Molecular Pharmaceutics最新文献

{"title":"E-Urea-K-Based PSMA Imaging Served as an Alternative in Assessing Tumor Neovascularization via Targeting CD31.","authors":"Lan Wang, Shengnan Ren, Jingjing Lou, Shuai Xue, Pan Zhou, Xiaobei Zheng, Fengling Shan, Xiao Li, Yangchun Chen, Xingdang Liu","doi":"10.1021/acs.molpharmaceut.4c01252","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01252","url":null,"abstract":"<p><p>To reveal the natural correlation between prostate-specific membrane antigen (PSMA) imaging and tumor neovascularization in prostate cancer and further explore E-urea-K-based PSMA-targeted (EK-PSMA) imaging as a potential indicator of tumor neovascularization, the 22Rv1 mouse models were established and underwent ^99mTc-HYNIC-ALUG SPECT/CT. Pearson correlation analysis was applied to assess the relationship between tumor tracer uptake and tumor characteristics, including size, glucose metabolism, and cell phenotypes (e.g., Ki-67, VEGF, CD31, and PSMA). Then, molecular docking further identified the key factors of EK-PSMA imaging, specifically related to tumor neovascularization. Finally, animal models with positive and negative PSMA expression (22Rv1, LNCaP, U87, SAOS-2, A549, and ACHN) were subjected to antibody-targeted blockade to verify the role of these key factors in EK-PSMA imaging. The Pearson's <i>r</i> values of tracer uptake correlated with CD31 and tumor size were 0.82 and 0.99, respectively (<i>P</i> < 0.05), and the correlations of tracer uptake with SUV_max, SUV_mean, Ki-67, VEGF, and PSMA expressions were 0.47, 0.20, 0.69, -0.65, and 0.20, respectively (all <i>P</i> > 0.05). Molecular docking confirmed the affinity of E-urea-K to PSMA (two sites, binding scores, -5.4 kcal/mol and -6.0 kcal/mol) and CD31 (one site, binding score, -5.1 kcal/mol). The blockade of the CD31 antibody partially reduced the ^99mTc-HYNIC-ALUG uptake in five other types of tumors (paired <i>t</i> test, <i>P</i> = 0.0478). The Pearson's <i>r</i> value of CD31 staining and tracer uptake prior to the antibody blockade was 0.84 (<i>P</i> < 0.05). Additionally, when removing the PSMA-positive models (22Rv1 and LNCaP), the Pearson's <i>r</i> value of CD31 staining and tracer uptake prior to the antibody blockade was 0.99 (<i>P</i> < 0.05). Thus, CD31 was found to be a mutual target of EK-PSMA imaging; therefore, EK-PSMA imaging provides a viable assessment option for tumor neovascularization, especially for PSMA-negative tumors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514145","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":"Amphiphilic Acyclic Cucurbit[<i>n</i>]uril: Synthesis, Self-Assembly, and Chemotherapeutic Delivery to Overcome Multidrug Resistance.","authors":"Zizhen Zhao, Danying Ma, Shuyi Wang, Wei Zhou, Dan-Wei Zhang, Zhan-Ting Li, Da Ma","doi":"10.1021/acs.molpharmaceut.5c00012","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00012","url":null,"abstract":"<p><p>A new amphiphilic acyclic cucurbit[<i>n</i>]uril (CB[<i>n</i>]) is designed and synthesized. This amphiphilic acyclic CB[<i>n</i>] could encapsulate pharmaceutical drugs via a host-guest interaction. Self-assembly of this acyclic CB[<i>n</i>] forms spherical nanoparticles with diameters of 91 nm in water. The self-assembled nanoparticles are capable of delivering doxorubicin with high efficiency. Cell experiments show that the doxorubicin-loaded nanoparticles can improve cellular uptake and cytotoxicity by using the MCF-7/ADR cell line. The A549 tumor-bearing mouse model shows that self-assembled nanoparticles help overcome multidrug resistance in vivo. Cell study and histological assays confirm the biocompatibility of self-assembled nanoparticles.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514138","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 and Evaluation of ⁶⁸Ga-Labeled TMTP1-Based Cyclic Peptide Probes for Targeting Hepatocellular Carcinoma.","authors":"Yesen Li, Yanjie Wang, Yaoxuan Wang, Jinxiong Huang, Zhide Guo","doi":"10.1021/acs.molpharmaceut.4c01123","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01123","url":null,"abstract":"<p><p>This study focused on the development and evaluation of four [⁶⁸Ga]-labeled cyclic TMTP1 peptide-based probes for targeting highly metastatic hepatocellular carcinoma (HCC). The probes─[⁶⁸Ga]Ga-N-G-NVvRQ, [⁶⁸Ga]Ga-c[K(N)NVvRQ], [⁶⁸Ga]Ga-c[K(N)NVVRQ], and [⁶⁸Ga]Ga-c[K(N)NVvRQ]₂─were designed using a head-to-tail cyclization strategy to enhance their