Pharmaceutics最新文献

{"title":"In Vitro Oral Cavity Permeability Assessment to Enable Simulation of Drug Absorption.","authors":"Pankaj Dwivedi, Priyata Kalra, Haiying Zhou, Khondoker Alam, Eleftheria Tsakalozou, Manar Al-Ghabeish, Megan Kelchen, Giovanni M Pauletti","doi":"10.3390/pharmaceutics17070924","DOIUrl":"10.3390/pharmaceutics17070924","url":null,"abstract":"<p><p><b>Background/Objectives:</b> The oral cavity represents a convenient route of administration for drugs that exhibit significant hepatic first-pass extraction. In this study, the mucosal permeation properties of selected active pharmaceutical ingredients (APIs) incorporated into oral cavity drug products that are approved by the U.S. Food and Drug Administration were quantified using the human-derived sublingual HO-1-u-1 and buccal EpiOral™ in vitro tissue models. <b>Methods</b>: Epithelial barrier properties were monitored using propranolol and Lucifer Yellow as prototypic transcellular and paracellular markers. APIs were dissolved in artificial saliva, pH 6.7, and transepithelial flux from the apical to the basolateral compartment was quantified using HPLC. <b>Results</b>: Apparent permeability coefficients (Papp) calculated for these APIs in the sublingual HO-1-u-1 tissue model varied from Papp = 2.72 ± 0.06 × 10^-5 cm/s for asenapine to Papp = 6.21 ± 2.60 × 10^-5 cm/s for naloxone. In contrast, the buccal EpiOral™ tissue model demonstrated greater discrimination power in terms of permeation properties for the same APIs, with values ranging from Papp = 3.31 ± 0.83 × 10^-7 cm/s for acyclovir to Papp = 2.56 ± 0.68 × 10^-5 cm/s for sufentanil. The tissue-associated dose fraction recovered at the end of the transport experiment was significantly increased in the buccal EpiOral™ tissue model, reaching up to 8.5% for sufentanil. <b>Conclusions</b>: Experimental permeation data collected for selected APIs in FDA-approved oral cavity products will serve as a training set to aid the development of predictive computational models for improving algorithms that describe drug absorption from the oral cavity. Following a robust in vitro-in vivo correlation analysis, it is expected that such innovative in silico modeling strategies will the accelerate development of generic oral cavity products by facilitating the utility of model-integrated evidence to support decision making in generic drug development and regulatory approval.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 7","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12298201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clove Oil-Based Nanoemulsion Containing Amphotericin B as a Therapeutic Approach to Combat Fungal Infections.","authors":"Marcel Lucas de Almeida, Ana Paula Dos Santos Matos, Veronica da Silva Cardoso, Tatielle do Nascimento, Ralph Santos-Oliveira, Leandro Machado Rocha, Francisco Paiva Machado, Franklin Chimaobi Kenechukwu, Alane Beatriz Vermelho, Eduardo Ricci-Júnior","doi":"10.3390/pharmaceutics17070925","DOIUrl":"10.3390/pharmaceutics17070925","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Candidiasis, primarily caused by <i>Candida albicans</i>, and sporotrichosis, mainly caused by <i>Sporothrix schenckii</i>, are skin fungal infections that pose serious threats to global health. The <i>Candida auris</i> is a great concern in immunocompromised individuals, and while <i>Sporothrix brasiliensis</i> cause sporotrichosis, an infection commonly found in cats, this disease can be transmitted to humans through scratches or bites. Existing treatments for these fungal infections often cause problems related to resistance and significant side effects. Consequently, development of alternative therapeutic approaches such as nanotechnology-based topical lipid-based formulations is interesting. Thus, the objectives of this study were to prepare clove oil (CO)-in-water nanoemulsions (NEs) containing amphotericin B (AmB) and characterize them with respect to stability, release profile, and in vitro cytotoxic activity against <i>Candida</i> and <i>Sporothrix</i> strains. As a future alternative for the treatment of fungal skin diseases. <b>Methods:</b> Chemical analysis of clove oil was obtained by GC-MS. The NEs were produced using an ultrasound (sonicator) method with varying proportions of CO, Pluronic^® F-127, and AmB. The NEs were characterized by droplet size, morphology, stability and in vitro release profile. The antifungal and cytotoxic activity against <i>C. albicans</i>, <i>C. auris</i>, <i>S. schenckii</i>, and <i>S. brasiliensis</i> were ascertained employing agar diffusion and colorimetric MTT assay methods. A checkerboard assay was carried out using clove oil and amphotericin B against <i>C. auris</i>. <b>Results:</b> Eugenol was the major compound identified in CO at a concentration of 80.09%. AmB-loaded NEs exhibited particle sizes smaller than 50 nm and a polydispersity index below 0.25. The optimal Ne (NEMLB-05) remained stable after 150 days of storage at 4 °C. It exhibited rapid release within the first 24 h, followed by a slow and controlled release up to 96 h. NEMLB-05 more effectively inhibited <i>C. auris</i> compared to free AmB and also demonstrated greater activity against <i>C. albicans</i>, <i>S. schenckii</i>, and <i>S. brasiliensis</i>. Clove oil and amphotericin B presented synergism inhibiting the growth of <i>C. auris</i>. <b>Conclusions:</b> The selected CO-in-water NEs containing AmB demonstrated promising potential as a topical therapeutic alternative for treating fungal infections.