Molecular Pharmaceutics最新文献

{"title":"Impact of Microemulsion Oil Components on Liquid–Liquid Phase Separation of a Supersaturated Drug Revealed by Cryo-TEM and 1H NMR Analysis","authors":"Risa Edera,&nbsp;Keisuke Ueda*,&nbsp;Saeko Tomita,&nbsp;Kenjirou Higashi and Kunikazu Moribe,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0125710.1021/acs.molpharmaceut.4c01257","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01257https://doi.org/10.1021/acs.molpharmaceut.4c01257","url":null,"abstract":"<p >Supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) has recently been utilized to enhance the oral absorption of poorly water-soluble drugs. S-SMEDDS forms drug-incorporated microemulsions (MEs) during aqueous dispersion with the formation of drug supersaturation in the bulk water phase. However, the liquid–liquid phase separation (LLPS) behavior of the supersaturated drugs within MEs has not been well studied. This study investigated the impact of S-SMEDDS components on the LLPS of the supersaturated drug and the achievable supersaturation level of the drug in MEs. Fenofibrate (FFB)-loaded S-SMEDDS formulations composed of different oils, Labrafil M 1944 CS (M1944) and Labrafac PG (PG), were prepared and dispersed into water to form MEs (M1944 ME and PG ME). Cryo-TEM measurements revealed the coexistence of swelling micelles and nanosized FFB-rich droplets in highly FFB-loaded MEs, indicating that FFB underwent LLPS even in the MEs. The FFB-rich droplet size was significantly reduced in PG ME. NMR-based quantification of the solubilized FFB in swelling micelles and phase-separated FFB revealed that apparent amorphous solubility of FFB increased with increasing M1944 components in MEs, while that was almost constant regardless of PG contents. On the other hand, PG was largely partitioned into the FFB-rich phase, resulting in the reduction of the chemical potential of FFB in the FFB-rich phase and the maximum free FFB concentration in the bulk water phase. The mixing of PG with the FFB-rich phase would work to maintain the FFB-rich droplet as a smaller size. Meanwhile, M1944 was minimally distributed to the FFB-rich phase, keeping the maximum supersaturation level of FFB. This study highlights that the impact of S-SMEDDS oil components on the physicochemical properties of the drug-rich phase formed via LLPS and achievable drug supersaturation should be considered when designing S-SMEDDS formulations to enhance drug absorption.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1539–1554 1539–1554"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528574","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":"Designing the <i>Aplysia punctata</i> Arginine-Depleting Enzyme for Tumor Targeting.","authors":"Alena Maria Wolkersdorfer, Yuri Endo, Josef Kehrein, Maximilian Kappus, Sumitto Hattori, Marcus Gutmann, Thomas Rudel, Neva Caliskan, Tessa Lühmann, Yoshinori Kato, Lorenz Meinel","doi":"10.1021/acs.molpharmaceut.4c00964","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00964","url":null,"abstract":"<p><p>l-Amino acid oxidases (LAAO) deaminate amino acids to α-keto acids and generate hydrogen peroxide, a reactive oxygen species (ROS) with potential value for cancer therapy. We recombinantly expressed the LAAO from <i>Aplysia punctata</i>, called APIT (Cuvier 1803). The resulting wild-type APIT (APIT_wt) was conjugated to polyethylene glycol (APIT-PEG). Furthermore, an APIT mutant with an affibody targeting the human epidermal growth factor receptor 2 (HER2; zHER2-APIT) was genetically engineered resulting in a binding affinity K_D of ∼ 2.2 nM to the HER2 receptor ectodomain. Further, we evaluated if the APIT and tumor-targeted APIT can be used as an APIT-drug conjugate by covalently amidating the lysine residues on the protein surface. However, for the HER2-targeted APIT, the affibody contains lysines as well, and amidation of these lysines could have impaired the affibody's affinity to the HER2 receptor. Therefore, we designed a lysine-free variant of the tumor-targeting part of zHER2-APIT using an <i>in silico</i> mutation analysis, suggesting the replacement of the lysines of the affibody by arginine or alanine. This new variant is referred to as zHER2(K-del)-APIT. To simulate a covalent drug loading to APIT and the targeting constructs, we attached biotin by amidation. Biotin-zHER2(K-del)-APIT successfully allowed binding to HER2-positive but not HER2-negative cells <i>in vitro</i>. The biodistribution of these novel constructs was tested in xenografted mice with a HER2-positive and negative tumor in each animal. The zHER2(K-del)-APIT lost its ability to target HER2-positive tumors despite the <i>in vitro</i> data suggesting otherwise. The