Molecular Pharmaceutics最新文献

{"title":"Impact of Permeation Enhancers on the Release of Insulin from Tablets in Biorelevant Media.","authors":"Andrew Fagan, Lorraine M Bateman, Abina M Crean, Joseph P O'Shea, Lynne S Taylor","doi":"10.1021/acs.molpharmaceut.5c00249","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00249","url":null,"abstract":"<p><p>The use of chemical permeation enhancers (PEs) to improve the permeation of peptides across gastric and intestinal epithelia has proven an effective strategy in the development of oral dosage forms of peptides. However, there remains a poor understanding of how the presence of PEs impacts the dissolution characteristics of oral formulations containing peptides, nor is it known how the complex composition of biological media can influence their behavior <i>in vivo</i>. This investigation sought to examine the effect of two widely studied PEs, sodium caprate (C10) and salcaprozate sodium (SNAC), on the release behavior of a model peptide, insulin, from minitablets in a variety of biorelevant media. First, the equilibrium solubilities of insulin, C10, and SNAC were determined in simulated gastric and intestinal media. Insulin, C10, and SNAC all displayed pH-dependent solubility across a physiologically relevant range of pH conditions. Moreover, at high concentrations, C10 was found to overwhelm the buffer capacity of the simulated media, increasing the pH of fasted state simulated intestinal fluid (FaSSIF) from 6.5 to 9.0, fed state simulated intestinal fluid (FeSSIF) from pH 5.0 to 8.8 and fasted state simulated gastric fluid (FaSSGF) from pH 1.6 to 9.2. Similarly, SNAC caused an increase in the pH of FaSSIF from 6.5 to 7.9, FeSSIF from pH 5.0 to 7.7, and FaSSGF from pH 1.6 to 7.6. Relative to in simulated intestinal media, the solubility of insulin was found to increase significantly in media at pH representative of saturated C10 and SNAC solutions, increasing from 0.1 mg/mL in blank FaSSIF to 14.0 mg/mL in phosphate buffer at pH 7.6 and to 23.7 mg/mL in phosphate buffer at pH 9.2, suggesting that the presence of C10 and SNAC at high concentrations could have a considerable favorable impact on insulin solubility. Furthermore, the release profiles of insulin from minitablets containing C10 and SNAC were investigated in each of the biorelevant media and compared with the release profiles of insulin from blank minitablets in the absence of PEs. Insulin release from the blank minitablets was found to be media dependent, following an apparent solubility trend. Complete release of insulin was observed in simulated gastric media; however, only between 67 and 82% release was observed in the simulated intestinal media. On the other hand, on the addition of C10 and SNAC to the formulation, greater than 90% release was observed across all media investigated. This difference in release behavior was determined to be caused by an increase in pH at the surface of the minitablets due to the presence of high local concentrations of C10 and SNAC, respectively, as confirmed by a change in color of a universal indicator solution. These findings offer a key insight into the influence that C10 and SNAC have on the dissolution characteristics of insulin from an oral dosage form in a variety of simulated gastric and intestinal media.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315563","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":"Intermolecular Dynamics of Monoglyceride Mesophases with Their Biomacromolecular Corona.","authors":"Wye-Khay Fong, Dimitri Vanhecke, Daniel Hauser, Sandor Balog, Philipp Lemal, Shiva Montasseri, Barbara Rothen-Rutishauser, Alke Petri-Fink","doi":"10.1021/acs.molpharmaceut.5c00435","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00435","url":null,"abstract":"<p><p>Advances in the development of lipid nanoparticles have resulted in delivery systems that both protect the encapsulated drug and improve therapeutic outcomes. When introduced in vivo, nanoparticles are rapidly covered by a biomolecular corona, influencing their biological fate, i.e., interaction with cells, uptake, and intracellular fate. This study explores the interactions between nonlamellar lipidic drug delivery systems and non-lipolytic components of complex cell culture media, focusing on the dynamic formation of the corona and its effects on the lipid nanoparticle behavior. Monoglyceride formulations were monitored for changes in nanostructure and particle size, and mechanisms for these changes were elucidated. Not only do these biomacromolecules influence the size and structure of the nanoparticles themselves, but