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 7","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12300589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triple-Loaded Nanoemulsions Incorporating Coffee Extract for the Photoprotection of Curcumin and Capsaicin: Experimental and Computational Evaluation.","authors":"Nuttapol Boonrueang, Siripat Chaichit, Wipawadee Yooin, Siriporn Okonogi, Kanokwan Kiattisin, Chadarat Ampasavate","doi":"10.3390/pharmaceutics17070926","DOIUrl":"10.3390/pharmaceutics17070926","url":null,"abstract":"<p><p><b>Background/Objectives</b>: This study aims to present a strategic approach to enhancing the photostability and antioxidative resilience of curcumin and capsaicin by integrating selected natural stabilizers within a nanoemulsion-based delivery system. <b>Methods</b>: Coffee extract (<i>Coffea arabica</i> Linn.), along with its active components and vitamin E-containing natural oils, was assessed in terms of improving the photostabilizing and antioxidative retention abilities of curcumin and capsaicin. An optimized ratio of the active mixture was then loaded into a nanoformulation. <b>Results</b>: The analysis of active contents with validated high-performance liquid chromatography (HPLC), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays confirmed the stabilization enhancement after irradiation with UV and white light for 72,000-84,000 lux hours. The optimized combination of coffee extract with turmeric and chili mixtures loaded into the optimized nanoemulsion enhanced the half-lives (T_1/2) of curcumin and capsaicin by 416% and 390%, respectively. The interactions of curcumin and capsaicin with caffeine and chlorogenic acid were elucidated using computational calculations. Interaction energies (E_int), HOMO-LUMO energy gap (HLG) analysis, and global reactivity descriptors revealed hydrogen bonding interactions be-tween capsaicin and chlorogenic acid, as well as between curcumin and caffeine. <b>Conclusions</b>: By leveraging the synergistic antioxidative properties of coffee extract and vitamin E within a nanoemulsion matrix, this study overcomes the intrinsic stability limitations of curcumin and capsaicin, offering a robust platform for future pharmaceutical and nutraceutical applications.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 7","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12299237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tyrosine Kinase Inhibitors for Gastrointestinal Stromal Tumor After Imatinib Resistance.","authors":"Xian-Hao Xiao, Qian-Shi Zhang, Ji-Yuan Hu, Yin-Xu Zhang, He Song","doi":"10.3390/pharmaceutics17070923","DOIUrl":"10.3390/pharmaceutics17070923","url":null,"abstract":"<p><p>Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, primarily driven by activating mutations in KIT (CD117) and platelet-derived growth factor receptor alpha (PDGFRA). The introduction of tyrosine kinase inhibitors (TKIs), especially imatinib, has significantly transformed GIST treatment. However, the emergence of both primary and secondary resistance to imatinib presents ongoing therapeutic challenges. This review comprehensively explores the mechanisms underlying imatinib resistance and evaluates subsequent TKI therapies. Sunitinib, regorafenib, and ripretinib are currently approved as standard second-, third-, and fourth-line therapies, each demonstrating efficacy against distinct mutational profiles. Avapritinib, notably effective against PDGFRA D842V mutations, represents a milestone for previously untreatable subgroups. Several alternative agents-such as nilotinib, masitinib, sorafenib, dovitinib, pazopanib, and ponatinib-have shown varying degrees of success in refractory cases or specific genotypes. Investigational compounds, including crenolanib, bezuclastinib, famitinib, motesanib, midostaurin, IDRX-42, and olverembatinib, are under development to address resistant or wild-type GISTs. Despite progress, long-term efficacy remains limited due to evolving resistance. Future strategies include precision medicine approaches such as ctDNA-guided therapy, rational drug combinations, and novel drug delivery systems to optimize bioavailability and reduce toxicity. Ongoing research will be crucial for refining treatment sequencing and expanding therapeutic options, especially for rare GIST subtypes.