Pub Date : 2025-02-05DOI: 10.1016/j.ijpharm.2025.125321
Jaslene A. Francis , Leah Wright , Richard van Wegen , Chun-Xia Zhao , Robert J. Falconer
Repulsion between proteins is an advantageous attribute in aqueous protein formulations as it enhances solubility, and reduces precipitation, opalescence and viscosity. The interaction parameter () of lysozyme in solution was measured using dynamic light scattering (DLS). is a measure of attraction and repulsion between particles. All anions tested caused a drop in the of lysozyme consistent with charge screening. The buffer, citrate caused the greatest negative impact on the value of lysozyme, possibly due to a combination of charge screening, charge reversal and non-covalent crosslinking of the lysozyme molecules. Conversely, histidine buffer, had the least impact on the value of lysozyme. The ionic and non-ionic tonicity modifiers, sodium chloride and sucrose, both reduced repulsion between lysozyme molecules in both citrate and histidine buffers.
{"title":"Effects of salts, buffers and sucrose on protein–protein attractive and repulsive interactions","authors":"Jaslene A. Francis , Leah Wright , Richard van Wegen , Chun-Xia Zhao , Robert J. Falconer","doi":"10.1016/j.ijpharm.2025.125321","DOIUrl":"10.1016/j.ijpharm.2025.125321","url":null,"abstract":"<div><div>Repulsion between proteins is an advantageous attribute in aqueous protein formulations as it enhances solubility, and reduces precipitation, opalescence and viscosity. The interaction parameter (<span><math><mrow><msub><mi>k</mi><mi>D</mi></msub></mrow></math></span>) of lysozyme in solution was measured using dynamic light scattering (DLS). <span><math><mrow><msub><mi>k</mi><mi>D</mi></msub></mrow></math></span> is a measure of attraction and repulsion between particles. All anions tested caused a drop in the <span><math><mrow><msub><mi>k</mi><mi>D</mi></msub></mrow></math></span> of lysozyme consistent with charge screening. The buffer, citrate caused the greatest negative impact on the <span><math><mrow><msub><mi>k</mi><mi>D</mi></msub></mrow></math></span> value of lysozyme, possibly due to a combination of charge screening, charge reversal and non-covalent crosslinking of the lysozyme molecules. Conversely, histidine buffer, had the least impact on the <span><math><mrow><msub><mi>k</mi><mi>D</mi></msub></mrow></math></span> value of lysozyme. The ionic and non-ionic tonicity modifiers, sodium chloride and sucrose, both reduced repulsion between lysozyme molecules in both citrate and histidine buffers.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125321"},"PeriodicalIF":5.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-05DOI: 10.1016/j.ijpharm.2025.125318
Yan Zhao, Jiahua Wang, Zixu Zhang, Liang Kong, Mo Liu, Muhan Chen, Lianjun Gao
Objective: Heart failure (HF) is a prevalent, refractory, and costly medical condition. As most current strategies have failed to yield beneficial clinical outcomes, microenvironment-responsive micelles have been developed to target cardiomyocyte mitochondria to improve HF.
Methods: In this paper, we constructed reactive oxygen species (ROS)-responsive triphenylphosphine (TPP)-modified tanshinone IIA (TIIA) micelles (TK-TPP-TIIA@Ms). TIIA was encapsulated within the micelles and utilized TPP-conjugated DSPE-PEG2000 as the targeting molecule and ROS-responsive bond TK as the linker arm connecting DSPE-PEG5000. The formation of a hydrated membrane on the micelle surface prolonged micelle circulation while preventing active targeting molecules from binding to the mitochondria of normal cardiomyocytes throughout the body, which reduced drug accumulation in healthy tissues. In the HF microenvironment, TK was cleaved by overexpressed ROS, which led to the shedding of the PEG5000 hydration layer and the subsequent exposure of the target ligand TPP. This process facilitated TPP uptake by activated cardiomyocyte mitochondria and exerted anti-HF effects. Furthermore, in vivo and in vitro experiments were conducted to verify its effect on improving doxorubicin (DOX)-induced HF, which focused on oxidative stress, apoptosis, and inflammation.
Results: TK-TPP-TIIA@Ms was successfully prepared and exhibited normal appearance and morphology, appropriate particle size, and zeta potential; and demonstrated good encapsulation efficiency, drug loading, and biological safety. In vitro studies showed that TK-TPP-TIIA@Ms had strong uptake ability in H9c2 cells, which led to reduced DOX-induced ROS expression, decreased secretion of inflammatory factors, inhibition of cell apoptosis, and restoration of normal mitochondrial membrane potential. In vivo, TK-TPP-TIIA@Ms effectively ameliorated DOX-induced myocardial tissue damage, reduced cell apoptosis, decreased the expression of inflammatory factors, and improved oxidative stress, which inhibited DOX-induced HF in mice.
