Molecular Pharmaceutics最新文献

{"title":"Anthraquinone Rhein Mitigates Heavy Ion Radiation-Induced Lung Injury by Maintaining Thioredoxin Reductase/Thioredoxin (TrxR/Trx) Redox Homeostasis.","authors":"Yaxiong Chen, Jufang Wang, Xiedong Zhou, Cui Xu, Dan Xu, Qingfeng Wu, Junmin Zhang, Jianguo Fang","doi":"10.1021/acs.molpharmaceut.5c00678","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00678","url":null,"abstract":"<p><p>While heavy ion radiation, particularly carbon-ion therapy exploits high linear energy transfer (LET) radiation for precise tumor targeting through DNA/oxidative damage, its concomitant toxicity to adjacent normal tissues remains a critical limitation. Here, we investigated the radioprotective potential of Rhein, a natural anthraquinone derivative, in ionizing radiation-irradiated lung cells and murine models. In vitro, Rhein pretreatment enhanced cell viability and clonogenic survival, mitigated DNA damage (evidenced by reduced γ-H2AX foci and micronucleus formation), attenuated reactive oxygen species (ROS) generation, and maintained mitochondrial membrane potential during X-irradiation and carbon-ion treatment. Molecular docking analysis indicated that Rhein binding to wild-type or mutant TrxR occurred without substantially changing docking sites, suggesting that Rhein likely interacts with a stable binding pocket distinct from the active sites. Significantly, the protective action of Rhein was not evident in thioredoxin reductase knockdown cells, suggesting the participation of an intact thioredoxin reductase/thioredoxin (TrxR/Trx) system. In <i>vivo</i>, Rhein pretreatment extended survival of heavy-ion radiation-irradiated mice and corrected the redox homeostasis of lung tissue by up-regulating reduced thioredoxin (Red-Trx) and down-regulating oxidized thioredoxin (Ox-Trx). These findings suggest that Rhein offers radioprotection against heavy-ion radiation-induced lung damage through modulating TrxR/Trx redox homeostasis, which suggests its potential as a radioprotective agent in heavy-ion therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147186","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":"Drug Delivery Systems for Overcoming Physical Barriers in Cancer Therapy.","authors":"Xiaofen Yi, Xiangyu Jin, Ying Hu, Zhuowei Shen, Xiaochun Zheng, Dan Luo, Tong Xu, Jieping Yan, Ping Huang","doi":"10.1021/acs.molpharmaceut.5c00474","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00474","url":null,"abstract":"<p><p>The efficacy of cancer therapy largely depends on the ability of drugs to penetrate the tumor tissues. However, therapeutic outcomes are often limited by formidable physical barriers in the tumor microenvironment (TME), including the blood-brain barrier (BBB), vascular barriers, extracellular matrix (ECM), elevated interstitial fluid pressure (IFP), and solid stress (SS). These barriers collectively restrict drug penetration, reducing the treatment effectiveness. Drug delivery systems (DDSs) have emerged as promising strategies to enhance drug penetration and distribution within tumors by overcoming these physical barriers. This review provides an in-depth examination of the characteristics of TME physical barriers and their impact on therapy as well as DDSs designed to overcome these barriers and improve drug delivery efficiency. Additionally, we discuss nanomaterials that have successfully reached the market or clinical trial phase, highlighting their challenges and significance. Overall, this review aims to inform and inspire the development of more effective DDSs, guiding future research and clinical applications to optimize tumor penetration and therapeutic outcomes.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147233","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":"BIOMEMS for Therapeutics and Sensing: Advances in Drug Delivery, Diagnostics, and Microfluidics.","authors":"Omnia M Sarhan, Mostafa I Gebril, Esraa E H Yahia, Shimaa M Ali, Tasneem A A Abo-Ghazala, Mariam M Ahmed, Mirna S Adbul-Latif, Yomna A Moussa","doi":"10.1021/acs.molpharmaceut.5c00724","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00724","url":null,"abstract":"<p><p>Biomedical micro-electromechanical systems (BIOMEMS) exemplify the fusion of microscale engineering with biological science, applying MEMS technology to enhance medical procedures, especially drug delivery. These platforms are engineered to deliver highly accurate and tightly controlled dosing, a