Ex vivo</i> insertion studies demonstrated that oscillation of MNs upon insertion into skin produced a favorable insertion profile, with reduced variation, compared to static MN insertion. Histological staining showed that this could be due to the repeated motion of the oscillating MN disrupting elastic fibers in the dermis. Additionally, permeation studies demonstrated that increased quantities of insulin were able to permeate the skin when oscillation was employed compared to static MN insertion. This study has shown that oscillation is a valuable tool in improving the transdermal delivery of insulin via a single hollow MN <i>in vitro</i>. Moving forward, <i>in vivo</i> studies should be completed to gain a fuller understanding of the benefits of the oscillation of MNs on transdermal drug delivery.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764847","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":"Highly Water-Soluble Microneedle Patch for Short Wear Time and Rapid Drug Delivery.","authors":"Amy J Wood-Yang, Abishek Sankaranarayanan, Max J Freidlin, Mark R Prausnitz","doi":"10.1021/acs.molpharmaceut.4c01207","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01207","url":null,"abstract":"<p><p>Treatment of acute medical conditions such as pain would benefit from rapid drug delivery and improved ease of administration of local anesthetics that currently have a slow onset of action by topical or oral administration and require expert administration by injection. To address this need, microneedle (MN) patches containing needlelike projections made from a polymer/drug matrix can be painlessly pressed into the skin for local or systemic drug delivery. To improve the speed and ease of drug delivery, we present a rapidly dissolving, highly water-soluble MN patch, which minimizes the wear time to 10 s to improve drug delivery in situations where rapid delivery with simplified administration is needed. MNs were made of polyvinylpyrrolidone (PVP), which is soluble in both water (enabling dissolution in the skin) and polar organic solvents (facilitating coformulation with lidocaine (L)). The addition of a highly water-soluble salt, sodium bicarbonate (NaB), to PVP/L MNs allowed for 60% faster MN dissolution in porcine skin ex vivo. Further addition of citric acid to generate effervescence upon reaction with NaB did not further decrease the MN dissolution time in the pig skin and led to poor shelf-life stability due to premature effervescence during storage. The PVP/L/NaB MNs delivered 23.8 ± 3.5 μg lidocaine to the skin ex vivo, well above the expected dose for local analgesic effect. Our highly water-soluble PVP/L/NaB MN design enables shorter wear time for faster delivery compared to the oral or topical route and easier administration compared to injection currently used for the delivery of drugs needing a rapid onset of action.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764822","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":"Three Strikingly Different Crystal Habits of Tadalafil: Design, Characterization, Pharmaceutical Performance, and Computational Studies.","authors":"Nagesh A Bhale, Saurabh Shah, Avvaru Subha Jahnavi, Arti Vishwakarma, Tejender S Thakur, Sajesh P Thomas, Saurabh Srivastava, Amol G Dikundwar","doi":"10.1021/acs.molpharmaceut.4c00601","DOIUrl":"10.1021/acs.molpharmaceut.4c00601","url":null,"abstract":"<p><p>The present study aims at improving the physicochemical properties of a widely used drug Tadalafil through crystal habit modification, without changing the polymorphic form. Three distinct types of crystal habits, namely, needle, plate, and block, were obtained under controlled crystallization protocols with optimized solvent compositions. Complete characterization of these three crystal habits was carried out using powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy. Morphological features were studied by optical and scanning electron microscopy. Evaluation of the pharmaceutical performance of different crystal habits reveals significant improvement in compressibility and flow properties for the block-shaped crystals in comparison to the needle- and plate-shaped crystals. Also, a more linear tablet compression behavior was noted for the plate and block morphologies of the API compared to their needle counterpart. <i>In vitro</i> dissolution studies showed distinct release profiles for the same API form with different crystal habits, i.e., needle > plate > block. Insights into crystal growth mechanism and the role of solvents in affording the observed crystal habits are presented based on molecular dynamics simulations of intermolecular interactions with crystal facets, in conjunction with the experimental crystal face indexing of the single crystals of different habits. These observations were further supported by interaction topology analysis and the electrostatic features on different crystal facets.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"6234-6244"},"PeriodicalIF":4.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646493","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}