Molecular Pharmaceutics最新文献

{"title":"Solubility Enhancement of Active Pharmaceutical Ingredients through Liquid Hydrotrope Addition: A Thermodynamic Analysis","authors":"Sahar Nasrallah,&nbsp; and ,&nbsp;Mirjana Minceva*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0111710.1021/acs.molpharmaceut.4c01117","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01117https://doi.org/10.1021/acs.molpharmaceut.4c01117","url":null,"abstract":"<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":"22 3","pages":"1408–1418 1408–1418"},"PeriodicalIF":4.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.molpharmaceut.4c01117","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528440","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}

{"title":"Modulating the Physical Form of Mannitol Crystallizing in Frozen Solutions: The Role of Cosolute and Processing.","authors":"Chaowang Zeng, Jinghan Li, Jiawanjun Shi, Simon Bates, Bhushan Munjal, Raj Suryanarayanan","doi":"10.1021/acs.molpharmaceut.4c01481","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01481","url":null,"abstract":"<p><p>Mannitol is widely employed as a bulking agent in lyophilized formulations. Our goal was to evaluate the role of noncrystallizing cosolutes in inhibiting mannitol crystallization and preventing the formation of mannitol hemihydrate (MHH) in frozen solutions. The individual influence of two common stabilizers (sucrose and trehalose) and three model proteins (lysozyme, bovine serum albumin, and immunoglobulin G) on the crystallization behavior of mannitol was investigated by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Sugars exerted a more pronounced crystallization inhibitory effect than proteins. In the presence of sugars, mannitol predominantly crystallized as MHH while the proteins facilitated the crystallization of δ-mannitol. Annealing the frozen solutions at -25 °C favored MHH crystallization. A higher annealing temperature of -10 °C accelerated mannitol crystallization and promoted the formation of the anhydrous δ-polymorph. The crystallization inhibitory effect of proteins was surmounted with annealing, while at a high sugar concentration, a substantial fraction of mannitol was retained amorphous even after annealing.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404902","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":"Modulating the Physical Form of Mannitol Crystallizing in Frozen Solutions: The Role of Cosolute and Processing","authors":"Chaowang Zeng,&nbsp;Jinghan Li,&nbsp;Jiawanjun Shi,&nbsp;Simon Bates,&nbsp;Bhushan Munjal and Raj Suryanarayanan*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0148110.1021/acs.molpharmaceut.4c01481","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01481https://doi.org/10.1021/acs.molpharmaceut.4c01481","url":null,"abstract":"<p >Mannitol is widely employed as a bulking agent in lyophilized formulations. Our goal was to evaluate the role of noncrystallizing cosolutes in inhibiting mannitol crystallization and preventing the formation of mannitol hemihydrate (MHH) in frozen solutions. The individual influence of two common stabilizers (sucrose and trehalose) and three model proteins (lysozyme, bovine serum albumin, and immunoglobulin G) on the crystallization behavior of mannitol was investigated by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Sugars exerted a more pronounced crystallization inhibitory effect than proteins. In the presence of sugars, mannitol predominantly crystallized as MHH while the proteins facilitated the crystallization of δ-mannitol. Annealing the frozen solutions at −25 °C favored MHH crystallization. A higher annealing temperature of −10 °C accelerated mannitol crystallization and promoted the formation of the anhydrous δ-polymorph. The crystallization inhibitory effect of proteins was surmounted with annealing, while at a high sugar concentration, a substantial fraction of mannitol was retained amorphous even after annealing.