they can simultaneously diffuse into the mesophase nanostructure. The study highlights that lipid nanoparticles undergo dynamic changes in physiological conditions influenced by adsorbed proteins and other nondegradative components in complex cell culture media, separate from effects caused by lipases or other enzymatic factors. These induced structural transformations can significantly alter the nanoparticles' physical properties and drug release profiles, potentially causing deviation from their intended therapeutic performance. Understanding these interactions is thus crucial for optimizing the design and functionality of lipid-based drug delivery systems in biomedical applications.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315564","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":"Challenges and Opportunities for Incorporating Physiological Information into Pharmacokinetic Models of Intranasal Drug Delivery to the Brain: A Review of the Current Status and Future Trajectories.","authors":"Saeed Rezaee, Zubida M Al-Majdoub, Aleksandra Galetin, Amin Rostami-Hodjegan, Kayode Ogungbenro","doi":"10.1021/acs.molpharmaceut.5c00297","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00297","url":null,"abstract":"<p><p>Intranasal (IN) drug delivery is a promising noninvasive route for targeting the central nervous system (CNS) bypassing the blood-brain-barrier (BBB). This review critically examines the underlying mechanisms, challenges in predicting nasal drug delivery outcomes, and future directions for applying physiologically based pharmacokinetic (PBPK) modeling to support such predictions. The nasal cavity comprises distinct anatomical and physiological features in the olfactory region (upper posterior part of the nasal cavity) and the respiratory region (middle part and lateral walls of the nasal cavity), both of which play essential roles in drug deposition, systemic absorption, and general passage. However, since the biological composition of the olfactory and trigeminal nerves in the nasal area is not well-known, the prediction of drug absorption to systemic circulation from nasal mucosa or direct transport from nose to brain are fraught with many challenges. Thus, addressing the impacts of drug permeability, mucociliary clearance, enzymatic degradation, and nasomucosal toxicity are still essential challenges when developing nasal formulations for drugs. PBPK models have the capability of integrating complex anatomical, physiological, and biological aspects of the systems when such data are available. Nevertheless, translation from in vitro experiments or animal studies into humans requires addressing knowledge gaps in systems parameters. Future investigations should focus on generating the necessary missing information as well as refining the models. Application of advanced modeling methods for simulation of drug deposition, in conjunction with refined nasal PBPK models, is envisaged to improve the prediction of clinical outcomes for CNS targeted IN drug delivery.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309285","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":"Oxygen-Dependent Accelerated Stability Modeling of Drug Products.","authors":"Kenneth C Waterman, Maria J Krisch, Tyler J McDonald, Rebekah Theriault, Chris Wood, Michael D Bielak, Connie Tang, Jana O'Donnell","doi":"10.1021/acs.molpharmaceut.5c00239","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00239","url":null,"abstract":"<p><p>A new formalism for accelerating the determination of shelf life with respect to temperature, relative humidity (when applicable), and oxygen concentration is proposed and exemplified for liquid sesame oil and formulated tablets of chlorpromazine. An oxygen-sensitivity parameter, <i>C</i>, is added to the moisture-modified Arrhenius equation with the reference condition being the atmospheric oxygen level (21% O₂). The resultant modified Arrhenius equation is used in conjunction with isoconversion, where rate determinations are focused only on the behavior to a specification limit. With sesame oil oxidation, peroxides are generated showing temperature and oxygen concentration terms that are independent of each other with a <i>C</i> term of approximately one. With chlorpromazine tablets, an <i>N</i>-oxide and a sulfoxide are formed with nonlinear kinetics. The degradant growth dependencies on temperature, relative humidity, and percent oxygen were found to be independent and consistent with the proposed moisture and oxygen-modified Arrhenius equation with <i>C</i> terms less than one. This inefficiency in oxidation suggests