necessity for treatments with narrow therapeutic margins. This review examines the major developments in BIOMEMS and their instrumental role in advancing drug delivery technologies. It organizes these devices into two primary categories: passive systems, which rely on diffusion or material degradation for drug release, and active systems, which use on-board pumps or other actuators for programmable delivery. Core elements covered include micropumps, microreservoirs, microsensors, microfluidic channels, and the associated control circuitry. The article also discusses the key fabrication methods and material choices that underpin state-of-the-art BIOMEMS. It compares silicon-based microfabrication, polymeric molding techniques, and the incorporation of biocompatible metals, each of which influences the mechanical integrity and functionality of the final device. Ultimately, the rise of BIOMEMS in drug delivery marks a shift toward more precise, controllable therapeutic strategies. To capitalize on this potential, engineers and researchers must refine release profiles to boost clinical outcomes and treatment efficacy. Future work should concentrate on advancing microfabrication processes and developing intelligent materials that will drive the next generation of BIOMEMS innovation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147214","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":"Synthesis and Biological Evaluation of a Novel ⁶⁸Ga-Labeled Ubiquicidin 29-41 Complex for PET Imaging of Bacterial Infections.","authors":"Yuhao Jiang, Qianna Wang, Xiaojiang Duan, Junhong Feng, Guangxing Yin, Peiwen Han, Qing Ruan, Ziqing Zhao, Jianyong Jiang, Junbo Zhang","doi":"10.1021/acs.molpharmaceut.5c00988","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00988","url":null,"abstract":"<p><p>The persistent challenge of bacterial infections in clinical practice necessitates the development of precise diagnostic tools capable of differentiating infectious and inflammatory processes. This study presents the development and evaluation of [⁶⁸Ga]Ga-NOTA-UBI 29-41, a novel PET radiotracer designed for specific bacterial infection imaging. The tracer was synthesized through ⁶⁸Ga-labeling of a NOTA-conjugated ubiquicidin 29-41 derivative, demonstrating excellent radiochemical properties and good <i>in vitro</i> stability in both saline and mouse serum. <i>In vitro</i> binding assays confirmed specific targeting of <i>Staphylococcus aureus</i>, while <i>in vivo</i> studies in mice models revealed significantly higher uptake in infected versus inflamed muscle tissue (<i>p</i> < 0.01). MicroPET imaging further validated the tracer's ability to selectively accumulate at infection sites, with pharmacokinetic analysis showing predominant renal clearance and rapid blood clearance kinetics. These findings collectively demonstrate the potential of [⁶⁸Ga]Ga-NOTA-UBI 29-41 as a clinically translatable agent for accurate discrimination between bacterial infections and sterile inflammation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147164","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":"\"Bigger, the Better?\"─The Influence of Sugar Size and Residual Moisture on Protein Stability and Accessibility in Lyophilizates.","authors":"Ken Lo Presti, Wolfgang Frieß","doi":"10.1021/acs.molpharmaceut.5c00596","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00596","url":null,"abstract":"<p><p>Lyophilization is a key technology to improve the long-term stability of protein drug products, traditionally using the disaccharides sucrose and trehalose for cryo- and lyoprotection. Monosaccharides are less favored due to the low glass transition temperature and Maillard reaction potential. Additionally, trisaccharides and tetrasaccharides typically do not play significant roles, as they are often not approved for parenteral use and have been associated with lower protein stabilization. Key stability parameters include the preserved protein structure, solid-state accessibility, and monomer content. This study explores the long-term monomer retention of human serum albumin (HSA) in lyophilizates at 2-8, 25, and 40 °C by investigating the effect of a series of mono- to tetrasaccharides based on glucose (glucose, maltose, maltotriose, and maltotetraose) as well as glucose maltose and glucose maltotriose mixtures. We varied the residual moisture (RM) content (1, 1.5, and 2%) postlyophilization to understand the effects of water