Conclusion: TK-TPP-TIIA@Ms is an effective and safe strategy for the targeted therapy of heart diseases and is expected to become a potential treatment for heart failure.
{"title":"A ROS-responsive TPP-modified tanshinone IIA micelle improves DOX-induced heart failure.","authors":"Yan Zhao, Jiahua Wang, Zixu Zhang, Liang Kong, Mo Liu, Muhan Chen, Lianjun Gao","doi":"10.1016/j.ijpharm.2025.125318","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.125318","url":null,"abstract":"<p><strong>Objective: </strong>Heart failure (HF) is a prevalent, refractory, and costly medical condition. As most current strategies have failed to yield beneficial clinical outcomes, microenvironment-responsive micelles have been developed to target cardiomyocyte mitochondria to improve HF.</p><p><strong>Methods: </strong>In this paper, we constructed reactive oxygen species (ROS)-responsive triphenylphosphine (TPP)-modified tanshinone IIA (TIIA) micelles (TK-TPP-TIIA@Ms). TIIA was encapsulated within the micelles and utilized TPP-conjugated DSPE-PEG<sub>2000</sub> as the targeting molecule and ROS-responsive bond TK as the linker arm connecting DSPE-PEG<sub>5000</sub>. The formation of a hydrated membrane on the micelle surface prolonged micelle circulation while preventing active targeting molecules from binding to the mitochondria of normal cardiomyocytes throughout the body, which reduced drug accumulation in healthy tissues. In the HF microenvironment, TK was cleaved by overexpressed ROS, which led to the shedding of the PEG<sub>5000</sub> hydration layer and the subsequent exposure of the target ligand TPP. This process facilitated TPP uptake by activated cardiomyocyte mitochondria and exerted anti-HF effects. Furthermore, in vivo and in vitro experiments were conducted to verify its effect on improving doxorubicin (DOX)-induced HF, which focused on oxidative stress, apoptosis, and inflammation.</p><p><strong>Results: </strong>TK-TPP-TIIA@Ms was successfully prepared and exhibited normal appearance and morphology, appropriate particle size, and zeta potential; and demonstrated good encapsulation efficiency, drug loading, and biological safety. In vitro studies showed that TK-TPP-TIIA@Ms had strong uptake ability in H9c2 cells, which led to reduced DOX-induced ROS expression, decreased secretion of inflammatory factors, inhibition of cell apoptosis, and restoration of normal mitochondrial membrane potential. In vivo, TK-TPP-TIIA@Ms effectively ameliorated DOX-induced myocardial tissue damage, reduced cell apoptosis, decreased the expression of inflammatory factors, and improved oxidative stress, which inhibited DOX-induced HF in mice.</p><p><strong>Conclusion: </strong>TK-TPP-TIIA@Ms is an effective and safe strategy for the targeted therapy of heart diseases and is expected to become a potential treatment for heart failure.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"125318"},"PeriodicalIF":5.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374111","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}
Pub Date : 2025-02-04DOI: 10.1016/j.ijpharm.2025.125300
Connor T. Murphy , Eric M. Bachelder , Kristy M. Ainslie
Mast cells have roles in immune regulation, allergy, and host response to pathogens. Compounds that activate mast cells (MCAs) can serve as vaccine adjuvants, potentially outperforming current FDA-approved options, especially for mucosal vaccines. While most vaccines are administered intramuscularly, intranasal and needle-free formulations offer benefits like improved compliance and accessibility. However, the lack of effective adjuvants limits mucosal vaccine development. This review explores MCAs as promising alternatives to traditional adjuvants, aiming to enhance mucosal vaccine efficacy. We summarize the nascent work of formulating MCAs like compound 48/80 into nanoparticles, with excipients such as chitosan and chitosan/alginate. Other MCAs like the peptide mastoparan 7 complexed with CpG have formed nanoparticle complexes that illustrate protective mucosal immunity in a model of influenza. The small molecule MCA ST101036, when encapsulated in acetalated dextran particles, has demonstrated enhanced immune responses and protection in a West Nile Virus model of infection. This review highlights the potential of MCAs as potent vaccine adjuvants, particularly for mucosal vaccines, and summarizes, recent advancements in formulating these activators into nanoparticles to enhance immune responses and protection.
