Physical stresses such as agitation induce protein aggregation, which causes adverse effects on the immune system of patients, leading to challenges in drug development. Aggregation induced by physical stresses can be minimized by formulation optimization. In this study, 120 combinations of 10 therapeutic proteins and 12 different formulations (4 pH conditions and 3 salt concentrations) were prepared. Subsequently, the agitation-induced aggregation propensity of each protein was investigated by evaluating its monomer recovery (%) using size exclusion chromatography. Hierarchical clustering was applied to categorize each protein according to its aggregation propensity, resulting in two groups of proteins: group A and B. The aggregation propensity of proteins in group A was insensitive to changes in formulation conditions because conformational, colloidal, and interfacial stabilities were minimally affected by changes in the pH and salt concentration and a compensation mechanism existed between conformational and colloidal stabilities. Thus, proteins in group A can be formulated with a relatively high degree of freedom. In contrast, the aggregation propensity of proteins in group B was sensitive to changes in formulation conditions. Multiple regression analysis of the physicochemical parameters and monomer recovery of proteins in group B clarified that changes in conformational stability in response to changes in formulations primarily contributed to the sensitivity of the monomer recovery to changes in formulation conditions. For all antibodies, there was a positive correlation between the monomer recovery after agitation and that after quiescent storage at 40 °C for 1 month, suggesting that a stable formulation can be obtained without the quiescent testing. Therefore, a proposed formulation optimization strategy based on the agitation-induced monomer recovery can improve the efficiency of formulating selected therapeutic proteins. This strategic approach is expected to accelerate the development of therapeutic proteins while reflecting the importance of aggregation factors and quiescent stability in the optimization of therapeutic protein formulations.
{"title":"Hierarchical clustering of therapeutic proteins based on agitation-induced aggregation propensity and its relation to physicochemical parameters","authors":"Rio Okada , Kosei Shibata , Risa Shibuya , Tetsuo Torisu , Susumu Uchiyama","doi":"10.1016/j.ejps.2025.107060","DOIUrl":"10.1016/j.ejps.2025.107060","url":null,"abstract":"<div><div>Physical stresses such as agitation induce protein aggregation, which causes adverse effects on the immune system of patients, leading to challenges in drug development. Aggregation induced by physical stresses can be minimized by formulation optimization. In this study, 120 combinations of 10 therapeutic proteins and 12 different formulations (4 pH conditions and 3 salt concentrations) were prepared. Subsequently, the agitation-induced aggregation propensity of each protein was investigated by evaluating its monomer recovery (%) using size exclusion chromatography. Hierarchical clustering was applied to categorize each protein according to its aggregation propensity, resulting in two groups of proteins: group A and B. The aggregation propensity of proteins in group A was insensitive to changes in formulation conditions because conformational, colloidal, and interfacial stabilities were minimally affected by changes in the pH and salt concentration and a compensation mechanism existed between conformational and colloidal stabilities. Thus, proteins in group A can be formulated with a relatively high degree of freedom. In contrast, the aggregation propensity of proteins in group B was sensitive to changes in formulation conditions. Multiple regression analysis of the physicochemical parameters and monomer recovery of proteins in group B clarified that changes in conformational stability in response to changes in formulations primarily contributed to the sensitivity of the monomer recovery to changes in formulation conditions. For all antibodies, there was a positive correlation between the monomer recovery after agitation and that after quiescent storage at 40 °C for 1 month, suggesting that a stable formulation can be obtained without the quiescent testing. Therefore, a proposed formulation optimization strategy based on the agitation-induced monomer recovery can improve the efficiency of formulating selected therapeutic proteins. This strategic approach is expected to accelerate the development of therapeutic proteins while reflecting the importance of aggregation factors and quiescent stability in the optimization of therapeutic protein formulations.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"208 ","pages":"Article 107060"},"PeriodicalIF":4.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610232","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}
Pub Date : 2025-03-10DOI: 10.1016/j.ejps.2025.107062
Mai I Shahin, Mai A Elyamani, Ahmed E Elsawi, Ahmed T Negmeldin, Shahenda Naguib, Heba Safwat, Hatem A Abdel-Aziz, Wagdy M Eldehna
In the current medical era, the proliferation and dissemination of drug-resistant strains of Mycobacterium tuberculosis continue to pose a significant worldwide health hazard, necessitating the development of new and innovative medications to combat tuberculosis. Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) is a crucial enzyme for cell wall synthesis in Mycobacterium tuberculosis (Mtb). Its importance is due to its eminent contribution in forming lipoarabinomannan and arabinogalactan. The emergence of the DprE1 enzyme as a druggable target was based on inhibitors discovered in high-throughput screening. Since then, inhibitors with different types of chemical scaffolds have been reported for their activity against it. DprE1 inhibitors can be categorized according to the formation of a covalent or non-covalent bond in the enzyme's active site, causing a loss of its catalytic activity, leading to Mtb's demise. Herein, we describe diverse DprE1 inhibitors that have had anti-tubercular activity reported over the past fifteen years and till the present time.