replacement, vitrification, and matrix mobility on protein stability. The molar ratios of maltose to HSA were set at 360:1 and 180:1 to investigate the impact of the sugar concentration at overall low sugar ratios. Solid-state hydrogen-deuterium exchange mass spectrometry (ssHDX MS) was performed on a QDa benchtop mass spectrometer to evaluate protein accessibility and structural preservation using RMs of 1% D₂O, 2% D₂O, and 1% D₂O + 1% H₂O. The larger the sugar, the lower its stabilizing potential and the higher the protein accessibility, indicating insufficient water replacement. Increasing the RM from 1 to 1.5 and 2% enhanced stability, highlighting the superiority of residual water molecules, which was especially the case for the tri- and tetrasaccharides. Mixtures of small and large sugars showed stabilization benefits in maintaining the monomer content and structural preservation, indicating a good balance of water replacement and vitrification. Overall, the ssHDX MS findings of samples with headspace-spiked D₂O did correspond with monomer retention, indicating that it could be a valuable tool for characterization and understanding the stabilizing capacity of lyophilized formulations. Our findings highlight the importance of RM control for optimal stability as well as the importance of the sugar size on lyoprotection based on water replacement and the potential of sugar mixtures to optimize the stability of lyophilized proteins.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129639","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 Universal In Vivo Predictive Dissolution Method for a Borderline BCS III/IV Drug Guided by Modeling and Simulations─Acyclovir as a Case Study.","authors":"Mauricio A García, Fernando Tapia, Benjamín Escares, Peter Langguth","doi":"10.1021/acs.molpharmaceut.5c00981","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00981","url":null,"abstract":"<p><p>Establishing in vivo predictive dissolution (IPD) conditions requires the consideration of biopredictive aspects during dissolution. For acyclovir, lower dose strengths (200 and 400 mg) can dissolve completely in the gastrointestinal fluids. However, luminal concentrations after administering the highest strength (800 mg) exceed the BCS solubility threshold. Given its poor permeability, sink conditions are not granted for the highest strength. In this study, a universal IPD method for acyclovir tablets was developed using the mini-vessel/mini-paddle apparatus. Computational simulations in a physiologically based pharmacokinetic (PBPK) model further guided the development. Apparatuses with different volumes and stirring conditions were explored, and results served as input for the model. Dissolution of 800 mg of acyclovir tablets in 900 mL of medium largely overpredicted observed plasma profiles due to poor resemblance of nonsink conditions in the lumen. Conversely, dissolution in the mini-vessel filled with 135 mL of HCl, pH 2.0, at 150 rpm, produced accurate predictions of plasma profiles, without affecting previous successful predictions with the lowest strength tablets. Furthermore, in-human and virtual bioequivalence studies confirmed the predictive potential of this method. Therefore, the aforementioned dissolution conditions can be considered as a universal IPD method for acyclovir immediate-release tablets.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123853","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":"Triple-Responsive Cross-Linked Micelles for Synergistic Chemo-Photothermal Cancer Therapy.","authors":"Yaning Ou, Yudong Wang, Kanglin Chen, Wenxin Liao, Zhaomin Tang","doi":"10.1021/acs.molpharmaceut.5c01130","DOIUrl":"10.1021/acs.molpharmaceut.5c01130","url":null,"abstract":"<p><p>We have developed a novel triple-responsive (pH/reduction/near-infrared (NIR) light) cross-linked polymer micelle PEG-P(LL/LL-LA)-PCL-IR820 for enhanced synergistic cancer therapy. This micelle was synthesized using a triblock amphiphilic polymer based on polylysine, functionalized with maleic anhydride (LA) as a cross-linking site and polycaprolactone (PCL) for encapsulating the anticancer drug doxorubicin (DOX). The photosensitizer IR820 was grafted onto PCL to enable photothermal and photodynamic effects under NIR irradiation. The DOX-loaded cross-linked micelles (DCMs) demonstrated exceptional stability under physiological conditions, effectively preventing premature drug release. Rapid DOX release was