stability, improve tumor targeting, and reduce uptake in nontarget organs. The microPET imaging results showed that although tumor uptake for all four probes was similar at each time point, renal evaluation revealed that [⁶⁸Ga]Ga-c[K(N)NVvRQ] had the lowest value at 15 min (1.90 ± 0.87%ID/g), significantly outperforming linear analog [⁶⁸Ga]Ga-N-G-NVvRQ (2.87 ± 0.86%ID/g) and dimeric peptide, [⁶⁸Ga]Ga-c[K(N)NVvRQ]₂ (3.92 ± 0.68%ID/g), and the probe exhibited the lowest physiological uptake across major organs. At 30 min, the liver uptake of [⁶⁸Ga]Ga-c[K(N)NVvRQ] was 0.29 ± 0.08%ID/g, with a tumor-to-liver (T/L) ratio of 2.45 ± 0.03. This low nonspecific uptake in normal organs contributed to high-contrast PET imaging, facilitating the diagnosis of small tumor lesions. In addition, the probe demonstrated sustained low renal radioactivity retention, which may offer potential benefits for minimizing additional radioactive damage to the kidneys. Overall, [⁶⁸Ga]Ga-c[K(N)NVvRQ] achieved a good balance between strong tumor uptake and low nonspecific uptake in organs (especially in kidneys), making it an ideal candidate for further investigation in HCC imaging applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490333","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":"Monitoring Sorafenib Resistance and Efficacy in Hepatocellular Carcinoma Using [¹⁸F]Alfatide II and [¹⁸F]Fluorodeoxyglucose Positron Emission Tomography.","authors":"Guanyun Wang, Yue Pan, Lingling Zheng, Xiaojun Zhang, Huanhuan Liu, Yanfeng Xu, Wenwen Zhang, Xiaohui Luan, Xiaojie Liu, Xiaodan Xu, Shina Wu, Guangyu Ma, Ying Kan, Jinming Zhang, Ruimin Wang, Jigang Yang","doi":"10.1021/acs.molpharmaceut.4c01218","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01218","url":null,"abstract":"<p><p>Integrin αvβ3 expression is associated with sorafenib resistance in hepatocellular carcinoma (HCC). Therefore, monitoring its expression in HCC may serve as a valuable indicator of the efficacy of sorafenib treatment. In this study, longitudinal positron emission tomography (PET) was performed to assess [¹⁸F]Alfatide II and [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) as suitable probes for evaluating the treatment efficacy of sorafenib in a Huh-7 human (HCC) xenograft model. Huh-7 tumor cells were used to establish both normal and sorafenib-resistant cell lines, and xenograft models were developed. The mice were categorized into four groups based on the cell type and treatment: normal nontreatment, normal treatment, sorafenib-resistant nontreatment, and sorafenib-resistant treatment. Huh-7 tumor mice received intragastric injections of sorafenib (30 mg/kg/day) or vehicle for 15 consecutive days. Tumor size and weight were assessed throughout the study. Longitudinal microPET/computed tomography (CT) scans with [¹⁸F]Alfatide II and [¹⁸F]FDG were acquired to quantitatively measure angiogenesis on days -2, 3, 7, and 14 and metabolism on days -1, 4, 8, and 15 following therapy initiation. The tumor uptake (ID%/g_mean) of each probe was calculated. No significant difference in [¹⁸F]FDG uptake was observed between the normal and sorafenib-resistant groups (<i>P</i> = 0.452); however, [¹⁸F]Alfatide II uptake differed significantly between the two groups (<i>P</i> < 0.001). Sorafenib successfully inhibited normal Huh-7 tumor growth, inducing significant differences in tumor size 9 days after sorafenib treatment (<i>P</i> < 0.05). The uptake of [¹⁸F]Alfatide II in the tumor lesions changed significantly on day 14 (<i>P</i> = 0.001). However, no change was observed in the uptake of [¹⁸F]FDG (<i>P</i> > 0.05). The PET imaging data of [¹⁸F]Alfatide II and [¹⁸F]FDG were validated through <i>ex vivo</i> immunohistochemistry analysis targeting integrin αvβ3, VEGF, and GULT-1. [¹⁸F]Alfatide II PET was more effective in monitoring sorafenib resistance and therapeutic efficacy in the Huh-7 human HCC xenograft model than [¹⁸F]FDG.