{"title":"DprE1 Inhibitors: An insight into the recent developments and synthetic approaches.","authors":"Mai I Shahin, Mai A Elyamani, Ahmed E Elsawi, Ahmed T Negmeldin, Shahenda Naguib, Heba Safwat, Hatem A Abdel-Aziz, Wagdy M Eldehna","doi":"10.1016/j.ejps.2025.107062","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107062","url":null,"abstract":"<p><p>In the current medical era, the proliferation and dissemination of drug-resistant strains of Mycobacterium tuberculosis continue to pose a significant worldwide health hazard, necessitating the development of new and innovative medications to combat tuberculosis. Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) is a crucial enzyme for cell wall synthesis in Mycobacterium tuberculosis (Mtb). Its importance is due to its eminent contribution in forming lipoarabinomannan and arabinogalactan. The emergence of the DprE1 enzyme as a druggable target was based on inhibitors discovered in high-throughput screening. Since then, inhibitors with different types of chemical scaffolds have been reported for their activity against it. DprE1 inhibitors can be categorized according to the formation of a covalent or non-covalent bond in the enzyme's active site, causing a loss of its catalytic activity, leading to Mtb's demise. Herein, we describe diverse DprE1 inhibitors that have had anti-tubercular activity reported over the past fifteen years and till the present time.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107062"},"PeriodicalIF":4.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143614075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-10DOI: 10.1016/j.ejps.2025.107068
Jonas Binder , Matja Zalar , Martin Huelsmeyer , Michael Siedler , Robin Curtis , Wolfgang Friess
Coarse-grained molecular dynamics simulations are highly valuable for studying protein-protein interactions. Unfortunately, commonly used force fields often overestimate these interactions. Here, we investigate the performance of the Martini 3 force field in predicting the self-interaction behavior of lysozyme and subtilisin using Metadynamics. The original Martini 3, despite improvements over its predecessor, overestimates interaction strength. Through reparameterization of bead interactions, we achieve good agreement with experimental data of the second virial coefficient and the diffusion coefficient. The new, refined force field enables more accurate CG-MD simulations, with potential applications in understanding and prediction of protein stability, aggregation tendencies, and solubility, with the possibility to aid in the development of protein-based drugs.
{"title":"Enhancing Martini 3 for protein self-interaction simulations","authors":"Jonas Binder , Matja Zalar , Martin Huelsmeyer , Michael Siedler , Robin Curtis , Wolfgang Friess","doi":"10.1016/j.ejps.2025.107068","DOIUrl":"10.1016/j.ejps.2025.107068","url":null,"abstract":"<div><div>Coarse-grained molecular dynamics simulations are highly valuable for studying protein-protein interactions. Unfortunately, commonly used force fields often overestimate these interactions. Here, we investigate the performance of the Martini 3 force field in predicting the self-interaction behavior of lysozyme and subtilisin using Metadynamics. The original Martini 3, despite improvements over its predecessor, overestimates interaction strength. Through reparameterization of bead interactions, we achieve good agreement with experimental data of the second virial coefficient and the diffusion coefficient. The new, refined force field enables more accurate CG-MD simulations, with potential applications in understanding and prediction of protein stability, aggregation tendencies, and solubility, with the possibility to aid in the development of protein-based drugs.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107068"},"PeriodicalIF":4.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143614076","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}
Pub Date : 2025-03-09DOI: 10.1016/j.ejps.2025.107067
Eric Lehner , Marie-Luise Trutschel , Matthias Menzel , Jonas Jacobs , Julian Kunert , Jonas Scheffler , Wolfgang H. Binder , Christian E.H. Schmelzer , Stefan K. Plontke , Arne Liebau , Karsten Mäder
Poly(lactic-co-glycolic acid) (PLGA) is a prominent biodegradable polymer used in biomedical applications, including drug delivery systems (DDS) and tissue engineering. PLGA's ability to control drug release is often hindered by nonlinear release profiles and slow initial drug release for hydrophobic drugs. This study investigates the incorporation of dexamethasone phosphate (DEXP) into polyethylene glycol–poly(lactic-co-glycolic acid) (PEG-PLGA) implants to enhance the initial release rate of dexamethasone (DEX). Implants were fabricated via hot-melt extrusion with varying DEX to DEXP ratios. X-ray diffraction (XRD) analysis confirmed that DEX remained crystalline in all formulations, whereas DEXP's crystallinity was detectable only in higher concentrations. Energy-dispersive X-ray spectroscopy (EDX) provided insights into the distribution of DEX and DEXP within the polymer matrix. Drug release studies revealed that PEG-PLGA implants accelerated initial drug release with increasing quantity of DEXP, though it also led to a shorter overall release duration. Despite these improvements, all implants exhibited a biphasic release profile. DEXP also influenced the characteristics of the polymer matrix, evidenced by increased swelling, water absorption, and mass loss. 1H NMR analysis revealed a faster decrease in glycolic acid monomers in DEXP-containing implants. These findings demonstrate that DEXP enhances early drug release of DEX-loaded PEG-PLGA implants prepared by hot-melt extrusion. However, balancing initial and sustained release profiles remains challenging.