triggered by the intracellular high glutathione (GSH) level and acidic pH in tumor cells. Under NIR irradiation, DCM micelles exhibited significant photothermal and photodynamic effects, which markedly enhanced the cytotoxicity against B16 tumor cells. In B16 tumor-bearing mice, the DCM-treated group achieved superior tumor growth inhibition and prolonged survival under NIR irradiation compared to un-cross-linked micelles (DUCM) or free DOX, with minimal systemic toxicity. The tumor volume in the DCM + NIR group was significantly inhibited compared with other groups, reaching only about 300 mm³ within 15 days, while for the PBS-treated group, it reached approximately 1400 mm³. The survival rate of the DCM + NIR group was also significantly higher, with an over 70% survival rate within a 40-day observation period. This work presents a robust nanoplatform that combines stability, microenvironment responsiveness, and multimodal therapy, offering a promising strategy for targeted cancer treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111629","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":"Enhanced Polarity of Sulfonamide Metformin Derivatives Increases Cellular Uptake and Apoptosis-Inducing Effects in Human Breast Cancer Cells.","authors":"Ville Kuorikoski, Janne Tampio, Soumeya Kerachni, Daria Timonen, Arun Kumar Tonduru, Magdalena Markowicz-Piasecka, Tetsuya Terasaki, Antti Poso, Kristiina M Huttunen","doi":"10.1021/acs.molpharmaceut.5c00432","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00432","url":null,"abstract":"<p><p>Multitarget agent metformin, a compound originally developed as an antidiabetic agent, has been extensively studied as a repurposed medicine for various diseases. Over the past few decades, the mechanisms by which metformin is transported across cell membranes have also been identified. These include various solute carriers (SLCs), such as plasma membrane monoamine transporter (PMAT), organic cation transporters 1-3 (OCT1-3), and multidrug and toxin extrusion 1-2 (MATE1-2), which can facilitate the bidirectional transport of metformin depending on the cell type. Since metformin is a highly polar and easily excreted compound, more lipophilic derivatives and prodrugs of metformin have been, in turn,developed to improve the targeted delivery, e.g., into cancer cells. However, the required interactions of novel metformin derivatives with cationic transporters are not yet well understood. In the present study, the cellular uptake of nine metformin sulfonamides with various polar substituents was explored in human breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The interactions of the novel derivatives with OCT1 and OCT3 were investigated by docking and molecular dynamics simulations. Curiously, the highest cellular uptake was achieved with a compound that effectively released metformin and thus behaved as a prodrug (compound <b>6</b>). This highlights that despite the molecular interactions with the protein, the greatest driving force into the cancer cells was the intracellular bioconversion. Subsequently, the cell viability and apoptosis-inducing effects of the most effectively uptaken compounds were evaluated, which revealed, in turn, that the prodrug approach may not be the most efficient strategy to attain anticancer effects with metformin. Some more stable metformin derivatives with polar substituents were many times more effective in inducing apoptosis with smaller intracellular concentrations compared with metformin released from the prodrug <b>6</b>. Therefore, the rational design of novel metformin derivatives should focus on analogical structures of metformin with functionalities that can increase apoptosis-inducing effects while maintaining appropriate interactions with transmembrane proteins, and thus, have a balanced cellular uptake. The polar ring substituents in the sulfonamide moiety of metformin sulfonamides may offer a potential solution.