{"title":"Mast cell activators as adjuvants for intranasal mucosal vaccines","authors":"Connor T. Murphy , Eric M. Bachelder , Kristy M. Ainslie","doi":"10.1016/j.ijpharm.2025.125300","DOIUrl":"10.1016/j.ijpharm.2025.125300","url":null,"abstract":"<div><div>Mast cells have roles in immune regulation, allergy, and host response to pathogens. Compounds that activate mast cells (MCAs) can serve as vaccine adjuvants, potentially outperforming current FDA-approved options, especially for mucosal vaccines. While most vaccines are administered intramuscularly, intranasal and needle-free formulations offer benefits like improved compliance and accessibility. However, the lack of effective adjuvants limits mucosal vaccine development. This review explores MCAs as promising alternatives to traditional adjuvants, aiming to enhance mucosal vaccine efficacy. We summarize the nascent work of formulating MCAs like compound 48/80 into nanoparticles, with excipients such as chitosan and chitosan/alginate. Other MCAs like the peptide mastoparan 7 complexed with CpG have formed nanoparticle complexes that illustrate protective mucosal immunity in a model of influenza. The small molecule MCA ST101036, when encapsulated in acetalated dextran particles, has demonstrated enhanced immune responses and protection in a West Nile Virus model of infection. This review highlights the potential of MCAs as potent vaccine adjuvants, particularly for mucosal vaccines, and summarizes, recent advancements in formulating these activators into nanoparticles to enhance immune responses and protection.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125300"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348547","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}
Pub Date : 2025-02-04DOI: 10.1016/j.ijpharm.2025.125295
Shiwei Feng , Yan Li , Zheng Tan , Shiyang Shen
Nucleic acid drugs utilize DNA or RNA molecules to modulate abnormal gene expression or protein translation in cells, enabling precise treatment for specific conditions. In recent years, nucleic acid drugs have demonstrated tremendous potential in vaccine development and treating genetic disorders. Currently, the primary carriers for clinically approved nucleic acid therapies include lipid nanoparticles and viral vectors. Beyond that, metal–organic frameworks (MOFs) are highly ordered, porous nanomaterials formed through the self-assembly of metal ions and organic ligands via coordination bonds. Their porosity structure offers great loading efficiency, stability, tunability, and biocompatibility, making them an attractive option for nucleic acid delivery. Given the research on MOFs as nucleic acid carriers has garnered significant attention in recent years, this review provides an overview of the therapeutic strategies and advancements in MOF-mediated nucleic acid delivery. The unique properties of various MOF carriers are introduced, and different approaches for nucleic acid loading are parallelly compared. Moreover, a systematic classification based on the type of nucleic acid cargo loaded in MOFs and corresponding applications is thoroughly described. This summary outlines the unique mechanisms through MOFs enhance nucleic acid delivery and emphasizes their substantial impact on therapeutic efficacy. In addition, the utilization of MOF-mediated nucleic acid treatment in combination with other therapies against malignant tumors is discussed in particular. Finally, an outlook on the challenges and potential opportunities of this technology in future translational production and clinical implementation is presented and explored.
{"title":"Current landscape of metal–organic framework-mediated nucleic acid delivery and therapeutics","authors":"Shiwei Feng , Yan Li , Zheng Tan , Shiyang Shen","doi":"10.1016/j.ijpharm.2025.125295","DOIUrl":"10.1016/j.ijpharm.2025.125295","url":null,"abstract":"<div><div>Nucleic acid drugs utilize DNA or RNA molecules to modulate abnormal gene expression or protein translation in cells, enabling precise treatment for specific conditions. In recent years, nucleic acid drugs have demonstrated tremendous potential in vaccine development and treating genetic disorders. Currently, the primary carriers for clinically approved nucleic acid therapies include lipid nanoparticles and viral vectors. Beyond that, metal–organic frameworks (MOFs) are highly ordered, porous nanomaterials formed through the self-assembly of metal ions and organic ligands via coordination bonds. Their porosity structure offers great loading efficiency, stability, tunability, and biocompatibility, making them an attractive option for nucleic acid delivery. Given the research on MOFs as nucleic acid carriers has garnered significant attention in recent years, this review provides an overview of the therapeutic strategies and advancements in MOF-mediated nucleic acid delivery. The unique properties of various MOF carriers are introduced, and different approaches for nucleic acid loading are parallelly compared. Moreover, a systematic classification based on the type of nucleic acid cargo loaded in MOFs and corresponding applications is thoroughly described. This summary outlines the unique mechanisms through MOFs enhance nucleic acid delivery and emphasizes their substantial impact on therapeutic efficacy. In addition, the utilization of MOF-mediated nucleic acid treatment in combination with other therapies against malignant tumors is discussed in particular. Finally, an outlook on the challenges and potential opportunities of this technology in future translational production and clinical implementation is presented and explored.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125295"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364719","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}