{"title":"Enhancing drug release from PEG-PLGA implants: The role of Hydrophilic Dexamethasone Phosphate in modulating release kinetics and degradation behavior","authors":"Eric Lehner , Marie-Luise Trutschel , Matthias Menzel , Jonas Jacobs , Julian Kunert , Jonas Scheffler , Wolfgang H. Binder , Christian E.H. Schmelzer , Stefan K. Plontke , Arne Liebau , Karsten Mäder","doi":"10.1016/j.ejps.2025.107067","DOIUrl":"10.1016/j.ejps.2025.107067","url":null,"abstract":"<div><div>Poly(lactic-co-glycolic acid) (PLGA) is a prominent biodegradable polymer used in biomedical applications, including drug delivery systems (DDS) and tissue engineering. PLGA's ability to control drug release is often hindered by nonlinear release profiles and slow initial drug release for hydrophobic drugs. This study investigates the incorporation of dexamethasone phosphate (DEXP) into polyethylene glycol–poly(lactic-co-glycolic acid) (PEG-PLGA) implants to enhance the initial release rate of dexamethasone (DEX). Implants were fabricated via hot-melt extrusion with varying DEX to DEXP ratios. X-ray diffraction (XRD) analysis confirmed that DEX remained crystalline in all formulations, whereas DEXP's crystallinity was detectable only in higher concentrations. Energy-dispersive X-ray spectroscopy (EDX) provided insights into the distribution of DEX and DEXP within the polymer matrix. Drug release studies revealed that PEG-PLGA implants accelerated initial drug release with increasing quantity of DEXP, though it also led to a shorter overall release duration. Despite these improvements, all implants exhibited a biphasic release profile. DEXP also influenced the characteristics of the polymer matrix, evidenced by increased swelling, water absorption, and mass loss. <sup>1</sup>H NMR analysis revealed a faster decrease in glycolic acid monomers in DEXP-containing implants. These findings demonstrate that DEXP enhances early drug release of DEX-loaded PEG-PLGA implants prepared by hot-melt extrusion. However, balancing initial and sustained release profiles remains challenging.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107067"},"PeriodicalIF":4.3,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604336","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}
Pub Date : 2025-03-08DOI: 10.1016/j.ejps.2025.107063
Audrey Derobertmasure , Li Shean Toh , Virginia E Wotring , Philip M Williams , Lucia Morbidelli , Julia C Stingl , Mathieu Vinken , Raghda Ramadan , Stephanie Chhun , Pierre Boutouyrie
Future long-duration crewed space missions beyond Low Earth Orbit (LEO) will bring new healthcare challenges for astronauts for which pharmacological countermeasures (pharmacological countermeasures) are crucial. This paper highlights current pharmacological countermeasures challenges described in the ESA SciSpacE Roadmap, with a focus on the cardiovascular system as a model to demonstrate the potential implication of the challenges and recommendations. New pharmacological approaches and procedures need to be adapted to spaceflight (spaceflight) conditions, including ethical and reglementary considerations. Potential strategies include combining pharmacological biomarkers such as pharmacogenomics with therapeutic drug monitoring, advancing microsampling techniques, and implementing a pharmacovigilance system to gain deep insights into pharmacokinetics/pharmacodynamics (PK/PD) spaceflight alteration on drug exposure. Emerging therapeutic approaches (such as long-term regimens) or manufacturing drugs in the space environment, can address specific issues related to drug storage and stability.