that indirect oxidation occurs, implicating the formation of reactive oxygen species in the reaction process. The models are in good agreement with real-time data for both case studies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309286","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":"Polymeric-Based Theranostic Nanocarriers of Neuroprotective Drugs: Development, Imaging, and Bioanalysis.","authors":"Krzysztof Szczepanowicz, Magdalena Procner, Marta Szczęch, Natalia Łopuszyńska, Danuta Jantas, Magdalena Regulska, Monika Leśkiewicz, Krzysztof Jasiński, Kamil Stachurski, Lilianna Szyk-Warszyńska, Adam Roman, Władysław Lasoń, Władysław P Węglarz, Piotr Warszyński","doi":"10.1021/acs.molpharmaceut.5c00170","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00170","url":null,"abstract":"<p><p>Inefficient delivery of neuroprotective drugs to their target sites remains a major impediment in the treatment of neurodegenerative disorders. Therefore, our research was focused on a new strategy for the preparation of polymeric-based theranostic nanocarriers of neuroprotective drugs. Polymeric theranostic nanocarriers of calcineurin inhibitors, Cyclosporin A (CsA) and Tacrolimus (FK506), as potential neuroprotective agents, were prepared via the self-emulsification solvent evaporation (SESE) method with the combination of a layer-by-layer technique. For magnetic resonance imaging, gadolinium-labeled poly-l-lysine (PLL-Gd) was used, while for optical imaging, rhodamine-labeled poly-l-lysine (PLL-ROD) was used. Developed nanocarriers were characterized for their properties: the size was below 250 nm, the encapsulation efficiency was ∼100%, and they could serve as transport devices for therapeutic cargo and imaging compounds, e.g., distribution assessment. Developed nanocarriers were safe for tested cells (human neuroblastoma cells, primary neuronal cell cultures, and brain microvascular endothelial cells). Equally important, they willingly traversed the artificial blood-brain barrier. Our study demonstrated that the newly designed polymeric-based theranostic nanocarriers possess favorable physicochemical and biological properties and may serve as a useful platform for neuroprotective compound delivery.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300636","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":"Intranasal Absorption Enhancement of Antidiabetic Therapeuticals by the Functional Peptide Segment of Latroeggtoxin-VI.","authors":"Minglu Sun, Panfeng Yin, Si Chen, Xianchun Wang","doi":"10.1021/acs.molpharmaceut.5c00293","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00293","url":null,"abstract":"<p><p>Latroeggtoxin-VI (LETX-VI) is an active peptide found from the eggs of the spider <i>Latrodectus tredecimguttatus</i>. Previous studies demonstrated that LETX-VI can penetrate the plasma membrane of secretory PC12 cells and its 17-residue C-terminal sequence is the functional peptide segment (FPS), suggesting that the FPS may act as a vector for drug transmembrane delivery. In the present proof-of-concept study, the ability and efficiency of FPS to transmembrane delivery of antidiabetic therapeuticals were preliminarily evaluated. The FPS was covalently fused with a glucagon-like peptide-1 analogue (FPS-GLP) or insulin (FPS-Ins) using solid phase chemical synthesis or heterologous expression, respectively. Western blot analysis indicated that, compared with GLP-1 analogue that itself could hardly enter the cultured A549 cells, FPS-GLP efficiently entered the cells in a concentration-dependent manner, confirming the vector role of FPS in transmembrane delivery of drugs. When intranasally administrated to mice, FPS-GLP showed the hypoglycemic effect significantly superior to that of GLP-1 analogue, and the hypoglycemic effect of intranasally administrated FPS-Ins was approximately comparable to that of the intramuscularly injected FPS-Ins. These observations demonstrated that FPS can act as a vector to efficiently enhance the intranasal absorption of proteinaceous drugs, showing application prospect in combating diabetes mellitus and related CNS disorders.