Pub Date : 2025-02-04DOI: 10.1016/j.ijpharm.2025.125265
Junxiao Zhu , Tianjian Ye , Mi Tang , Yuan Gao , Jianjun Zhang , Shuai Qian , Yuanfeng Wei
Deep eutectic solvents (DES) enhance drug solubility but require delivery systems, while the Ouzo effect enables surfactant-free microemulsion formation despite limitations in oil phase ratio. By integrating DES as the oil phase, this study develops a dual Ouzo effect microemulsion system that induces both microemulsions and nanoprecipitations simultaneously. Through detailed analysis of composition diagrams, precise adjustment of the mass ratio of VA64 to propylene glycol enables strict control over particle size from 200 nm to 550 nm. This approach enhanced curcumin’s solubility to 17.11 mg/mL, a 1700-fold increase compared to its water solubility, with excellent stability showing only 22.4 % degradation after 4 h of light exposure (versus 90–95 % in conventional carriers). The system increased the cumulative release amount of curcumin and presented a rapid initial release followed by a sustained release. Compared with traditional Ouzo effect systems, introducing DES significantly increased the oil phase ratio from 0.05 % to 30 % through enhanced molecular interactions and supersaturation. DES composition adjustment enabled microemulsion stabilization without complex processing, achieving optimal stability with a three-phase contact angle of 89.2° (±0.3°), approaching the theoretical ideal value of 90° for interface stability.
{"title":"Eco-Friendly high Drug-Loading microemulsions with Incorporation of Deep eutectic Solvents: Advancing precision with the dual Ouzo effect","authors":"Junxiao Zhu , Tianjian Ye , Mi Tang , Yuan Gao , Jianjun Zhang , Shuai Qian , Yuanfeng Wei","doi":"10.1016/j.ijpharm.2025.125265","DOIUrl":"10.1016/j.ijpharm.2025.125265","url":null,"abstract":"<div><div>Deep eutectic solvents (DES) enhance drug solubility but require delivery systems, while the Ouzo effect enables surfactant-free microemulsion formation despite limitations in oil phase ratio. By integrating DES as the oil phase, this study develops a dual Ouzo effect microemulsion system that induces both microemulsions and nanoprecipitations simultaneously. Through detailed analysis of composition diagrams, precise adjustment of the mass ratio of VA64 to propylene glycol enables strict control over particle size from 200 nm to 550 nm. This approach enhanced curcumin’s solubility to 17.11 mg/mL, a 1700-fold increase compared to its water solubility, with excellent stability showing only 22.4 % degradation after 4 h of light exposure (versus 90–95 % in conventional carriers). The system increased the cumulative release amount of curcumin and presented a rapid initial release followed by a sustained release. Compared with traditional Ouzo effect systems, introducing DES significantly increased the oil phase ratio from 0.05 % to 30 % through enhanced molecular interactions and supersaturation. DES composition adjustment enabled microemulsion stabilization without complex processing, achieving optimal stability with a three-phase contact angle of 89.2° (±0.3°), approaching the theoretical ideal value of 90° for interface stability.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125265"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143348548","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}
Pub Date : 2025-02-04DOI: 10.1016/j.ijpharm.2025.125304
Francesco Patitucci , Marisa Francesca Motta , Olga Mileti , Marco Dattilo , Rocco Malivindi , Giuseppe Pezzi , Domenico Gabriele , Ortensia Ilaria Parisi , Francesco Puoci
Burn wounds remain a major clinical challenge due to the limitations of traditional dressings, which often fail to address the diverse needs of patients and varying wound types. This study aimed to advance burn care by developing a 3D-printed patch incorporating natural bioactive compounds from bromelain and aloe vera. The patch was formulated using pre-crosslinked chitosan and alginate hydrogels to ensure suitability for 3D printing and subsequent use. Rheological analysis revealed weak gel behaviour and shear-thinning properties, ensuring excellent printability. The patches exhibited outstanding swelling behaviour and controlled degradation (30 %), alongside notable antioxidant and anti-inflammatory potential, with a polyphenolic content of 1.43 ± 0.07 mg CAE/g and effective scavenging of DPPH, ABTS, and NO radicals, with IC50 values of 29.51 ± 0.30, 10.31 ± 0.28, and 5.94 ± 0.42 mg/mL, respectively. Bioactive compounds from bromelain were consistently released across various pH levels, supporting their therapeutic efficacy. Cell viability studies confirmed strong support for cell growth, while in vitro scratch tests demonstrated biocompatibility and promotion of wound closure. Histological analysis of ex vivo burn models revealed cellular necrosis and protein denaturation characteristic of burn wounds. Application of the patches significantly improved epidermal morphology and enhanced proliferation markers such as Ki67 and α-SMA, indicative of accelerated wound healing. While further clinical validation is needed, these findings underscore the potential of the 3D-printed patches as an innovative solution for burn wound care, offering improved bioactive delivery and enhanced healing outcomes compared to conventional dressings.