The integration of biobanks and innovative technologies like organoids and organ-on-a-chip, artificial intelligence (AI), including machine learning will further enhance PK modelling leading to personalized treatments. These innovative pharmaceutical tools will also enable reciprocal game-changing healthcare developments to be made on Earth as well as in space and are essential to ensure space explorers receive safe effective pharmaceutical care.
{"title":"Pharmacological countermeasures for long-duration space missions: addressing cardiovascular challenges and advancing space-adapted healthcare","authors":"Audrey Derobertmasure , Li Shean Toh , Virginia E Wotring , Philip M Williams , Lucia Morbidelli , Julia C Stingl , Mathieu Vinken , Raghda Ramadan , Stephanie Chhun , Pierre Boutouyrie","doi":"10.1016/j.ejps.2025.107063","DOIUrl":"10.1016/j.ejps.2025.107063","url":null,"abstract":"<div><div>Future long-duration crewed space missions beyond Low Earth Orbit (LEO) will bring new healthcare challenges for astronauts for which pharmacological countermeasures (pharmacological countermeasures) are crucial. This paper highlights current pharmacological countermeasures challenges described in the ESA SciSpacE Roadmap, with a focus on the cardiovascular system as a model to demonstrate the potential implication of the challenges and recommendations. New pharmacological approaches and procedures need to be adapted to spaceflight (spaceflight) conditions, including ethical and reglementary considerations. Potential strategies include combining pharmacological biomarkers such as pharmacogenomics with therapeutic drug monitoring, advancing microsampling techniques, and implementing a pharmacovigilance system to gain deep insights into pharmacokinetics/pharmacodynamics (PK/PD) spaceflight alteration on drug exposure. Emerging therapeutic approaches (such as long-term regimens) or manufacturing drugs in the space environment, can address specific issues related to drug storage and stability.</div><div>The integration of biobanks and innovative technologies like organoids and organ-on-a-chip, artificial intelligence (AI), including machine learning will further enhance PK modelling leading to personalized treatments. These innovative pharmaceutical tools will also enable reciprocal game-changing healthcare developments to be made on Earth as well as in space and are essential to ensure space explorers receive safe effective pharmaceutical care.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107063"},"PeriodicalIF":4.3,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596329","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}
Pub Date : 2025-03-08DOI: 10.1016/j.ejps.2025.107066
Federica Poggialini, Paolo Governa, Chiara Vagaggini, Samuele Maramai, Stefania Lamponi, Claudia Mugnaini, Antonella Brizzi, Rosa Purgatorio, Modesto De Candia, Marco Catto, Elena Dreassi, Fabrizio Manetti, Federico Corelli, Cosimo Damiano Altomare, Andrea Cappelli, Marco Paolino
The possibility to control the effects of drugs in time and space represents an ideal condition for developing safer and more personalized therapies against different disorders. In this context, photopharmacology has paved the way for the use of light in the modulation of drugs activity. Our interest is directed to photo-switchable molecules, capable of interconverting between two different isoforms upon light irradiation. We recently reported compound 1, a donepezil-like based on 2-benzylidenindan-1-one structure, as a dual AChE and MAO-B inhibitor, which can be converted into the E- (active form) and Z- (about tenfold less active form) diastereoisomers by irradiating with UV-vis light. Aiming at identifying compounds with remarkable activity in a physiological conditions, we herein report a fine characterization of compound 1 in PBS solutions. First, we evaluated its ability to act as a photoswitch comparing PBS solution with organic solvents (e.g. methanol), demonstrating that a wavelength in the UV range (330 nm) can convert the E- into the Z-diastereoisomer, while the use of a visible light (400 nm) allows the interconversion from Z to E in both media. Along with its photoinducible behavior, we investigated the passive diffusion across cellular membrane with PAMPA experiments, plasma and microsomal stability, and binding to plasma proteins. Interestingly, the results of such studies suggested that compound 1 could persist in the blood circulation for a long time, which is desirable for application in photopharmacological therapies. Cytotoxicity studies highlighted the potential of our prototypic compound as a lead photodrug against neurodegenerative disorders, deserving to advance in molecular optimization studies and further in vitro and in vivo characterization.