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 7","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12298759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Development of a Multilayer Transdermal Patch Platform Based on Electrospun Nanofibers for the Delivery of Caffeine.","authors":"Jorge Teno, Zoran Evtoski, Cristina Prieto, Jose M Lagaron","doi":"10.3390/pharmaceutics17070921","DOIUrl":"10.3390/pharmaceutics17070921","url":null,"abstract":"<p><p><b>Background/Objectives</b>: The work presented herein focused on the development and characterization of a transdermal caffeine platform fabricated from ultrathin micro- and submicron fibers produced via electrospinning. <b>Methods</b>: The formulations incorporated caffeine encapsulated in a polyethylene oxide (PEO) matrix, combined with various permeation enhancers. A backing layer made of annealed electrospun polycaprolactone (PCL) facilitated the lamination of the two layers to form the final multilayer patch. Comprehensive characterization was conducted, utilizing scanning electron microscopy (SEM) to assess the fiber morphology, attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) for chemical detection and to assess the stability of the caffeine, and differential scanning calorimetry (DSC) along with wide-angle X-ray scattering (WAXS) to analyze the physical state of the caffeine within the fibers of the active layer. Additionally, Franz cell permeation studies were performed using both synthetic membranes (Strat-M) and ex vivo human stratum corneum (SC) to evaluate and model the permeation kinetics. <b>Results:</b> These experiments demonstrated the significant role of enhancers in modulating the caffeine permeation rates provided by the patch, achieving permeation rates of up to 0.73 mg/cm² within 24 h. <b>Conclusions:</b> This work highlights the potential of using electro-hydrodynamic processing technology to develop innovative transdermal delivery systems for drugs, offering a promising strategy for enhancing efficacy and innovative therapeutic direct plasma administration.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 7","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12300557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Co-Amorphous Systems for Inhalation Therapy-Part 1: From Model Prediction to Clinical Success.","authors":"Eleonore Fröhlich, Aurora Bordoni, Nila Mohsenzada, Stefan Mitsche, Hartmuth Schröttner, Sarah Zellnitz-Neugebauer","doi":"10.3390/pharmaceutics17070922","DOIUrl":"10.3390/pharmaceutics17070922","url":null,"abstract":"<p><p><b>Background/Objectives</b>: The integration of machine learning (ML) and artificial intelligence (AI) has revolutionized the pharmaceutical industry by improving drug discovery, development and manufacturing processes. Based on literature data, an ML model was developed by our group to predict the formation of binary co-amorphous systems (COAMSs) for inhalation therapy. The model's ability to develop a dry powder formulation with the necessary properties for a predicted co-amorphous combination was evaluated. <b>Methods</b>: An extended experimental validation of the ML model by co-milling and X-ray diffraction analysis for 18 API-API (active pharmaceutical ingredient) combinations is presented. Additionally, one COAMS of rifampicin (RIF) and ethambutol (ETH), two first-line tuberculosis (TB) drugs are developed further for inhalation therapy. <b>Results</b>: The ML model has shown an accuracy of 79% in predicting suitable combinations for 35 APIs used in inhalation therapy; experimental accuracy was demonstrated to be 72%. The study confirmed the successful development of stable COAMSs of RIF-ETH either via spray-drying or co-milling. In particular, the milled COAMSs showed better aerosolization properties (higher ED and FPF with lower standard deviation). Further, RIF-ETH COAMSs show much more reproducible results in terms of drug quantity dissolved over time. <b>Conclusions</b>: ML has been shown to be a suitable tool to predict COAMSs that can be developed for TB treatment by inhalation to save time and cost during the experimental screening phase.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 7","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12299485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantification of Total and Unbound Selinexor Concentrations in Human Plasma by a Fully Validated Liquid Chromatography-Tandem Mass Spectrometry Method.","authors":"Suhyun Lee, Seungwon Yang, Hyeonji Kim, Wang-Seob Shim, Eunseo Song, Seunghoon Han, Sung-Soo Park, Suein Choi, Sungpil Han, Sung Hwan Joo, Seok Jun Park, Beomjin Shin, Donghyun Kim, Hyeon Su Kim, Kyung-Tae Lee, Eun Kyoung Chung","doi":"10.3390/pharmaceutics17070919","DOIUrl":"10.3390/pharmaceutics17070919","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Selinexor is a selective nuclear-export inhibitor