{"title":"Enhancing burn wound care with pre-crosslinked 3D-printed patches: Bromelain delivery and aloe vera bioactives integration for improved healing outcomes","authors":"Francesco Patitucci , Marisa Francesca Motta , Olga Mileti , Marco Dattilo , Rocco Malivindi , Giuseppe Pezzi , Domenico Gabriele , Ortensia Ilaria Parisi , Francesco Puoci","doi":"10.1016/j.ijpharm.2025.125304","DOIUrl":"10.1016/j.ijpharm.2025.125304","url":null,"abstract":"<div><div>Burn wounds remain a major clinical challenge due to the limitations of traditional dressings, which often fail to address the diverse needs of patients and varying wound types. This study aimed to advance burn care by developing a 3D-printed patch incorporating natural bioactive compounds from bromelain and aloe vera. The patch was formulated using pre-crosslinked chitosan and alginate hydrogels to ensure suitability for 3D printing and subsequent use. Rheological analysis revealed weak gel behaviour and shear-thinning properties, ensuring excellent printability. The patches exhibited outstanding swelling behaviour and controlled degradation (30 %), alongside notable antioxidant and anti-inflammatory potential, with a polyphenolic content of 1.43 ± 0.07 mg CAE/g and effective scavenging of DPPH, ABTS, and NO radicals, with IC50 values of 29.51 ± 0.30, 10.31 ± 0.28, and 5.94 ± 0.42 mg/mL, respectively. Bioactive compounds from bromelain were consistently released across various pH levels, supporting their therapeutic efficacy. Cell viability studies confirmed strong support for cell growth, while in vitro scratch tests demonstrated biocompatibility and promotion of wound closure. Histological analysis of ex vivo burn models revealed cellular necrosis and protein denaturation characteristic of burn wounds. Application of the patches significantly improved epidermal morphology and enhanced proliferation markers such as Ki67 and α-SMA, indicative of accelerated wound healing. While further clinical validation is needed, these findings underscore the potential of the 3D-printed patches as an innovative solution for burn wound care, offering improved bioactive delivery and enhanced healing outcomes compared to conventional dressings.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125304"},"PeriodicalIF":5.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-03DOI: 10.1016/j.ijpharm.2025.125317
Hans Rollema, Robert Volkmann, Panayiotis Zagouras, Fred Nelson, Tamim Braish, Anthony Marfat, Jan H M Schellens, John S Kovach
LB-100, a small molecule PP2A inhibitor currently in phase 1 and 2 dose-finding and efficacy trials, is an amide that is stable at pH ≥ 10.5, but can hydrolyze at lower pH values to endothall and N-methylpiperazine. Endothall has been detected in plasma of patients after i.v. LB-100 administration, but in vitro LB-100 hydrolysis has not been studied in detail. LC-MS/MS assays of various LB-100 solutions showed that LB-100 rapidly hydrolyzes in aqueous solutions at room temperature (RT) at pH 5.6-6.5 to endothall (t1/2 = 2.1-3.3 h). Although hydrolysis is much slower in PP2A assay medium HEPES pH 7.5 at RT (t1/2 ∼ 20 h), sufficiently high concentrations of the potent phosphatase inhibitor endothall (IC50 = 95 nM) are formed during a 2-hour incubation at RT to inhibit PP2A activity. At 37 °C LB-100 hydrolysis is much faster, with t1/2 values of 3.2 h and 4.9 h in cell culture medium pH 6.8 and pH 7.4, respectively. LB-100 stock in DMSO contains low endothall concentrations, from 0.2 % of LB-100 when dissolved at RT, to 3 % of LB-100 when DMSO is heated at 65 °C. Endothall added via stock solutions and/or formed during incubations, is thus always present in PP2A assays of LB-100. Data from in vitro PP2A assays using DMSO stocks made at RT show that LB-100 is a weak PP2A inhibitor with an apparent IC50 of 12.2 μM, and is 20-fold more potent (IC50 = 0.59 μM), when DMSO stocks are heated to 65 °C and endothall concentrations in assay medium are higher. Endothall concentrations present in LB-100 assays can account for the observed PP2A inhibition, indicating that inhibitory activity measured in LB-100 assays is mainly due to endothall. These data suggest that LB-100 is a prodrug that acts as a PP2A inhibitor through hydrolysis to endothall, which is ultimately responsible for PP2A inhibition and LB-100's pharmacological activity.