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144292981","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":"Slurry Conversion: A General Method for Formulating Amorphous Solid Dispersions and Fully Integrating Drug and Polymer Components.","authors":"Amy Lan Neusaenger, Caroline Fatina, Yichun Shen, Junguang Yu, Lian Yu","doi":"10.1021/acs.molpharmaceut.5c00240","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00240","url":null,"abstract":"<p><p>A solvent-sparing method, called \"slurry conversion\", has been tested as a general approach to preparing amorphous solid dispersions (ASDs). In this method, a solid mixture of a drug and a polymer is stirred in the presence of a small quantity of a solvent, which is subsequently removed. In previous work, the method enabled more complete salt formation between lumefantrine (LMF), a basic antimalarial, with acidic polymers, than the common methods of hot melt extrusion and spray drying, leading to improved physical stability and release. Here, we apply this method to 18 poorly soluble drugs formulated as binary and ternary ASDs. For a rigorous test, the drugs were formulated with a single polymer, poly(acrylic acid) (PAA), under the same condition: room temperature stirring in 1:1 ethanol-dichloromethane at 4:1 solvent/solid ratio. ASDs were prepared for 16 of the 18 drugs at 25% drug loading and 11 at 50% drug loading. The drugs that were not fully amorphized did not dissolve in the default solvent or crystallized during drying. For most drugs, an abrupt \"clearing\" of the slurry occurred during stirring, indicating complete dissolution and amorphization before drying. While clearing did not occur for some drugs (e.g., clofazimine), the product was still fully amorphous, through solvent-mediated conversion. For a basic drug, the degree of protonation by PAA increases smoothly with PAA concentration and is ordered by its basic strength, supporting the conclusion that the method allows the system to reach thermodynamic equilibrium. In addition to binary ASDs, ternary ASDs containing two drugs (LMF and artemether or LMF and artesunate) were successfully prepared to support applications in combination therapies. In these ternary formulations, the protonation of LMF follows the trend established for binary systems. We find that slurry conversion can be scaled up 60-fold from the typical batch size without any difficulties or adverse effect on the structure and properties of the product. Overall, our results demonstrate that slurry conversion is a general, low-cost, and green alternative to conventional methods for manufacturing ASDs where the components are fully integrated.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289349","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":"Kinetic Modeling and Parametric Imaging of ¹³N-NH₃ in Treatment-Naïve Lung Cancer.","authors":"Hui Yuan, Fanghu Wang, Yang Chen, Xiaoqiang Pan, Qing Zhang, Tao Sun, Lei Jiang","doi":"10.1021/acs.molpharmaceut.5c00602","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00602","url":null,"abstract":"<p><p>¹³N-NH₃ PET imaging provides insights into tumor perfusion and metabolism, hence potentially valuable in oncological diagnosis, staging, and prognosis. However, its <i>in vivo</i> kinetic characteristics and the optimal protocol for kinetic modeling and parametric imaging remain unclear. This study aims to elucidate the kinetic features of ¹³N-NH₃ in lung cancer and its clinical value. Nine lung cancer surgical candidates were prospectively incorporated. Using total-body PET/CT scanner, 35 min ¹³N-NH₃ acquisitions were conducted immediately postinjection. Subsequently, routine 5 min ¹⁸F-FDG acquisitions were made. ¹³N-NH₃ PET data were reconstructed into dynamic image series. Tumor lesions and normal organs were segmented using nonthreshold dependent automatic or semiautomatic tools. Reversible and irreversible 2-tissue compartment models (2TC vs 2TiC) using image-derived input functions (IDIFs) with population-based metabolite correction were adopted for parametric modeling. Akaike Information Criterion (AIC) was calculated for model selection. Parametric images were produced with the optimal model for lesions. A total of 9 patients presented with 9 primary lung tumors and 17 histologically confirmed lymphadenopathy. All primary lung tumors and regional lymph node metastases were detectable using both ¹³N-NH₃ and ¹⁸F-FDG imaging. Primary lung tumors, regional lymphadenopathy, and lung backgrounds demonstrated smaller AIC using 2TC models with pulmonary artery as IDIF, while other organs favored either 2TC or 2TiC models with the descending aorta as IDIF. Lesion-to-background lung ratios reached around 2.218-3.407 for primary lung tumors and 1.932-2.537 for regional lymphadenopathy 10-20 min postinjection of ¹³N-NH₃. Vt images derived from 2TC modeling showed better lesion-to-background lung ratios (4.511 ± 2.955 for primary tumor, and 2.991 ± 2.152 for regional lymphadenopathy). For ¹³N-NH₃ imaging in lung cancer, a static image can be acquired at 10-20 min postinjection for clinical diagnosis. The reversible 2TC model is preferred over 2TiC, and the Vt image is preferred over other parametric images in terms of lesion contrast.