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1686–1696 1686–1696"},"PeriodicalIF":4.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528484","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":"68Ga-FAPI Small Animal PET/CT in Rats with Peritoneal Fibrosis and the Therapeutic Effect of Sodium Butyrate","authors":"Jingyi Chen,&nbsp;Zibei Wan,&nbsp;Mengxia Cao,&nbsp;Yuexi Huang,&nbsp;Yan Li,&nbsp;Weihua Wu,&nbsp;Chunmei Guo,&nbsp;Zhanwen Huang* and Santao Ou*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0099810.1021/acs.molpharmaceut.4c00998","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00998https://doi.org/10.1021/acs.molpharmaceut.4c00998","url":null,"abstract":"<p >Peritoneal fibrosis (PF) is a common complication in peritoneal dialysis patients with end-stage renal disease. This study established a rat model of PF, used ⁶⁸Ga-FAPI PET/CT imaging to visualize PF, and evaluated the therapeutic effects and mechanism of action of sodium butyrate. The rat model of PF (<i>n</i> = 20) was induced by hyperglycemic peritoneal dialysate combined with lipopolysaccharide, the control group (<i>n</i> = 20) was given the same amount of normal saline, and the intervention group (<i>n</i> = 20) was given sodium butyrate by intraperitoneal injection. At 2, 4, 6, and 8 weeks, a peritoneal equilibration test was performed, and peritoneal tissues were collected for histological staining. Three rats from each group were randomly selected for ⁶⁸Ga-FAPI small animal PET/CT imaging. Compared with control rats, model group rats presented a decreased ultrafiltration volume, increased maximum glucose transport (<i>P</i> &lt; 0.05), increased peritoneal thickness and fibrosis area, and upregulated α-SMA, COL I, TGF-β1, Smad3, and p-Smad3 expression in peritoneal tissues (<i>P</i> &lt; 0.05) in a time-dependent manner. The sodium butyrate group improved peritoneal transport function (<i>P</i> &lt; 0.05), alleviated collagen deposition, and downregulated α-SMA, COL I, TGF-β1, Smad3, and p-Smad3 while increasing Smad7 expression in peritoneal tissues (<i>P</i> &lt; 0.05). ⁶⁸Ga uptake was markedly increased in the model group (<i>P</i> &lt; 0.05) but was reduced after sodium butyrate treatment (<i>P</i> &lt; 0.05). The SUVmax was positively correlated with peritoneal thickness; maximum glucose transport; and α-SMA, COL I, and FAP-α expression (<i>r</i> = 0.871, 0.845, 0.843, 0.659, 0.926) but negatively correlated with ultrafiltration volume (<i>r</i>= −0.894). In summary, ⁶⁸Ga-FAPI PET/CT could be a promising noninvasive approach for assessing peritoneal fibrosis that is superior to and safer than peritoneal biopsy. Sodium butyrate may attenuate peritoneal fibrosis by regulating the TGF-β1/Smad3 signaling pathway.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1329–1338 1329–1338"},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528458","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":"Nitroaromatic Compounds Dictate Electrochemical Properties of <i><i>Escherichia coli</i></i> by Manipulating the Cellular Membrane.","authors":"Neha Yadav, Santosh K Misra","doi":"10.1021/acs.molpharmaceut.4c01537","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01537","url":null,"abstract":"<p><p>Nitroaromatic compounds (NACs) are generally used as starting materials and/or generated as byproducts during the manufacturing of dyes, fertilizers, and therapeutic agents. Though NACs are beneficial when used appropriately, inadequate management, disposal, and application methods have led to their introduction to bacterial ecosystems where NACs act as mutagenic agents and may even contribute to antimicrobial resistance. Many of these bacterial systems are known to have different pathways to adapt to the presence of NACs such as altering the lipid composition of cellular membranes and intracellular degradation of NACs. In general, these processes require sophisticated