{"title":"In vitro studies on stability and phosphatase activity of the anticancer agent LB-100 and its active hydrolysis product endothall.","authors":"Hans Rollema, Robert Volkmann, Panayiotis Zagouras, Fred Nelson, Tamim Braish, Anthony Marfat, Jan H M Schellens, John S Kovach","doi":"10.1016/j.ijpharm.2025.125317","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.125317","url":null,"abstract":"<p><p>LB-100, a small molecule PP2A inhibitor currently in phase 1 and 2 dose-finding and efficacy trials, is an amide that is stable at pH ≥ 10.5, but can hydrolyze at lower pH values to endothall and N-methylpiperazine. Endothall has been detected in plasma of patients after i.v. LB-100 administration, but in vitro LB-100 hydrolysis has not been studied in detail. LC-MS/MS assays of various LB-100 solutions showed that LB-100 rapidly hydrolyzes in aqueous solutions at room temperature (RT) at pH 5.6-6.5 to endothall (t<sub>1/2</sub> = 2.1-3.3 h). Although hydrolysis is much slower in PP2A assay medium HEPES pH 7.5 at RT (t<sub>1/2</sub> ∼ 20 h), sufficiently high concentrations of the potent phosphatase inhibitor endothall (IC<sub>50</sub> = 95 nM) are formed during a 2-hour incubation at RT to inhibit PP2A activity. At 37 °C LB-100 hydrolysis is much faster, with t<sub>1/2</sub> values of 3.2 h and 4.9 h in cell culture medium pH 6.8 and pH 7.4, respectively. LB-100 stock in DMSO contains low endothall concentrations, from 0.2 % of LB-100 when dissolved at RT, to 3 % of LB-100 when DMSO is heated at 65 °C. Endothall added via stock solutions and/or formed during incubations, is thus always present in PP2A assays of LB-100. Data from in vitro PP2A assays using DMSO stocks made at RT show that LB-100 is a weak PP2A inhibitor with an apparent IC<sub>50</sub> of 12.2 μM, and is 20-fold more potent (IC<sub>50</sub> = 0.59 μM), when DMSO stocks are heated to 65 °C and endothall concentrations in assay medium are higher. Endothall concentrations present in LB-100 assays can account for the observed PP2A inhibition, indicating that inhibitory activity measured in LB-100 assays is mainly due to endothall. These data suggest that LB-100 is a prodrug that acts as a PP2A inhibitor through hydrolysis to endothall, which is ultimately responsible for PP2A inhibition and LB-100's pharmacological activity.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"125317"},"PeriodicalIF":5.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255652","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}
Pub Date : 2025-02-03DOI: 10.1016/j.ijpharm.2025.125316
Yizhi Zhang , Jintao Shen , Junzhe Yang , Guiyu Huang , Hong Niu , Shuxiu Zhang , Ziyan Tang , Yaxin Wang , Yaomin Tan , Jingjing Liu , Xi Chen , Lina Du , Yiguang Jin
Traumatic brain injury (TBI) is highly incidental but effective solutions are absent. Moreover, the secondary injury following TBI is arising due to the Ca2+ influx of injured neural cells. Here, a Ca2+ influx inhibitor, nimodipine, was loaded in M2 macrophage membrane-hybrid biomimetic liposomes (NM2Ls). NM2Ls significantly inhibited the influx of Ca2+ into inflammatory neural cells and reduced the expression of inflammatory factors. More importantly, intravenously injected NM2Ls avoided the clearance of the immune system and targeted the brain via CCR2 following TBI; the inflammation in the brain was greatly alleviated in the TBI mouse model. NM2Ls improved the long-term learning and memory abilities as well as the motor abilities of TBI mice. Oxidative stress indicators were reduced and the repair of nerve cells was improved. NM2Ls is a promising brain-targeted medicine by the biomembrane biomimetic strategy.