{"title":"Light-mediated Activation/Deactivation Control and in vitro ADMETox Profiling of a Donepezil-like Dual AChE/MAO-B Inhibitor.","authors":"Federica Poggialini, Paolo Governa, Chiara Vagaggini, Samuele Maramai, Stefania Lamponi, Claudia Mugnaini, Antonella Brizzi, Rosa Purgatorio, Modesto De Candia, Marco Catto, Elena Dreassi, Fabrizio Manetti, Federico Corelli, Cosimo Damiano Altomare, Andrea Cappelli, Marco Paolino","doi":"10.1016/j.ejps.2025.107066","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107066","url":null,"abstract":"<p><p>The possibility to control the effects of drugs in time and space represents an ideal condition for developing safer and more personalized therapies against different disorders. In this context, photopharmacology has paved the way for the use of light in the modulation of drugs activity. Our interest is directed to photo-switchable molecules, capable of interconverting between two different isoforms upon light irradiation. We recently reported compound 1, a donepezil-like based on 2-benzylidenindan-1-one structure, as a dual AChE and MAO-B inhibitor, which can be converted into the E- (active form) and Z- (about tenfold less active form) diastereoisomers by irradiating with UV-vis light. Aiming at identifying compounds with remarkable activity in a physiological conditions, we herein report a fine characterization of compound 1 in PBS solutions. First, we evaluated its ability to act as a photoswitch comparing PBS solution with organic solvents (e.g. methanol), demonstrating that a wavelength in the UV range (330 nm) can convert the E- into the Z-diastereoisomer, while the use of a visible light (400 nm) allows the interconversion from Z to E in both media. Along with its photoinducible behavior, we investigated the passive diffusion across cellular membrane with PAMPA experiments, plasma and microsomal stability, and binding to plasma proteins. Interestingly, the results of such studies suggested that compound 1 could persist in the blood circulation for a long time, which is desirable for application in photopharmacological therapies. Cytotoxicity studies highlighted the potential of our prototypic compound as a lead photodrug against neurodegenerative disorders, deserving to advance in molecular optimization studies and further in vitro and in vivo characterization.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107066"},"PeriodicalIF":4.3,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-07DOI: 10.1016/j.ejps.2025.107061
Rofida Albash , Abdurrahman M. Fahmy , Hesham A. Shamsel-Din , Ahmed B. Ibrahim , Hanin A. Bogari , Rania T. Malatani , Manar Adel Abdelbari , Shaimaa Mosallam
The present work aimed to load propranolol hydrochloride (PN), a beta-blocking agent with low oral bioavailability, into PLGA-lipid hybrid nanoparticles (PLHNPs) for augmenting its efficacy. PLHNPs contain phospholipid (PC) in addition to PLGA to augment the potential of PLGA nanoparticles in the intranasal delivery and PN avoidance of the blood–brain barrier for the management of migraine. PLHNPs were prepared by single emulsion/ solvent evaporation method and then optimized by applying 23 full factorial design using PC amount (mg) (X1), PLGA amount (mg) (X2), and surface active agent type (X3) as independent variables, whilst their effect was inspected for entrapment efficiency percent (EE%) (Y1) and particle size (PS) (Y2). Design-Expert® was utilized to choose the optimum PLHNPs for more explorations. The optimum PLHNPs formulation (F2) had EE% of 78.00 ± 0.71 %, PS of 104.50 ± 2.04 nm, polydispersity index of 0.429 ± 0.033, and zeta potential of 23.70 ± 0.10 mV. The optimum PLHNPs formulation was stable for up to 90 days. Moreover, it showed a sustained release profile compared to PN solution. It also showed a spherical shape under a transmission electron microscope. The optimized PN-loaded PLHNPs formulation was radio formulated with radiolabeled isotope ([99mTc]Tc) in maximum radiolabeling yield (91.40 ± 1.85 %) of [99mTc]Tc-PLHNPs to be used in radiological evaluation for in-vivo biodistribution and brain targeting after oral and intranasal administration. [99mTc]Tc-PLHNPs showed higher brain targeting (5.80 ± 0.12 % ID/g) with a high brain-to-blood ratio of (2.42 ± 0.14) at 0.5 h after intranasal administration in addition to controlled blood levels and sustained release up to 8 h that confirm the efficacy of PLHNPs for brain targeting.