zHER2-APIT accumulated within the HER2-positive tumors but not in the negative tumors. APIT-PEG had increased uptake in HER2-positive and negative tumors compared to APIT_wt, which can be attributed to a prolonged serum half-life achieved by PEGylation, due to the absence of any tumor-targeting effect. These biodistribution studies point to HER2-targeting LAAOs for cancer therapy and PEGylation increasing tumor accumulation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412349","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":"Impact of Microemulsion Oil Components on Liquid-Liquid Phase Separation of a Supersaturated Drug Revealed by Cryo-TEM and ¹H NMR Analysis.","authors":"Risa Edera, Keisuke Ueda, Saeko Tomita, Kenjirou Higashi, Kunikazu Moribe","doi":"10.1021/acs.molpharmaceut.4c01257","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01257","url":null,"abstract":"<p><p>Supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) has recently been utilized to enhance the oral absorption of poorly water-soluble drugs. S-SMEDDS forms drug-incorporated microemulsions (MEs) during aqueous dispersion with the formation of drug supersaturation in the bulk water phase. However, the liquid-liquid phase separation (LLPS) behavior of the supersaturated drugs within MEs has not been well studied. This study investigated the impact of S-SMEDDS components on the LLPS of the supersaturated drug and the achievable supersaturation level of the drug in MEs. Fenofibrate (FFB)-loaded S-SMEDDS formulations composed of different oils, Labrafil M 1944 CS (M1944) and Labrafac PG (PG), were prepared and dispersed into water to form MEs (M1944 ME and PG ME). Cryo-TEM measurements revealed the coexistence of swelling micelles and nanosized FFB-rich droplets in highly FFB-loaded MEs, indicating that FFB underwent LLPS even in the MEs. The FFB-rich droplet size was significantly reduced in PG ME. NMR-based quantification of the solubilized FFB in swelling micelles and phase-separated FFB revealed that apparent amorphous solubility of FFB increased with increasing M1944 components in MEs, while that was almost constant regardless of PG contents. On the other hand, PG was largely partitioned into the FFB-rich phase, resulting in the reduction of the chemical potential of FFB in the FFB-rich phase and the maximum free FFB concentration in the bulk water phase. The mixing of PG with the FFB-rich phase would work to maintain the FFB-rich droplet as a smaller size. Meanwhile, M1944 was minimally distributed to the FFB-rich phase, keeping the maximum supersaturation level of FFB. This study highlights that the impact of S-SMEDDS oil components on the physicochemical properties of the drug-rich phase formed via LLPS and achievable drug supersaturation should be considered when designing S-SMEDDS formulations to enhance drug absorption.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Evaluation of Novel ⁶⁸Ga/¹⁷⁷Lu-Labeled PSMA Inhibitors with Enhanced Pharmacokinetics and Tumor Imaging for Prostate Cancer.","authors":"Haiyang Li, Yang Liu, Hongmei Yuan, Ping Cai, Tongtong Wu, Zhicong Yang, Jiaqi Nie, Wei Zhang, Zhanwen Huang, Nan Liu, Yue Chen, Zhijun Zhou","doi":"10.1021/acs.molpharmaceut.4c01302","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01302","url":null,"abstract":"<p><p>Prostate-specific membrane antigen (PSMA) has been a key target for diagnosing and treating prostate cancer, particularly in high-grade, metastatic, and therapy-resistant tumors. This study presents a series of novel ⁶⁸Ga- and ¹⁷⁷Lu-labeled PSMA inhibitors, derived from the previously developed [⁶⁸Ga]Ga-Flu-1. We explored the impact of PEG chains, lipophilic macrocycles, and dimerization on their in vivo properties. The ⁶⁸Ga- and ¹⁷⁷Lu-labeled inhibitors were assessed for biodistribution and tumor targeting in PC3-PIP tumor xenografts, leading to the identification of several promising candidates based on imaging and tumor-specific uptake. Positron emission tomography (PET) imaging revealed that the poly(ethylene glycol)-modified [⁶⁸Ga]Ga-BisPSMA-P4 demonstrated rapid tumor penetration and excellent tumor-to-background contrast. In comparative biodistribution studies, the naphthalene ring-modified [⁶⁸Ga]Ga-BisPSMA-Nph-P4 showed higher tumor uptake (∼60% ID/g at 1 h postinjection) and rapid renal clearance (∼25% ID/g at 2 h postinjection). Additionally, [¹⁷⁷Lu]Lu-BisPSMA-Nph-P4 displayed superior retention, with significant uptake on day 7, highlighting its potential as a novel PSMA inhibitor for prostate cancer diagnosis and treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416770","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":"Designing the Aplysia punctata Arginine-Depleting