{"title":"Brain-targeted M2 macrophage membrane-hybrid biomimetic liposomes for treatment of traumatic brain injury","authors":"Yizhi Zhang , Jintao Shen , Junzhe Yang , Guiyu Huang , Hong Niu , Shuxiu Zhang , Ziyan Tang , Yaxin Wang , Yaomin Tan , Jingjing Liu , Xi Chen , Lina Du , Yiguang Jin","doi":"10.1016/j.ijpharm.2025.125316","DOIUrl":"10.1016/j.ijpharm.2025.125316","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is highly incidental but effective solutions are absent. Moreover, the secondary injury following TBI is arising due to the Ca<sup>2+</sup> influx of injured neural cells. Here, a Ca<sup>2+</sup> influx inhibitor, nimodipine, was loaded in M2 macrophage membrane-hybrid biomimetic liposomes (NM2Ls). NM2Ls significantly inhibited the influx of Ca<sup>2+</sup> into inflammatory neural cells and reduced the expression of inflammatory factors. More importantly, intravenously injected NM2Ls avoided the clearance of the immune system and targeted the brain via CCR2 following TBI; the inflammation in the brain was greatly alleviated in the TBI mouse model. NM2Ls improved the long-term learning and memory abilities as well as the motor abilities of TBI mice. Oxidative stress indicators were reduced and the repair of nerve cells was improved. NM2Ls is a promising brain-targeted medicine by the biomembrane biomimetic strategy.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125316"},"PeriodicalIF":5.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143227840","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}
Pub Date : 2025-02-03DOI: 10.1016/j.ijpharm.2025.125314
Jong-Ju Lee , Minji Choi , Yuim Jeon , Dipesh Khanal , Juseung Lee , Dowoong Kim , Hak-Kim Chan , Sung-Joo Hwang
This study investigates the physicochemical transformation of ciprofloxacin (CIP) through hydrophobic ion pairing with five counter ions—sodium oleate, sodium laurate, sodium caprate, disodium pamoate, and sodium deoxycholate—to enhance compatibility with hydrophobic Poly (lactic-co-glycolic acid) (PLGA) nanoparticles. Complexation efficiencies (CE) reached up to 92.26 %, with ciprofloxacin pamoate (CIP-PAM) achieving over 90 % CE at a 1:0.5 M ratio. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses showed reduced crystallinity across all complexes, with CIP-PAM exhibiting an amorphous form. Optical photothermal infrared spectroscopy (O-PTIR) confirmed uniform complexation within particles, while CIP-PAM displayed a broad peak and weak intensity in the 900–1300 cm−1 region, supporting its amorphous nature. Log P values demonstrated increased hydrophobicity for all complexes, with ciprofloxacin oleate (CIP-OLE) showing a 93-fold increase (p < 0.001). In vitro dissociation patterns varied: CIP-OLE maintained steady release in DW (49.7 %) and PBS (32.3 %) over 48 h, whereas CIP-PAM exhibited strong stability in DW (25.2 %) and a contrasting 68.1 % release in PBS, highlighting solvent-dependent dissociation behaviors. PLGA nanoparticles prepared via S/O/W achieved particle sizes under 200 nm, with CIP-PAM showing the highest encapsulation efficiency (63.02 % vs 17.21 % (CIP)). These findings underscore the importance of counter ion selection to optimize CIP compatibility with hydrophobic carriers, providing a basis for improved drug loading of hydrophilic antibiotics.