techniques and skilled human resources to detect the changes by conventional characterization techniques. Hence, alternative methods are needed to investigate the short-term effects of NACs on bacterial cells with better precision. Herein, we report that bacterial cells adapt to the presence of NACs initially by incorporation in the cellular membrane, which can be predicted by further altered electrical and electrochemical properties of the cells. It was observed that the whole cell bacteria were negatively charged entities that could generate varying levels of surface charges on being incubated with model NACs of biomedical importance viz. niclosamide and <i>p</i>-nitrophenol. Such variations were also reflected in dye entrapment assays performed by using lipidic membranes collected from NAC-treated bacterial cells after the cells. Further studies with gel electrophoresis and differential pulse voltammetry revealed the significant alterations in electrochemical properties of NAC-incubated bacterial cells. Overall, results indicate that bacterial adaptation to NACs was found to be closely linked to variations in the electrochemical properties of the bacterial cells. These outcomes advance our understanding of influences imparted by NACs during bacterial infections and might facilitate the way for developing therapies to combat antibacterial resistance in the near future.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389516","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":"⁶⁸Ga-FAPI Small Animal PET/CT in Rats with Peritoneal Fibrosis and the Therapeutic Effect of Sodium Butyrate.","authors":"Jingyi Chen, Zibei Wan, Mengxia Cao, Yuexi Huang, Yan Li, Weihua Wu, Chunmei Guo, Zhanwen Huang, Santao Ou","doi":"10.1021/acs.molpharmaceut.4c00998","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00998","url":null,"abstract":"<p><p>Peritoneal fibrosis (PF) is a common complication in peritoneal dialysis patients with end-stage renal disease. This study established a rat model of PF, used ⁶⁸Ga-FAPI PET/CT imaging to visualize PF, and evaluated the therapeutic effects and mechanism of action of sodium butyrate. The rat model of PF (<i>n</i> = 20) was induced by hyperglycemic peritoneal dialysate combined with lipopolysaccharide, the control group (<i>n</i> = 20) was given the same amount of normal saline, and the intervention group (<i>n</i> = 20) was given sodium butyrate by intraperitoneal injection. At 2, 4, 6, and 8 weeks, a peritoneal equilibration test was performed, and peritoneal tissues were collected for histological staining. Three rats from each group were randomly selected for ⁶⁸Ga-FAPI small animal PET/CT imaging. Compared with control rats, model group rats presented a decreased ultrafiltration volume, increased maximum glucose transport (<i>P</i> < 0.05), increased peritoneal thickness and fibrosis area, and upregulated α-SMA, COL I, TGF-β1, Smad3, and p-Smad3 expression in peritoneal tissues (<i>P</i> < 0.05) in a time-dependent manner. The sodium butyrate group improved peritoneal transport function (<i>P</i> < 0.05), alleviated collagen deposition, and downregulated α-SMA, COL I, TGF-β1, Smad3, and p-Smad3 while increasing Smad7 expression in peritoneal tissues (<i>P</i> < 0.05). ⁶⁸Ga uptake was markedly increased in the model group (<i>P</i> < 0.05) but was reduced after sodium butyrate treatment (<i>P</i> < 0.05). The SUVmax was positively correlated with peritoneal thickness; maximum glucose transport; and α-SMA, COL I, and FAP-α expression (<i>r</i> = 0.871, 0.845, 0.843, 0.659, 0.926) but negatively correlated with ultrafiltration volume (<i>r</i>= -0.894). In summary, ⁶⁸Ga-FAPI PET/CT could be a promising noninvasive approach for assessing peritoneal fibrosis that is superior to and safer than peritoneal biopsy. Sodium butyrate may attenuate peritoneal fibrosis by regulating the TGF-β1/Smad3 signaling pathway.