Enzyme for Tumor Targeting","authors":"Alena Maria Wolkersdorfer,&nbsp;Yuri Endo,&nbsp;Josef Kehrein,&nbsp;Maximilian Kappus,&nbsp;Sumitto Hattori,&nbsp;Marcus Gutmann,&nbsp;Thomas Rudel,&nbsp;Neva Caliskan,&nbsp;Tessa Lühmann,&nbsp;Yoshinori Kato* and Lorenz Meinel*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0096410.1021/acs.molpharmaceut.4c00964","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00964https://doi.org/10.1021/acs.molpharmaceut.4c00964","url":null,"abstract":"<p ><span>l</span>-Amino acid oxidases (LAAO) deaminate amino acids to α-keto acids and generate hydrogen peroxide, a reactive oxygen species (ROS) with potential value for cancer therapy. We recombinantly expressed the LAAO from <i>Aplysia punctata</i>, called APIT (Cuvier 1803). The resulting wild-type APIT (APIT_wt) was conjugated to polyethylene glycol (APIT-PEG). Furthermore, an APIT mutant with an affibody targeting the human epidermal growth factor receptor 2 (HER2; zHER2-APIT) was genetically engineered resulting in a binding affinity K_D of ∼ 2.2 nM to the HER2 receptor ectodomain. Further, we evaluated if the APIT and tumor-targeted APIT can be used as an APIT-drug conjugate by covalently amidating the lysine residues on the protein surface. However, for the HER2-targeted APIT, the affibody contains lysines as well, and amidation of these lysines could have impaired the affibody’s affinity to the HER2 receptor. Therefore, we designed a lysine-free variant of the tumor-targeting part of zHER2-APIT using an <i>in silico</i> mutation analysis, suggesting the replacement of the lysines of the affibody by arginine or alanine. This new variant is referred to as zHER2(K-del)-APIT. To simulate a covalent drug loading to APIT and the targeting constructs, we attached biotin by amidation. Biotin-zHER2(K-del)-APIT successfully allowed binding to HER2-positive but not HER2-negative cells <i>in vitro</i>. The biodistribution of these novel constructs was tested in xenografted mice with a HER2-positive and negative tumor in each animal. The zHER2(K-del)-APIT lost its ability to target HER2-positive tumors despite the <i>in vitro</i> data suggesting otherwise. The zHER2-APIT accumulated within the HER2-positive tumors but not in the negative tumors. APIT-PEG had increased uptake in HER2-positive and negative tumors compared to APIT_wt, which can be attributed to a prolonged serum half-life achieved by PEGylation, due to the absence of any tumor-targeting effect. These biodistribution studies point to HER2-targeting LAAOs for cancer therapy and PEGylation increasing tumor accumulation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1253–1261 1253–1261"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Evaluation of Novel 68Ga/177Lu-Labeled PSMA Inhibitors with Enhanced Pharmacokinetics and Tumor Imaging for Prostate Cancer","authors":"Haiyang Li,&nbsp;Yang Liu,&nbsp;Hongmei Yuan,&nbsp;Ping Cai,&nbsp;Tongtong Wu,&nbsp;Zhicong Yang,&nbsp;Jiaqi Nie,&nbsp;Wei Zhang,&nbsp;Zhanwen Huang,&nbsp;Nan Liu*,&nbsp;Yue Chen* and Zhijun Zhou*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0130210.1021/acs.molpharmaceut.4c01302","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01302https://doi.org/10.1021/acs.molpharmaceut.4c01302","url":null,"abstract":"<p >Prostate-specific membrane antigen (PSMA) has been a key target for diagnosing and treating prostate cancer, particularly in high-grade, metastatic, and therapy-resistant tumors. This study presents a series of novel ⁶⁸Ga- and ¹⁷⁷Lu-labeled PSMA inhibitors, derived from the previously developed [⁶⁸Ga]Ga-Flu-1. We explored the impact of PEG chains, lipophilic macrocycles, and dimerization on their in vivo properties. The ⁶⁸Ga- and ¹⁷⁷Lu-labeled inhibitors were assessed for biodistribution and tumor targeting in PC3-PIP tumor xenografts, leading to the identification of several promising candidates based on imaging and tumor-specific uptake. Positron emission tomography (PET) imaging revealed that the poly(ethylene glycol)-modified [⁶⁸Ga]Ga-BisPSMA-P4 demonstrated rapid tumor penetration and excellent tumor-to-background contrast. In comparative biodistribution studies, the naphthalene ring-modified [⁶⁸Ga]Ga-BisPSMA-Nph-P4 showed higher tumor uptake (∼60% ID/g at 1 h postinjection) and rapid renal clearance (∼25% ID/g at 2 h postinjection). Additionally, [¹⁷⁷Lu]Lu-BisPSMA-Nph-P4 displayed superior retention, with significant uptake on day 7, highlighting its potential as a novel PSMA inhibitor for prostate cancer diagnosis and treatment.