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481733","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":"Chitosan-Coated Silver Nanourchins for Imatinib Mesylate Delivery: Biophysical Characterization, <i>In-Silico</i> Profiling, and Anti-Colon Cancer Efficacy.","authors":"Sankha Bhattacharya, Aalind Joshi, Vishal Beldar, Ashwani Mishra, Satyam Sharma, Rehan Khan, Mohammad Rashid Khan","doi":"10.1021/acs.molpharmaceut.4c01241","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01241","url":null,"abstract":"<p><p>This study investigates the synthesis and characterization of silver nanourchins coated with chitosan (IMT-CS-AgNUs) as a novel platform for the delivery of imatinib mesylate (IMT) for the treatment of colon cancer. <i>In-silico</i> analysis discovered 10 key metabolites for IMT, which have associated respiratory and neurotoxic risks. Molecular docking studies showed the high affinity binding of IMT to critical proteins, including BCL2 (-6.637 kcal/mol), Caspase-6, and EGFR, which proved its potential therapeutic value. IMT-CS-AgNUs were prepared by ionic gelation, and the nanoparticles had a size of 192.98 nm, with an entrapment efficiency of 85.7%. The FTIR and XRD structural characterization confirmed that the nanocarriers were stable and amorphous in nature. In vitro studies of HCT116 cells showed significantly increased cytotoxicity with an IC50 of 0.4 μg/mL; apoptosis by 42.5% and ROS generation by 47.8% when compared to only IMT. The release of drugs from the nanoparticles was sustained over 85% over 60 h, selectively inhibited pathogenic bacteria without harming beneficial microbes, and showed antiangiogenic activity, which is validated through the HET-CAM assay. Gene expression analyses showed that there was marked downregulation of BCL2 and upregulation of apoptotic genes. Pharmacokinetic studies in Wistar rats showed improved bioavailability by 1.8, which allows targeted drug concentrations in the colon with lessened systemic toxicity. Thus, the development of IMT-CS-AgNUs represents a potent approach for targeted colon therapy against cancer, providing therapeutic efficacy, controlled drug release, and added safety.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471996","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":"Mucin Mimics and Impacts the Function of Polymeric Inhibitors in Stabilizing Drug Supersaturation.","authors":"Victus Kordorwu, Steven Castleberry, Steve Lustig, Rebecca L Carrier","doi":"10.1021/acs.molpharmaceut.4c01102","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01102","url":null,"abstract":"<p><p>Many drugs entering clinical trials today are poorly water-soluble and rely on supersaturating formulations, such as amorphous solid dispersions (ASD) to enhance their bioavailability. The <i>in vivo</i> performance of these formulations is often investigated through biorelevant dissolution testing using simulated intestinal fluid. Often overlooked in biorelevant dissolution is the presence of mucus within the intestinal environment and its possible role in affecting the formulation performance. In this study, the impact of mucins, the main structural glycoproteins of mucus, on the precipitation of two model compounds, carvedilol and nifedipine, from supersaturated solutions was investigated. The presence of mucin within the supersaturated environment was demonstrated to significantly alter the rate of drug precipitation <i>in vitro</i>. The impact of mucin on precipitation was then compared to commercially available polymer precipitation inhibitors hydroxypropyl methylcellulose (HPMC) and Kollidon VA 64, which are commonly used in ASD formulations. Surprisingly, when present at the same concentration (0.2% (w/v)), mucin reduces drug precipitation to an extent comparable to that of polymer precipitation inhibitors. Additionally, we observed that the presence of mucin in the supersaturated environment altered the precipitation inhibitory effects of HPMC and Kollidon VA64, suggesting that mucin could play an important and complicated role in formulation performance in the intestine.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466574","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":"Meta-Analysis of Permeability Literature Data Shows Possibilities and Limitations of Popular Methods.","authors":"Kateřina Storchmannová, Martin Balouch, Jakub Juračka, František Štěpánek, Karel Berka","doi":"10.1021/acs.molpharmaceut.4c00975","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00975","url":null,"abstract":"<p><p>Permeability is an important molecular property in drug discovery, as it co-determines pharmacokinetics whenever a drug crosses the phospholipid bilayer, e.g., into the cell, in the gastrointestinal tract, or across the blood-brain barrier. Many methods for the determination of permeability have been developed, including cell line assays (CACO-2 and MDCK), cell-free model systems like parallel artificial membrane permeability assay (PAMPA) mimicking, e.g., gastrointestinal epithelia or the skin, as well as the black lipid membrane (BLM) and submicrometer liposomes. Furthermore, many in silico approaches have been developed for permeability prediction: meta-analysis of publicly available databases for permeability data (MolMeDB and ChEMBL) was performed to establish their usability. Four experimental and two computational methods were evaluated. It was shown that repeatability of the reported permeability measurement is not great even for the same method. For the PAMPA method, two different permeabilities are reported: intrinsic and apparent. They can vary in degrees of magnitude; thus, we suggest being extra cautious using literature data on permeability. When we compared data for the same molecules using different methods, the best agreement was between cell-based methods and between BLM and computational methods. Existence of unstirred water layer (UWL) permeability limits the data agreement between cell-based methods (and apparent PAMPA) with data that are not limited by UWL permeability (computational methods, BLM, intrinsic PAMPA). Therefore, different methods have different limitations. Cell-based methods provide results only in a small range of permeabilities (-8 to -4 in cm/s), and computational methods can predict a wider range of permeabilities beyond physical limitations, but their precision is therefore limited. BLM with liposomes can be used for both fast and slow permeating molecules, but its usage is more complicated than standard transwell techniques. To sum up, when working with in-house measured or published permeability data, we recommend caution in interpreting and combining them.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466573","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 ¹⁸F-Labeled Radioligand for Imaging Phosphodiesterase 7 with Positron Emission Tomography.","authors":"Jian Rong, Chunyu Zhao, Ahmad F Chaudhary, Evan Jones, Richard Van, Zhendong Song, Yinlong Li, Jiahui Chen, Xin Zhou, Jimmy S Patel, Yabiao Gao, Zhenkun Sun, Siyan Feng, Zachary Zhang, Thomas L Collier, Chongzhao Ran, Achi Haider, Yihan Shao, Hongjie Yuan, Steven H Liang","doi":"10.1021/acs.molpharmaceut.4c01379","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01379","url":null,"abstract":"<p><p>Phosphodiesterases (PDEs) are phosphohydrolytic enzymes responsible for degrading cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), two key second messengers involved in regulating cellular functions. The PDE superfamily can be subdivided into 11 families, with PDE7 playing a crucial role in the proinflammatory process, T-cell activation and proliferation. As such, PDE7 has emerged as a potential therapeutic target for treating inflammatory, immunological, and neurological disorders. To date, only a limited number of PDE7 PET ligands have been reported. These ligands often suffer from low <i>in vivo</i> stability or moderate binding affinity, underscoring the need for highly specific PET radioligands for imaging PDE7 <i>in vivo</i>. Here, we report the development of [¹⁸F]<b>7</b> ([¹⁸F]P7-2302<b>)-</b>a highly potent (IC₅₀ = 0.18 nM) and selective (>400 folds over other PDEs) PDE7 PET ligand. <i>In vitro</i> autoradiography studies using rat brain sections revealed high PDE7-specific binding for [¹⁸F]<b>7</b>. Notwithstanding these encouraging findings, PET imaging experiments in rats demonstrated low brain uptake of [¹⁸F]<b>7</b>, potentially owing to brain efflux mechanism. Indeed, <i>in vivo</i> studies with combined P-gp and BCRP inhibition substantially improved brain uptake and enabled us to demonstrate <i>in vivo</i> binding specificity of [¹⁸F]<b>7</b> with PDE<b>7-</b>targeted blockade. Overall, [¹⁸F]<b>7</b> ([¹⁸F]P7-2302<b>)</b> exhibits promising pharmacological properties and chemical scaffold which holds potential as a PDE7-specific PET radioligand, though further work is required to enhance blood-brain barrier permeability.