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397606","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":"Correction to \"Enhancing the Antitumor Effect of Doxorubicin with Photosensitive Metal-Organic Framework Nanoparticles against Breast Cancer\".","authors":"Qianqian Jiang, Mengmeng Zhang, Quanwei Sun, Dengke Yin, Zihua Xuan, Ye Yang","doi":"10.1021/acs.molpharmaceut.5c00049","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00049","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397607","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":"Preliminary Study of a Novel 68Ga-Labeled Probe Targeting Neuropilin-1 for Tumor Diagnosis","authors":"Shuyue Cai,&nbsp;Rui Tang,&nbsp;Jichen Yang,&nbsp;Manxuan Ge,&nbsp;Yuxuan Zhou,&nbsp;Quan Xie,&nbsp;Qingzhu Liu,&nbsp;Ling Qiu* and Jianguo Lin*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0140610.1021/acs.molpharmaceut.4c01406","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01406https://doi.org/10.1021/acs.molpharmaceut.4c01406","url":null,"abstract":"<p >Neuropilin-1 (NRP-1), a transmembrane protein related to tumor progression and invasion, presents potential as a prospective biomarker for tumor diagnosis and therapy. Positron emission tomography (PET) is acknowledged as an ideal modality for accurately monitoring NRP-1 expression <i>in vivo</i> due to its superior sensitivity and resolution. In this study, a novel peptide-based PET imaging probe, [⁶⁸Ga]Ga-DOTA-NEP, was successfully developed for specifically visualizing NRP-1 expression in tumors. The probe was prepared with a radiochemical yield (RCY) and radiochemical purity (RCP) greater than 95%, a molar activity of 13.28 ± 0.97 GBq/μmol, and a lipid–water partition coefficient (log <i>P</i>) of −2.20 ± 0.13. <i>In vitro</i> stability assay showed that the probe possessed sufficient stability for biological evaluation. The cellular uptake of the probe in U87 and A549 cells (4.91 ± 0.14 and 4.58 ± 0.40%AD) with high expression of NRP-1 was higher than that observed in NRP-1 negative cells HCT116 and NCI-H1299 (2.84 ± 0.23 and 1.76 ± 0.25%AD) at 1 h. <i>In vivo</i> PET imaging revealed that the maximum tumor uptake of the probe in U87 (7.20 ± 1.03%ID/mL) and A549 (5.90 ± 0.57%ID/mL) tumor-bearing mice was also markedly higher compared to that in HCT116 (3.09 ± 0.43%ID/mL) and NCI-H1299 (2.90 ± 0.70%ID/mL) tumor-bearing mice. <i>Ex vivo</i> analysis further confirmed the targeting specificity of the probe [⁶⁸Ga]Ga-DOTA-NEP for NRP-1. These results suggest that [⁶⁸Ga]Ga-DOTA-NEP could serve as a promising PET imaging probe for the diagnosis of NRP-1 positive tumors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1667–1676 1667–1676"},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528482","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":"Preliminary Study of a Novel ⁶⁸Ga-Labeled Probe Targeting Neuropilin-1 for Tumor Diagnosis.","authors":"Shuyue Cai, Rui Tang, Jichen Yang, Manxuan Ge, Yuxuan Zhou, Quan Xie, Qingzhu Liu, Ling Qiu, Jianguo Lin","doi":"10.1021/acs.molpharmaceut.4c01406","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01406","url":null,"abstract":"<p><p>Neuropilin-1 (NRP-1), a transmembrane protein related to tumor progression and invasion, presents potential as a prospective biomarker for tumor diagnosis and therapy. Positron emission tomography (PET) is acknowledged as an ideal modality for accurately monitoring NRP-1 expression <i>in vivo</i> due to its superior sensitivity and resolution. In this study, a novel peptide-based PET imaging probe, [⁶⁸Ga]Ga-DOTA-NEP, was successfully developed for specifically visualizing NRP-1 expression in tumors. The probe was prepared with a radiochemical yield (RCY) and radiochemical purity (RCP) greater than 95%, a molar activity of 13.28 ± 0.97 GBq/μmol, and a lipid-water partition coefficient (log <i>P</i>) of -2.20 ± 0.13. <i>In vitro</i> stability assay showed that the probe possessed sufficient stability for biological evaluation. The cellular