approved for hematologic malignancies, characterized by extensive plasma protein binding (>95%). However, a validated analytical method to accurately measure the clinically relevant unbound fraction of selinexor in human plasma has not yet been established. This study aimed to develop a fully validated bioanalytical assay for simultaneous quantification of total and unbound selinexor concentrations in human plasma. <b>Methods:</b> We established and fully validated an analytical method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) capable of quantifying total and unbound selinexor concentrations in human plasma. Unbound selinexor was separated using ultrafiltration, and selinexor was efficiently extracted from 50 μL of plasma by liquid-liquid extraction. Chromatographic separation was achieved on a C18 column using an isocratic mobile phase (0.1% formic acid:methanol, 12:88 <i>v</i>/<i>v</i>) with a relatively short runtime of 2.5 min. <b>Results:</b> Calibration curves showed excellent linearity over a range of 5-2000 ng/mL for total selinexor (r² ≥ 0.998) and 0.05-20 ng/mL for unbound selinexor (r² ≥ 0.995). The precision (%CV ≤ 10.35%) and accuracy (92.5-104.3%) for both analytes met the regulatory criteria. This method successfully quantified selinexor in plasma samples from renally impaired patients with multiple myeloma, demonstrating potential inter-individual differences in unbound drug concentrations. <b>Conclusions:</b> This validated bioanalytical assay enables precise clinical pharmacokinetic assessments in a short runtime using a small plasma volume and, thus, assists in individualized dosing of selinexor, particularly for renally impaired patients with altered protein binding.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 7","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12300842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis Among the Antiproliferative Pathways Activated by a Lipophilic Ruthenium(III) Complex as a Candidate Drug for Triple-Negative Breast Cancer.","authors":"Maria Grazia Ferraro, Federica Iazzetti, Marco Bocchetti, Claudia Riccardi, Daniela Montesarchio, Rita Santamaria, Gabriella Misso, Marialuisa Piccolo, Carlo Irace","doi":"10.3390/pharmaceutics17070918","DOIUrl":"10.3390/pharmaceutics17070918","url":null,"abstract":"<p><p><b>Background/Objectives</b>: In the context of preclinical studies, we have hitherto showcased that a low-molecular-weight ruthenium(III) complex we named AziRu holds significant potential for further developments as an anticancer candidate drug. When appropriately converted into stable nanomaterials and delivered into tumor cells, AziRu exhibits superior antiproliferative activity, benefiting from a multimodal mechanism of action. The activation of regulated cell death (RCD) pathways (i.e., apoptosis and autophagy) has been proved in metastatic phenotypes, including triple-negative breast cancer (TNBC) cells. This study focuses on a bioengineered lipophilic derivative of AziRu, named PalmiPyRu, that we are currently developing as a potential anticancer drug in preclinical studies. When delivered in this way, AziRu confirms a multimodal mechanism of action in effectively blocking the growth and proliferation of TNBC phenotypes. Special focus is reserved for the activation of the ferroptotic pathway as a consequence of redox imbalance and interference with iron homeostasis, as well as the glutathione biosynthetic pathway. <b>Methods</b>: Human preclinical models of specific TNBC phenotypes and healthy cell cultures of different histological origin were selected. After in vitro treatments, cellular responses were carefully analyzed, and targeted biochemical and molecular biology experiments coupled to confocal microscopy allowed us to explore the antiproliferative effects of PalmiPyRu. <b>Results</b>: In this study, we unveil that PalmiPyRu can enter TNBC cells and interfere with both the iron homeostasis and the cystine-glutamate antiporter system Xc-, causing significant oxidative stress and the accumulation of lipid oxidation products. The increase in intracellular reactive free iron and depletion of glutathione engender a lethal condition, driving cancer cells toward the activation of ferroptosis. <b>Conclusions</b>: Overall, these outcomes allow us, for the first time, to couple the antiproliferative effect of a ruthenium-based candidate drug with the inhibition of the Xc- antiporter system and Fenton chemistry, thereby branding PalmiPyRu as an effective multimodal inducer of ferroptosis. Molecular mechanisms of action deserve further investigations, and new studies are underway to uncover how interference with Xc- controls cell fate, allowing us to explore the connection between iron metabolism regulation, oxidative stress and RCD pathways activation.