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1584–1597 1584–1597"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528572","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":"Water’s Dual Role as a Chemical Catalyst and Physical Stabilizer in Deamidation of Lyophilized Proteins Studied via Molecular Dynamics Simulations","authors":"Shaoxin Feng*,&nbsp;Günther H. J. Peters and Evgenyi Shalaev,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0118510.1021/acs.molpharmaceut.4c01185","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01185https://doi.org/10.1021/acs.molpharmaceut.4c01185","url":null,"abstract":"<p >Water plays a critical role in chemical degradations, such as deamidation, in freeze-dried proteins. Two distinct patterns for deamidation in relation to water have been reported, that is a “hockey stick”-type behavior with a water-independent deamidation rate, followed by a sharp increase above a water content threshold, and an inverted bell-shaped profile. To understand the underlying mechanism, molecular dynamics simulations are employed to study the explicit water distributions around reactive sites for amorphous and crystalline insulin as well as amorphous IgG1. The simulated water distribution on the protein surface is first validated by successfully predicting water vapor sorption isotherms for both amorphous and crystalline insulin. The “hockey stick”-type behavior is explained by a water threshold level beyond which there are two (Asn-Gly sequence in IgG1) or three (Asn at the C-terminus in insulin) water molecules assisting the cyclization reactions. Regarding the inverted bell-shaped profile for amorphous IgG1, the initial decreases in deamidation rate with increasing water content at low water levels can be rationalized by a lower density and higher free volume of IgG1 at a lower water content. When the free volume exceeds a percolation threshold, the produced ammonia gas can easily diffuse away, lowering the back reaction rate and thus raising the overall reaction rate. The “free volume” mechanism can also be applied to the abnormal stability ranking orders of crystalline and amorphous insulin. The faster deamidation and dimerization rates in insulin crystals compared to amorphous insulin as reported by Pikal and Rigsbee are due to the lower density and higher free volume (above the percolation threshold) in crystalline insulin, assuming that dehydration of insulin crystals does not result in a major collapse of the crystal structure.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1462–1470 1462–1470"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528485","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":"SPECT Imaging of Cardiac Inflammation by Targeting IL4 Receptor-α on Macrophages.","authors":"Danzha Zheng, Mengyan Hu, Wenwen Wang, Shan Chen, Zhangyongxue Zhou, Yuhu Lv, Dawei Jiang, Jianjun Chen, Xiaoli Lan, Chunxia Qin","doi":"10.1021/acs.molpharmaceut.4c01336","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01336","url":null,"abstract":"<p><p>The inflammation response is a prominent sign of myocardial infarction (MI), mediating the process of cardiac fibrosis and ventricular remodeling. Inflammation visualization holds new promise for guiding cardiac anti-inflammatory therapy. Interleukin-4 receptor α (IL4Rα) interacts with IL4, closely related to macrophage polarization. This study aimed to evaluate the feasibility of a technetium-99m (^99mTc) labeled IL4Rα antibody probe ([^99mTc]Tc-HYNIC-CM310) for targeting postinfarction macrophage SPECT imaging. [^99mTc]Tc-HYNIC-CM310 was prepared by radiolabeling an IL4Rα-specific monoclonal antibody (CM310) with ^99mTc. Images were acquired at 0.5, 6, 12, 24, and 36 h postinjection on the next day after MI and the sham model preparation, and a biodistribution study was performed at 36 h. The mean percentage of injected dose per gram (%ID/g) of various tissues was obtained by drawing the regions of interest. [¹⁸F]FDG myocardial metabolism and inflammation imaging were performed for comparison and verification. Immunofluorescence costaining and flow cytometry were conducted to validate the coexpression of IL4Rα and macrophages. The radiolabeling yield of [^99mTc]Tc-HYNIC-CM310 was approximately 88.31% ± 1.70%, and the radiochemical purity was 93.70% ± 0.38%. The accumulation of [^99mTc]Tc-HYNIC-CM310 in infarcted myocardium was increased starting at 12 h postinjection. The tracer uptake was significantly higher in the infarcted myocardium than the same site in sham-operated rats (<i>P</i> < 0.05). The tracer uptake region was consistent with the cardiac metabolic defect and inflammatory region seen by [¹⁸F]FDG PET. Immunofluorescence staining and flow cytometry confirmed the colocalization of IL4Rα⁺ cells and macrophage markers in the infarcted myocardium. We successfully prepared and validated the SPECT probe [^99mTc]Tc-HYNIC-CM310 for precise visualization of macrophages, offering a new opportunity for guiding the treatment of cardiac inflammation.