{"title":"Physicochemical characterization and nanochemical analysis of ciprofloxacin hydrophobic ion Pairs for enhanced encapsulation in PLGA nanoparticle","authors":"Jong-Ju Lee , Minji Choi , Yuim Jeon , Dipesh Khanal , Juseung Lee , Dowoong Kim , Hak-Kim Chan , Sung-Joo Hwang","doi":"10.1016/j.ijpharm.2025.125314","DOIUrl":"10.1016/j.ijpharm.2025.125314","url":null,"abstract":"<div><div>This study investigates the physicochemical transformation of ciprofloxacin (CIP) through hydrophobic ion pairing with five counter ions—sodium oleate, sodium laurate, sodium caprate, disodium pamoate, and sodium deoxycholate—to enhance compatibility with hydrophobic Poly (lactic-co-glycolic acid) (PLGA) nanoparticles. Complexation efficiencies (CE) reached up to 92.26 %, with ciprofloxacin pamoate (CIP-PAM) achieving over 90 % CE at a 1:0.5 M ratio. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses showed reduced crystallinity across all complexes, with CIP-PAM exhibiting an amorphous form. Optical photothermal infrared spectroscopy (O-PTIR) confirmed uniform complexation within particles, while CIP-PAM displayed a broad peak and weak intensity in the 900–1300 cm<sup>−1</sup> region, supporting its amorphous nature. Log P values demonstrated increased hydrophobicity for all complexes, with ciprofloxacin oleate (CIP-OLE) showing a 93-fold increase (p < 0.001). In vitro dissociation patterns varied: CIP-OLE maintained steady release in DW (49.7 %) and PBS (32.3 %) over 48 h, whereas CIP-PAM exhibited strong stability in DW (25.2 %) and a contrasting 68.1 % release in PBS, highlighting solvent-dependent dissociation behaviors. PLGA nanoparticles prepared via S/O/W achieved particle sizes under 200 nm, with CIP-PAM showing the highest encapsulation efficiency (63.02 % vs 17.21 % (CIP)). These findings underscore the importance of counter ion selection to optimize CIP compatibility with hydrophobic carriers, providing a basis for improved drug loading of hydrophilic antibiotics.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125314"},"PeriodicalIF":5.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255653","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}
Pub Date : 2025-02-03DOI: 10.1016/j.ijpharm.2025.125315
Yunting Zhang , Yihua Xu , Weitong Hu , Xiaolu Ma , Jingyi Hu , Yuxian Ye , Shengfei Yang , Yawei Yu , Ni Li , Dawei Zheng , Tianyuan Zhang , Hangjuan Lin , Jianqing Gao
Diabetic wounds have garnered significant attention due to excessive reactive oxygen species (ROS), persistent inflammation, and vascular and neural impairments that hinder effective healing. ROS-scavenging hydrogels with phenylborate bonds possess inherent anti-ROS and anti-inflammatory properties, while human mesenchymal stem cell-derived exosomes (hMSC-exos) offer additional anti-inflammatory, pro-angiogenic, and neurogenic benefits, presenting a promising strategy to address these challenges. This study introduces a novel ROS-scavenging hydrogel loaded with hMSC-exos, which exhibits strong adhesion and self-healing capabilities. Upon application to the wound, it interacts with ROS to produce an anti-inflammatory response, concurrently allowing a sustained release of hMSC-exos. In vitro and in vivo experiments have demonstrated that this hydrogel effectively reduces ROS levels, mitigates inflammation, and promotes angiogenesis and neurogenesis, thus enhancing functional skin restoration and accelerating wound healing. In summary, we propose an innovative therapeutic approach for diabetic wound healing by combining ROS-scavenging hydrogels with hMSC-exos, with the potential to significantly benefit patients.
{"title":"An adhesive and self-healing ROS-scavenging hydrogel loading with hMSC-derived exosomes for diabetic wound healing","authors":"Yunting Zhang , Yihua Xu , Weitong Hu , Xiaolu Ma , Jingyi Hu , Yuxian Ye , Shengfei Yang , Yawei Yu , Ni Li , Dawei Zheng , Tianyuan Zhang , Hangjuan Lin , Jianqing Gao","doi":"10.1016/j.ijpharm.2025.125315","DOIUrl":"10.1016/j.ijpharm.2025.125315","url":null,"abstract":"<div><div>Diabetic wounds have garnered significant attention due to excessive reactive oxygen species (ROS), persistent inflammation, and vascular and neural impairments that hinder effective healing. ROS-scavenging hydrogels with phenylborate bonds possess inherent anti-ROS and anti-inflammatory properties, while human mesenchymal stem cell-derived exosomes (hMSC-exos) offer additional anti-inflammatory, pro-angiogenic, and neurogenic benefits, presenting a promising strategy to address these challenges. This study introduces a novel ROS-scavenging hydrogel loaded with hMSC-exos, which exhibits strong adhesion and self-healing capabilities. Upon application to the wound, it interacts with ROS to produce an anti-inflammatory response, concurrently allowing a sustained release of hMSC-exos. <em>In vitro</em> and <em>in vivo</em> experiments have demonstrated that this hydrogel effectively reduces ROS levels, mitigates inflammation, and promotes angiogenesis and neurogenesis, thus enhancing functional skin restoration and accelerating wound healing. In summary, we propose an innovative therapeutic approach for diabetic wound healing by combining ROS-scavenging hydrogels with hMSC-exos, with the potential to significantly benefit patients.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"672 ","pages":"Article 125315"},"PeriodicalIF":5.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255651","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}
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