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 7","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12300231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144743976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Evaluation of [¹⁸F]AlF-NOTA-iPD-L1 as a Potential Theranostic Pair for [¹⁷⁷Lu]Lu-DOTA-iPD-L1.","authors":"Guillermina Ferro-Flores, Myrna Luna-Gutiérrez, Blanca Ocampo-García, Nallely Jiménez-Mancilla, Nancy Lara-Almazán, Rigoberto Oros-Pantoja, Clara Santos-Cuevas, Erika Azorín-Vega, Laura Meléndez-Alafort","doi":"10.3390/pharmaceutics17070920","DOIUrl":"10.3390/pharmaceutics17070920","url":null,"abstract":"<p><p><b>Background/Objective</b>: Programmed cell death ligand-1 (PD-L1), which is overexpressed in certain tumors, inhibits the body's natural immune response by providing an \"off\" signal that enables cancer cells to evade the immune system. It has been demonstrated that [¹⁷⁷Lu]Lu-DOTA-iPD-L1 (PD-L1 inhibitor cyclic peptide) promotes immune responses. This study aimed to synthesize and evaluate [¹⁸F]AlF-NOTA-iPD-L1 as a novel radiotracer for PD-L1 positron emission tomography (PET) imaging and as a potential theranostic pair for [¹⁷⁷Lu]Lu-DOTA-iPD-L1. <b>Methods</b>: The NOTA-iPD-L1 peptide conjugate was synthesized and characterized by U.V.-vis, I.R.-FT, and UPLC-mass spectroscopies. Radiolabeling was performed using [¹⁸F]AlF as the precursor, and the radiochemical purity (HPLC), partition coefficient, and serum stability were assessed. Cellular uptake and internalization (in 4T1 triple-negative breast cancer cells), binding competition, immunofluorescence, and Western blot assays were applied for the radiotracer in vitro characterization. Biodistribution in mice bearing 4T1 tumors was performed, and molecular imaging (Cerenkov images) of [¹⁸F]AlF-NOTA-iPD-L1 and [¹⁷⁷Lu]Lu-DOTA-iPD-L1 in the same mouse was obtained. <b>Results</b>: [¹⁸F]AlF-NOTA-iPD-L1 was prepared with a radiochemical purity greater than 97%, and it demonstrated high in vitro and in vivo stability, as well as specific recognition by the PD-L1 protein (IC₅₀ = 9.27 ± 2.69 nM). Biodistribution studies indicated a tumor uptake of 6.4% ± 0.9% ID/g at 1-hour post-administration, and Cerenkov images showed a high tumor uptake of both [¹⁸F]AlF-NOTA-iPD-L1 and ¹⁷⁷Lu-iPD-L1 in the same mouse. <b>Conclusions</b>: These results warrant further studies to evaluate the clinical usefulness of [¹⁸F]AlF-NOTA-iPD-L1/[¹⁷⁷Lu]Lu-DOTA-iPD-L1 as a radiotheranostic pair in combination with anti-PD-L1/PD1 immunotherapy.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 7","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12298754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically Based Pharmacokinetic Simulation of Tofacitinib in Humans Using Extrapolation from Single-Species Renal Failure Model.","authors":"Sung Hun Bae, So Yeon Park, Hyeon Gyeom Choi, So Hee Kim","doi":"10.3390/pharmaceutics17070914","DOIUrl":"10.3390/pharmaceutics17070914","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Tofacitinib is a Janus kinase 1 and 3 inhibitor that was developed to treat rheumatoid arthritis. Accordingly, this study aimed to predict plasma tofacitinib concentrations and pharmacokinetic parameters in patients with renal failure through physiologically based pharmacokinetic (PBPK) simulations. <b>Methods</b>: PK-Sim and Simcyp simulators were used, as well as conventional Dedrick plot analysis, employing a single animal extrapolation method. The predictions were compared with previously published data. <b>Results:</b> PBPK simulations of tofacitinib in patients with renal failure closely matched the observed plasma concentration profiles and pharmacokinetic results, including the area under the plasma concentration-time curve (AUC), maximum plasma concentration (<i>C</i>_max), and time to reach <i>C</i>_max (<i>T</i>_max). The ratios of the simulated to observed plasma concentrations and pharmacokinetic parameters for tofacitinib were within a 0.5-2.0-fold error range. Although the results from the Dedrick plot were reasonably good, they were less accurate than those of the PBPK simulations. This was because the Dedrick plot relied solely on preclinical plasma concentration data without incorporating drug physicochemical properties, in vitro data, or physiological and pathophysiological variables. <b>Conclusions</b>: The findings suggest that PBPK simulations using single-species extrapolation effectively provide preliminary estimates of plasma tofacitinib concentration profiles and pharmacokinetic parameters in humans under specific conditions, including renal failure. Furthermore, the results provide a foundation for adjusting tofacitinib dosage and dosing schedules to maintain effective plasma concentrations by considering the pathophysiological characteristics of patients according to their specific diseases.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 7","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12299188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}