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404904","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":"Solubility Enhancement of Active Pharmaceutical Ingredients through Liquid Hydrotrope Addition: A Thermodynamic Analysis.","authors":"Sahar Nasrallah, Mirjana Minceva","doi":"10.1021/acs.molpharmaceut.4c01117","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01117","url":null,"abstract":"<p><p>The poor water solubility of active pharmaceutical ingredients (APIs) poses a significant challenge in pharmaceutical development, affecting their bioavailability and therapeutic efficacy. Consequently, there is an urgent demand for strategies to improve API solubility, with hydrotropy emerging as one of the most effective approaches. Hydrotropes, which can act as excipients in pharmaceutical formulations, enhance solubility by solubilizing hydrophobic compounds in aqueous solutions through mechanisms other than micellar solubilization. However, identifying the right hydrotropic agent requires a screening from a large pool of candidates. This work aims to analyze hydrotropy from a thermodynamic perspective by investigating the influence of the molecular interactions among the API, hydrotrope, and water on the API solubility in water at different temperatures. For this systematic study, hypothetical ternary systems were used and only liquid hydrotropes were considered. Utilizing the Two-Suffix Margules equation to model the liquid phase nonideality, the study revealed that strong API-hydrotrope interactions notably enhance the API solubility in water. Additionally, the interaction between the hydrotrope and water significantly influences API solubility; weaker hydrotrope-water interactions allow for increased API solubility in water. However, when hydrotrope-water interactions are stronger than API-hydrotrope interactions, this effect is diminished. The theoretical findings were validated using solubility experimental data of syringic acid with alkanediols in water from the literature. The results of this work will aid in selecting suitable liquid hydrotropes for enhancing the API solubility in aqueous solutions.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404903","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":"Water's Dual Role as a Chemical Catalyst and Physical Stabilizer in Deamidation of Lyophilized Proteins Studied via Molecular Dynamics Simulations.","authors":"Shaoxin Feng, Günther H J Peters, Evgenyi Shalaev","doi":"10.1021/acs.molpharmaceut.4c01185","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01185","url":null,"abstract":"<p><p>Water plays a critical role in chemical degradations, such as deamidation, in freeze-dried proteins. Two distinct patterns for deamidation in relation to water have been reported, that is a \"hockey stick\"-type behavior with a water-independent deamidation rate, followed by a sharp increase above a water content threshold, and an inverted bell-shaped profile. To understand the underlying mechanism, molecular dynamics simulations are employed to study the explicit water distributions around reactive sites for amorphous and crystalline insulin as well as amorphous IgG1. The simulated water distribution on the protein surface is first validated by successfully predicting water vapor sorption isotherms for both amorphous and crystalline insulin. The \"hockey stick\"-type behavior is explained by a water threshold level beyond which there are two (Asn-Gly sequence in IgG1) or three (Asn at the C-terminus in insulin) water molecules assisting the cyclization reactions. Regarding the inverted bell-shaped profile for amorphous IgG1, the initial decreases in deamidation rate with increasing water content at low water levels can be rationalized by a lower density and higher free volume of IgG1 at a lower water content. When the free volume exceeds a percolation threshold, the produced ammonia gas can easily diffuse away, lowering the back reaction rate and thus raising the overall reaction rate. The \"free volume\" mechanism can also be applied to the abnormal stability ranking orders of crystalline and amorphous insulin. The faster deamidation and dimerization rates in insulin crystals compared to amorphous insulin as reported by Pikal and Rigsbee are due to the lower density and higher free volume (above the percolation threshold) in crystalline insulin, assuming that dehydration of insulin crystals does not result in a major collapse of the crystal structure.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404905","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}