{"title":"Intranasal propranolol hydrochloride-loaded PLGA-lipid hybrid nanoparticles for brain targeting: Optimization and biodistribution study by radiobiological evaluation","authors":"Rofida Albash , Abdurrahman M. Fahmy , Hesham A. Shamsel-Din , Ahmed B. Ibrahim , Hanin A. Bogari , Rania T. Malatani , Manar Adel Abdelbari , Shaimaa Mosallam","doi":"10.1016/j.ejps.2025.107061","DOIUrl":"10.1016/j.ejps.2025.107061","url":null,"abstract":"<div><div>The present work aimed to load propranolol hydrochloride (PN), a beta-blocking agent with low oral bioavailability, into PLGA-lipid hybrid nanoparticles (PLHNPs) for augmenting its efficacy. PLHNPs contain phospholipid (PC) in addition to PLGA to augment the potential of PLGA nanoparticles in the intranasal delivery and PN avoidance of the blood–brain barrier for the management of migraine. PLHNPs were prepared by single emulsion/ solvent evaporation method and then optimized by applying 2<sup>3</sup> full factorial design using PC amount (mg) (X<sub>1</sub>), PLGA amount (mg) (X<sub>2</sub>), and surface active agent type (X<sub>3</sub>) as independent variables, whilst their effect was inspected for entrapment efficiency percent (EE%) (Y<sub>1</sub>) and particle size (PS) (Y<sub>2</sub>). Design-Expert® was utilized to choose the optimum PLHNPs for more explorations. The optimum PLHNPs formulation (F2) had EE% of 78.00 ± 0.71 %, PS of 104.50 ± 2.04 nm, polydispersity index of 0.429 ± 0.033, and zeta potential of 23.70 ± 0.10 mV. The optimum PLHNPs formulation was stable for up to 90 days. Moreover, it showed a sustained release profile compared to PN solution. It also showed a spherical shape under a transmission electron microscope. The optimized PN-loaded PLHNPs formulation was radio formulated with radiolabeled isotope ([<sup>99m</sup>Tc]Tc) in maximum radiolabeling yield (91.40 ± 1.85 %) of [<sup>99m</sup>Tc]Tc-PLHNPs to be used in radiological evaluation for <em>in-vivo</em> biodistribution and brain targeting after oral and intranasal administration. [<sup>99m</sup>Tc]Tc-PLHNPs showed higher brain targeting (5.80 ± 0.12 % ID/g) with a high brain-to-blood ratio of (2.42 ± 0.14) at 0.5 h after intranasal administration in addition to controlled blood levels and sustained release up to 8 h that confirm the efficacy of PLHNPs for brain targeting.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"208 ","pages":"Article 107061"},"PeriodicalIF":4.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585083","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}
Pub Date : 2025-03-04DOI: 10.1016/j.ejps.2025.107059
Roghayeh Kamran Samani, Masoud A Mehrgardi, Fatemeh Maghsoudinia, Mohammad Najafi, Fatemeh Mehradnia
The efficacy of radiation therapy can decrease due to the inherent radioresistance of different tumor cells. Gadolinium shows significant potential as a radiosensitivity enhancer due to its high atomic number. In this study, a novel theranostic nanoprobe based on folic acid-conjugated gadolinium-loaded nanodroplets (FA-Gd-NDs) has been introduced for ultrasound imaging (USI)-guided radiation therapy of hepatocellular carcinoma. The ultrasound echogenicity evaluation of NDs, Gd release studies, biocompatibility test of Gd-NDs, colony assay, cellular uptake of NDs via fluorescence microscopy, and flow cytometry analysis were performed on Hepa1-6 cancer and L929 normal cell lines. Our results showed that synthesized NDs significantly enhanced ultrasound signal intensity in PBS solution and agarose gel phantom. MTT and clonogenic assays indicated that Gd-NDs substantially reduced the cell viability and also surviving fraction of Hepa1-6 cancer cells under US and X-ray exposure. Additionally, FA-Gd-NDs exhibited sensitization enhancement factor (SER) of 1.8 after concurrent exposure to US and X-ray. Fluorescence imaging demonstrated more internalization of FA-Gd-NDs into cancer cells in comparison with normal cells. According to flow cytometry results, the Gd-NDs and FA-Gd-NDs uptake by L929 cell line were 20% and 28%, respectively, while their uptake by Hepa1-6 cells was 60% and 94%, respectively. In conclusion, the synthesized novel theranostic nanoprobe shows great potential for enhancing the efficacy of radiation therapy and enabling ultrasound image-guided radiation therapy of cancers.