uptake of the probe in U87 and A549 cells (4.91 ± 0.14 and 4.58 ± 0.40%AD) with high expression of NRP-1 was higher than that observed in NRP-1 negative cells HCT116 and NCI-H1299 (2.84 ± 0.23 and 1.76 ± 0.25%AD) at 1 h. <i>In vivo</i> PET imaging revealed that the maximum tumor uptake of the probe in U87 (7.20 ± 1.03%ID/mL) and A549 (5.90 ± 0.57%ID/mL) tumor-bearing mice was also markedly higher compared to that in HCT116 (3.09 ± 0.43%ID/mL) and NCI-H1299 (2.90 ± 0.70%ID/mL) tumor-bearing mice. <i>Ex vivo</i> analysis further confirmed the targeting specificity of the probe [⁶⁸Ga]Ga-DOTA-NEP for NRP-1. These results suggest that [⁶⁸Ga]Ga-DOTA-NEP could serve as a promising PET imaging probe for the diagnosis of NRP-1 positive tumors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397609","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":"Optimizing Triglyceride Prodrugs of a Model Immunomodulator: Conjugation through the Phenol of Mycophenolic Acid (MPA) Markedly Promotes Lymphatic Drug Transport","authors":"Luojuan Hu,&nbsp;Tim Quach,&nbsp;Dan Zheng,&nbsp;Nathania J. Leong,&nbsp;Garima Sharma,&nbsp;Shea Fern Lim,&nbsp;Daniel Bonner,&nbsp;Natalie L. Trevaskis,&nbsp;Jamie S. Simpson,&nbsp;Sifei Han* and Christopher J. H. Porter*,&nbsp;","doi":"10.1021/acs.molpharmaceut.4c0127210.1021/acs.molpharmaceut.4c01272","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01272https://doi.org/10.1021/acs.molpharmaceut.4c01272","url":null,"abstract":"<p >Enhanced transport of immunomodulators via the lymphatics may increase drug exposure to therapeutic targets in the immune system. Our laboratory has demonstrated a triglyceride (TG) mimetic prodrug approach to enhance the lymphatic delivery of a model immunomodulator, mycophenolic acid (MPA), via conjugation of the carboxylic acid of MPA to a TG backbone, where the so formed prodrug is able to incorporate into intestinal TG deacylation–reacylation and lymph lipoprotein transport pathways (up to 37% of the administered dose being absorbed via the lymphatics). In the current study, another conjugation site in the molecule of MPA, i.e., the phenolic group, was explored for its potential to optimize the lymphatic transport profiles of TG mimetic prodrugs of MPA. This offers an unusual opportunity to directly compare the utility of TG prodrugs formed via conjugation to an acid versus a phenol in the same core molecule, which has not been examined previously for other parent drugs. A series of linkers were examined to connect the MPA moiety with the TG backbone. Lymphatic transport was assessed in mesenteric lymph duct cannulated rats, and drug exposure in the mesenteric lymph nodes was examined following oral administration to mice. Compared to the data observed previously for MPA prodrugs conjugated via the carboxylic acid, the new phenol-conjugated prodrugs showed clearly different profiles in terms of the linker chemistry. Prodrugs with shorter chain alkyl spacers (e.g., C4 and C6) supported minimal lymphatic transport (&lt;3% of the dose recovered in lymph). When the chain lengths were longer (≥C10), the prodrugs demonstrated much higher potential for lymphatic transport (up to approximately 55% of dose). Although effectively promoting lymphatic transport, TG mimetic prodrugs with alkyl chain linkers did not necessarily result in marked increases in the exposure of MPA in the mesenteric lymph nodes in mice. Subsequently a number of self-immolative linkers conjugated via the phenol were explored to promote MPA liberation from the prodrugs, and these constructs demonstrated enhanced lymph node exposure. This study provides further insight into structure–lymphatic transport relationships for lymph-directing lipid mimetic prodrugs.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":"22 3","pages":"1555–1567 1555–1567"},"PeriodicalIF":4.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528479","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}