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111544","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":"Leveraging Biopharmaceutics Bridging Risk Assessment and In Vivo Predictive Tools to Accelerate Immediate Release Drug Product Development by Minimized Need for Clinical Bridging Studies.","authors":"Helena Engman, Sara Carlert, Maria Hammarberg, Richard Barker, James Mann, Anders Borde, Eva Karlsson, Johan Palm, Bertil Abrahamsson, Christer Tannergren","doi":"10.1021/acs.molpharmaceut.5c00910","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00910","url":null,"abstract":"<p><p>Accelerated development of oral solid dosage forms necessitates effective strategies to link clinical data across development stages. Emerging predictive tools present a viable alternative, ensuring targeted clinical performance with a significantly reduced dependence on traditional clinical bridging studies. This paper introduces a biopharmaceutics bridging risk assessment (BBRA) tool that extends opportunities to avoid clinical bridging studies beyond the biopharmaceutics classification system (BCS) classes 1 and 3, utilizing physiologically based biopharmaceutics modeling (PBBM) and advanced in vitro tools (such as the TNO (Netherlands Organisation for Applied Scientific Research) transit intestinal model, TIM). PBBM uses experimental solubility, dissolution, and permeability input, validated by clinical data, to enhance risk assessment granularity and understanding, while TIM uniquely simulates physiological gastrointestinal conditions, complementary to traditional dissolution tests. The decision-tree framework, aligned with ICH M9 principles, supports iterative decision-making across the drug development life cycle, from preclinical to postapproval phases. An analysis of 32 AstraZeneca bridging cases showed that application of BBRA could reduce the number of clinical studies by 70%. By leveraging in vivo predictions and comprehensive clinical insights, our strategic approach mitigates late-stage BE failure risks, expedites market introduction, and ensures effective patient treatments.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123799","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":"Kinetics of Polymorphic Phase Transformations of <i>o</i>-Aminobenzoic Acid: Application of a Dispersive Kinetic Model Plus Molecular Dynamics Simulation of Prenucleation Aggregates.","authors":"Peter J Skrdla, Benjamin J Coscia, Andrea Browning, John Shelley, Shiva Sekharan, Jacob Gavartin","doi":"10.1021/acs.molpharmaceut.5c00426","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00426","url":null,"abstract":"<p><p>The specific rate at which one crystalline phase converts to another can vary as a function of time under isothermal conditions. This behavior gives rise to sigmoidal kinetic transients that are characteristic of nucleation and growth. Such curves are commonly fitted using the Johnson-Mehl-Avrami-Erofe'ev-Kolmogorov (JMAEK) equation. However, due to the ambiguity surrounding the time exponent in the JMAEK model, we present an alternative two-parameter dispersive kinetic model (DKM) and apply it to the study of solution-mediated polymorphic conversions of the prototypical molecule, <i>o</i>-aminobenzoic acid (<i>o</i>-ABA) [Jiang, S.; Jansens, P. J.; ter Horst, J. H. Control over polymorph formation of <i>o</i>-aminobenzoic acid. <i>Cryst. Growth Des.</i> <b>2010</b>, <i>10</i>, 2541-2547]. Using our DKM, we reconstructed a distribution of activation energies, <i>D</i>(<i>E</i>), from each experimental transient. Then, using <i>D</i>(<i>E</i>), a corresponding particle size distribution (PSD) of the critical nuclei formed during phase transformation is predicted. Lastly, molecular dynamics (MD) simulations are performed to study the prenucleation aggregation behavior of <i>o</i>-ABA in solution, under experimentally relevant conditions, to complement the kinetic modeling of the macroscopic phase conversion in the solid state. We observe that <i>o</i>-ABA molecules weakly associate with each other to form a variety of \"loose\" aggregates. These aggregates are mostly dimers and trimers exhibiting H-bonding and π-π interactions in various configurations that generally do not conform to any of the known crystal packing arrangements of the most common <i>o</i>-ABA polymorphs. Therefore, the observed molecular self-association is more consistent with a nonclassical nucleation pathway whereby monomer densification occurs ahead of cluster formation and, eventually, structural ordering. Our molecular-level simulations in solution complement the original study performed using experimental measurements on bulk crystals, with the DKM serving to bridge the scale gap between the two approaches by providing a window into the nanoscale species (nuclei), ultimately impacting the overall rate of conversion.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111566","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}