{"title":"Evaluation of folic acid-targeted gadolinium-loaded perfluorohexane nanodroplets on the megavoltage X-ray treatment efficiency of liver cancer.","authors":"Roghayeh Kamran Samani, Masoud A Mehrgardi, Fatemeh Maghsoudinia, Mohammad Najafi, Fatemeh Mehradnia","doi":"10.1016/j.ejps.2025.107059","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107059","url":null,"abstract":"<p><p>The efficacy of radiation therapy can decrease due to the inherent radioresistance of different tumor cells. Gadolinium shows significant potential as a radiosensitivity enhancer due to its high atomic number. In this study, a novel theranostic nanoprobe based on folic acid-conjugated gadolinium-loaded nanodroplets (FA-Gd-NDs) has been introduced for ultrasound imaging (USI)-guided radiation therapy of hepatocellular carcinoma. The ultrasound echogenicity evaluation of NDs, Gd release studies, biocompatibility test of Gd-NDs, colony assay, cellular uptake of NDs via fluorescence microscopy, and flow cytometry analysis were performed on Hepa1-6 cancer and L929 normal cell lines. Our results showed that synthesized NDs significantly enhanced ultrasound signal intensity in PBS solution and agarose gel phantom. MTT and clonogenic assays indicated that Gd-NDs substantially reduced the cell viability and also surviving fraction of Hepa1-6 cancer cells under US and X-ray exposure. Additionally, FA-Gd-NDs exhibited sensitization enhancement factor (SER) of 1.8 after concurrent exposure to US and X-ray. Fluorescence imaging demonstrated more internalization of FA-Gd-NDs into cancer cells in comparison with normal cells. According to flow cytometry results, the Gd-NDs and FA-Gd-NDs uptake by L929 cell line were 20% and 28%, respectively, while their uptake by Hepa1-6 cells was 60% and 94%, respectively. In conclusion, the synthesized novel theranostic nanoprobe shows great potential for enhancing the efficacy of radiation therapy and enabling ultrasound image-guided radiation therapy of cancers.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107059"},"PeriodicalIF":4.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-03DOI: 10.1016/j.ejps.2025.107058
Lingling Ye , Hong Zhou , Guimu Guo, Ming Chen, Jinhua Zhang
Daptomycin is widely used in pediatric patients for serious infections caused by Gram-positive bacteria, however, studies regarding its safety and efficacy in infants within 1 year old are very limited. A physiologically-based pharmacokinetic (PBPK) model of daptomycin was built for children aged 1–17 years old and extrapolated to infants within 1 year old to evaluate pharmacodynamics (PD) based on efficacy and safety considerations. Monte Carlo Simulations (MCSs) were conducted to determine the probabilities of target attainment (PTA) and cumulative fractions of response (CFR) of daptomycin. The pharmacokinetic (PK) of daptomycin did not differ much in the population of infants within 1 year of age, with peak plasma concentration (Cmax) and area under the curve (AUC) maintained at an approximate level at all months of age, while the average trough concentration of daptomycin was 3.49 μg/mL when 10 mg/kg daptomycin was given, and 4.98 ug /mL at 15 mg/kg. According to the results of the MCSs, 10mg/kg daptomycin provides good antimicrobial effect for S.pneumoniae and MSSA. With the increase of dosage, the CFR value of daptomycin against MRSA, E.faecalis and E.faecium also gradually reached >90 %, except for E.faecalis with an average CFR of only 82.94 % at 12mg/kg. This is a daptomycin PBPK model in infants within 1 year of age, dose regimen higher than 10 mg/kg should be recommended for this population in the treatment of MRSA, E. faecalis, and E. faecalis.
{"title":"Physiologically-based pharmacokinetic modeling to predict the exposure and to assess pharmacodynamics of daptomycin in infants within 1 year old","authors":"Lingling Ye , Hong Zhou , Guimu Guo, Ming Chen, Jinhua Zhang","doi":"10.1016/j.ejps.2025.107058","DOIUrl":"10.1016/j.ejps.2025.107058","url":null,"abstract":"<div><div>Daptomycin is widely used in pediatric patients for serious infections caused by Gram-positive bacteria, however, studies regarding its safety and efficacy in infants within 1 year old are very limited. A physiologically-based pharmacokinetic (PBPK) model of daptomycin was built for children aged 1–17 years old and extrapolated to infants within 1 year old to evaluate pharmacodynamics (PD) based on efficacy and safety considerations. Monte Carlo Simulations (MCSs) were conducted to determine the probabilities of target attainment (PTA) and cumulative fractions of response (CFR) of daptomycin. The pharmacokinetic (PK) of daptomycin did not differ much in the population of infants within 1 year of age, with peak plasma concentration (C<sub>max</sub>) and area under the curve (AUC) maintained at an approximate level at all months of age, while the average trough concentration of daptomycin was 3.49 μg/mL when 10 mg/kg daptomycin was given, and 4.98 ug /mL at 15 mg/kg. According to the results of the MCSs, 10mg/kg daptomycin provides good antimicrobial effect for S.pneumoniae and MSSA. With the increase of dosage, the CFR value of daptomycin against MRSA, E.faecalis and E.faecium also gradually reached >90 %, except for E.faecalis with an average CFR of only 82.94 % at 12mg/kg. This is a daptomycin PBPK model in infants within 1 year of age, dose regimen higher than 10 mg/kg should be recommended for this population in the treatment of MRSA, E. faecalis, and E. faecalis.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"208 ","pages":"Article 107058"},"PeriodicalIF":4.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562933","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}