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144292982","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":"Application of Biomaterials in the Development of Enteric-Coated Luminar Capsule Microneedles for Selective Delivery of Sofosbuvir to the Liver: A Promising Treatment for Hepatitis C.","authors":"Musyfira Sahra, Nurul Fitrayani, Abigael Alik Samma, Christopher Kosasi Ko, Felicia Virginia Thios, Andi Dian Permana","doi":"10.1021/acs.molpharmaceut.4c01529","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01529","url":null,"abstract":"<p><p>In commercial applications, sofosbuvir (SOF) for hepatitis C is only available in tablet dosage form, resulting in minimal SOF accumulation in the liver (26.94%) due to its low intestinal permeability and high molecular weight (529.5 Da). Therefore, in this study, luminar capsule microneedles (LUCAMs) were developed, in which SOF was delivered via dissolving microneedles (DMN) attached to a branch and encapsulated in an enteric-coated hard capsule designed to dissolve exclusively in the intestinal environment. The needle on the DMN has the potential to facilitate SOF absorption in the intestine, thereby enabling maximum absorption. A thorough evaluation of DMN, branches, and capsules was conducted, encompassing formulation, characterization, differential scanning calorimetry, and dissolution time. This comprehensive evaluation demonstrated that the results obtained align with the established specifications. Furthermore, a series of evaluations, including capsule coating, revealed that the capsules dissolve selectively under intestinal pH conditions, as indicated by a hemolysis assay and irritation potential levels below 5%. These findings collectively demonstrate that the utilized biomaterial is nontoxic and nonirritating. In vitro and ex vivo permeability studies demonstrated that LUCAMs released 99.32 ± 11.92 and 203.97 ± 19.78 μg/mL SOF within 24 h, respectively. In vivo studies were conducted on two groups, namely, LUCAMs and controls, with measurements taken at 12, 24, and 36 h. The results demonstrated a significant increase in SOF concentration in the liver, reaching 1.26 ± 0.18 μg/mL in the LUCAM group by 36 h, in contrast to the control group, which was only detected at 12 h (0.83 ± 0.13 μg/mL) and not detected at 24 and 36 h. Histopathological analysis confirmed the absence of severe tissue damage, indicating that LUCAMs are a promising approach for enhancing the delivery of SOF to the liver and improving the efficacy of hepatitis C treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273707","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":"A Synergistically Enhanced Near-Infrared ESIPT Fluorescent Probe for High-Performance In Situ Imaging of Cellular Apoptosis.","authors":"Qian Lei, Xiang Cheng, Qian Chen, Xiaoqian Ma, Wei Wang, Pengfei Rong, Bin Feng, Shengwang Zhang, Wenbin Zeng","doi":"10.1021/acs.molpharmaceut.5c00615","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00615","url":null,"abstract":"<p><p>Monitoring apoptotic progression is critical for tracking disease development and evaluating therapeutic interventions. Fluorescent probes that integrate aggregation-induced emission (AIE) and excited-state intramolecular proton transfer (ESIPT) offer some advantages, including large Stokes shifts, high quantum yields in the aggregated state, and strong photostability. In this study, we developed an ESIPT-based fluorescent probe, <b>ABTT-DEVD</b>, with AIE properties for the highly sensitive detection of caspase-3 and real-time imaging of apoptosis. The probe design incorporates a hydrophilic DEVD peptide substrate linked to a hydrophobic ESIPT fluorophore. Caspase-3-mediated cleavage induces a significant change in water solubility, leading to strong fluorescence enhancement with an ultralow detection limit of 1.2 pM. Molecular docking studies corroborate the specific interaction of the DEVD peptide with the caspase-3 active site. Furthermore, <b>ABTT-DEVD</b> enabled the visualization of endogenous caspase-3 activity in living cells, facilitating the evaluation of antitumor drug efficacy. The probe's effectiveness in tracking apoptosis progression is further supported by fluorescence data and flow cytometry analysis, underscoring its potential as a valuable tool for apoptosis monitoring in biomedical research.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264835","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}