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456277","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":"Optimizing Andrographolide from Sambiloto Leaves (<i>Andrographis paniculata</i>) Using Cyclodextrin Metal-Organic Frameworks for Targeted Pulmonary Delivery via a Metered Dose Inhaler: A Proof-Of-Concept Study.","authors":"Muhammad Ammar Syauqi, Andi Zafirah Burhanuddin, Azzahra Putri Utami Muharam, Ni'mah Azizah, Caesar Putra Gattang, Andi Dian Permana","doi":"10.1021/acs.molpharmaceut.4c00967","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00967","url":null,"abstract":"<p><p><i>Andrographis paniculata</i> is recognized for its numerous applications in the pharmaceutical industry. The primary compound of this plant, andrographolide (AG), has demonstrated potent antibacterial properties, including against <i>K. pneumoniae</i>. However, its poor solubility limits its bioavailability. To address this, the creation of an inclusion complex (IC) using cyclodextrin (CD) and Metal-Organic Frameworks (MOFs) offers a promising solution for improving AG's solubility and bioavailability. The AG-CD-MOFs are intended to be delivered via a metered dose inhaler (MDI), allowing for direct targeting of lung tissue. This research focuses on designing AG encapsulated within CD-MOFs to boost solubility and enhance drug efficacy when delivered directly to the lungs via an MDI. Computational molecular modeling indicated that γ-CD is the most suitable host molecule for forming an inclusion complex (IC) with AG, surpassing α-CD and β-CD. The optimal AG to γ-CD ratio for the IC is 1:2 (w/w), with a particle size of 534.53 ± 49.11 nm, a PDI of 0.121 ± 0.01, an encapsulation efficiency (EE) of 89.45 ± 7.03%, and a drug loading (DL) of 26.09 ± 2.87%. The IC exhibits strong antibacterial activity comparable to AG crystal-DMSO, highlighting the importance of solubility in AG's antibacterial efficacy. Additionally, drug release studies revealed that the IC's release profile is nearly nine times greater than that of the AG crystal. In vivo studies further demonstrated the high selectivity of the MDI for lung tissue delivery compared to injection and oral administration, with drug concentrations of 7.44 ± 0.57 μg/mL, 1.52 ± 0.23 μg/mL, and 1.5 ± 0.16 μg/mL, respectively. Moreover, the MDI AG-CD-MOFs exhibited sustained-release properties, maintaining a drug concentration of 5.27 ± 0.75 μg/mL in lung tissue for up to 48 h, significantly higher than injection and oral administration, which only maintained concentrations of 1.52 ± 0.23 μg/mL and 1.50 ± 0.16 μg/mL at 8 h, respectively. The developed formulation shows high selectivity to lung tissue and shows sustained-release behavior. The formula was deemed safe based on in vitro hemolysis and irritation risk tests and did not cause inflammation in lung tissue, as confirmed by histopathology studies. Furthermore, in vivo studies are strongly recommended to validate this therapy and improve pneumonia treatment options.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447415","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":"Targeted Oral Fixed-Dose Combination of Amphotericin B-Miltefosine for Visceral Leishmaniasis.","authors":"Raquel Fernández-García, David Walsh, Peter O'Connell, Luiz Felipe D Passero, Jéssica A de Jesus, Marcia Dalastra Laurenti, María Auxiliadora Dea-Ayuela, M Paloma Ballesteros, Aikaterini Lalatsa, Francisco Bolás-Fernández, Anne Marie Healy, Dolores R Serrano","doi":"10.1021/acs.molpharmaceut.4c01133","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01133","url":null,"abstract":"<p><p>The incidence of visceral leishmaniasis (VL) remains a significant health threat in endemic countries. Fixed-dose combination (FDC) of amphotericin B (AmB) and miltefosine (MLT) is a promising strategy for treating VL, but the parenteral administration of AmB leads to severe side effects, limiting its use in clinical practice. Here, we developed novel FDC granules combining AmB in the core with a MLT coating using wet granulation followed by the fluidized bed technology. The granules maintained the crystalline structure of AmB throughout manufacturing, achieving an AmB loading of ∼20%. The MLT coating layer effectively sustained AmB release from 3 to 24 h following Korsmeyer-Peppas kinetics. The formulation demonstrated remarkable stability, maintaining >90% drug content for over a year at both 4 °C and room temperature under desiccated conditions. In vivo efficacy studies in <i>Leishmania infantum</i><i>-</i>infected hamsters showed 65-80% reduction in parasite burden in spleen and liver, respectively, suggesting potential as an oral alternative to current VL treatments. Uncoated and coated granules demonstrated comparable performance in key aspects, including <i>in vivo</i> efficacy and long-term stability.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439392","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}