Pub Date : 2025-03-03DOI: 10.1016/j.ejps.2025.107057
Nasreddine El Omari , Saad Bakrim , Hamza Elhrech , Tarik Aanniz , Abdelaali Balahbib , Learn-Han Lee , Waleed Al Abdulmonem , Abdelhakim Bouyahya
Lymphomas are complex malignancies of blood cells, characterized by the malignant transformation of lymphocytes. This transformation is partially driven by disruptions in epigenetic regulation, particularly the acetylation of histones. Among the key players in this process are histone deacetylases (HDACs), whose aberrant activity contributes significantly to lymphoma development. Consequently, targeting HDACs represents a promising pharmacotherapeutic approach. Several HDAC inhibitors (HDACis) have demonstrated significant anticancer effects, with four FDA-approved molecules—vorinostat, romidepsin, belinostat, and panobinostat—forming critical components of chemotherapy regimens for lymphoma treatment. These HDAC inhibitors exhibit their therapeutic efficacy through mechanisms that indirectly impact cellular memory and induce cancer cell death via apoptosis and cell cycle arrest. Their clinical effectiveness is particularly notable in various types of lymphomas, underscoring their therapeutic potential.
The objective of this review is to provide a detailed analysis of FDA-approved HDACis, focusing on their molecular mechanisms of action and clinical applications in lymphoma treatment. Specifically, we aim to elucidate how these inhibitors modulate epigenetic regulation to achieve therapeutic efficacy, highlight their utility across different lymphoma subtypes, and examine their integration into combination therapies with other anticancer agents. Furthermore, this review seeks to identify gaps in current knowledge and propose directions for future research, including the development of next-generation HDAC inhibitors and strategies for optimizing their clinical use. By consolidating existing evidence, we strive to enhance the understanding of HDACis' role in lymphoma therapy and inspire advancements in their therapeutic potential.
{"title":"Clinical efficacy and mechanistic insights of FDA-approved HDAC inhibitors in the treatment of lymphoma","authors":"Nasreddine El Omari , Saad Bakrim , Hamza Elhrech , Tarik Aanniz , Abdelaali Balahbib , Learn-Han Lee , Waleed Al Abdulmonem , Abdelhakim Bouyahya","doi":"10.1016/j.ejps.2025.107057","DOIUrl":"10.1016/j.ejps.2025.107057","url":null,"abstract":"<div><div>Lymphomas are complex malignancies of blood cells, characterized by the malignant transformation of lymphocytes. This transformation is partially driven by disruptions in epigenetic regulation, particularly the acetylation of histones. Among the key players in this process are histone deacetylases (HDACs), whose aberrant activity contributes significantly to lymphoma development. Consequently, targeting HDACs represents a promising pharmacotherapeutic approach. Several HDAC inhibitors (HDACis) have demonstrated significant anticancer effects, with four FDA-approved molecules—vorinostat, romidepsin, belinostat, and panobinostat—forming critical components of chemotherapy regimens for lymphoma treatment. These HDAC inhibitors exhibit their therapeutic efficacy through mechanisms that indirectly impact cellular memory and induce cancer cell death <em>via</em> apoptosis and cell cycle arrest. Their clinical effectiveness is particularly notable in various types of lymphomas, underscoring their therapeutic potential.</div><div>The objective of this review is to provide a detailed analysis of FDA-approved HDACis, focusing on their molecular mechanisms of action and clinical applications in lymphoma treatment. Specifically, we aim to elucidate how these inhibitors modulate epigenetic regulation to achieve therapeutic efficacy, highlight their utility across different lymphoma subtypes, and examine their integration into combination therapies with other anticancer agents. Furthermore, this review seeks to identify gaps in current knowledge and propose directions for future research, including the development of next-generation HDAC inhibitors and strategies for optimizing their clinical use. By consolidating existing evidence, we strive to enhance the understanding of HDACis' role in lymphoma therapy and inspire advancements in their therapeutic potential.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"208 ","pages":"Article 107057"},"PeriodicalIF":4.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566397","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号