Rheumatoid arthritis (RA) is a complex condition that is influenced by various causes, including immunological, genetic, and environmental factors. Several studies using animal models have documented immune system dysfunction and described the clinical characteristics of the disease. These studies have provided valuable insights into the pathogenesis of inflammatory arthritis and the identification of new targets for treatment. Nevertheless, none of these animal models successfully replicated all the characteristics of RA. Additionally, numerous experimental medications, which were developed based on our enhanced comprehension of the immune system’s function in RA, have shown potential in animal research but ultimately proved ineffective during different stages of clinical trials. There have been several novel therapy alternatives, which do not achieve a consistently outstanding therapeutic outcome in all patients. This underscores the importance of employing the progress in in vitro models, particularly 3D models like tissue explants, and diverse multicomponent approaches such as coculture strategies, synovial membrane, articular cartilage, and subchondral bone models that accurately replicate the structural characteristics of RA pathophysiology. These methods are crucial for the advancement of potential therapeutic strategies. This review discusses the latest advancements in in vitro models and their potential to greatly impact research on managing RA.
类风湿性关节炎（RA）是一种复杂的疾病，受多种原因的影响，包括免疫、遗传和环境因素。一些利用动物模型进行的研究记录了免疫系统功能紊乱的情况，并描述了该疾病的临床特征。这些研究为了解炎症性关节炎的发病机制和确定新的治疗靶点提供了宝贵的资料。然而，这些动物模型都没有成功复制出 RA 的所有特征。此外，根据我们对免疫系统在 RA 中的功能的进一步理解而开发的许多实验性药物在动物研究中显示出了潜力，但最终在不同阶段的临床试验中被证明无效。还有几种新的替代疗法，但并不是所有患者都能持续获得出色的治疗效果。这凸显了采用体外模型的重要性，尤其是三维模型，如组织外植体，以及多种多成分方法，如共培养策略、滑膜、关节软骨和软骨下骨模型，这些都能准确复制 RA 病理生理学的结构特征。这些方法对于推进潜在的治疗策略至关重要。本综述将讨论体外模型的最新进展及其对控制 RA 的研究产生重大影响的潜力。
{"title":"Emerging Landscape of In Vitro Models for Assessing Rheumatoid Arthritis Management","authors":"Abhay Prakash Mishra, Rajesh Kumar, Seetha Harilal, Manisha Nigam, Deepanjan Datta, Sudarshan Singh","doi":"10.1021/acsptsci.4c00260","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00260","url":null,"abstract":"Rheumatoid arthritis (RA) is a complex condition that is influenced by various causes, including immunological, genetic, and environmental factors. Several studies using animal models have documented immune system dysfunction and described the clinical characteristics of the disease. These studies have provided valuable insights into the pathogenesis of inflammatory arthritis and the identification of new targets for treatment. Nevertheless, none of these animal models successfully replicated all the characteristics of RA. Additionally, numerous experimental medications, which were developed based on our enhanced comprehension of the immune system’s function in RA, have shown potential in animal research but ultimately proved ineffective during different stages of clinical trials. There have been several novel therapy alternatives, which do not achieve a consistently outstanding therapeutic outcome in all patients. This underscores the importance of employing the progress in <i>in vitro</i> models, particularly 3D models like tissue explants, and diverse multicomponent approaches such as coculture strategies, synovial membrane, articular cartilage, and subchondral bone models that accurately replicate the structural characteristics of RA pathophysiology. These methods are crucial for the advancement of potential therapeutic strategies. This review discusses the latest advancements in <i>in vitro</i> models and their potential to greatly impact research on managing RA.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-18DOI: 10.1021/acsptsci.4c00296
Liu Tang, Huiliang Geng, Lei Zhang, Xinyi Wang, Mengdan Fei, Boyuan Yang, Haijie Sun, Zhongli Zhang
The oxidation of the complementarity-determining region (CDR) in monoclonal antibodies (mAbs) is a critical quality attribute that can affect the clinical efficacy and safety of recombinant mAb therapeutics. In this study, a robust hydrophobic interaction chromatography (HIC) method was developed to quantify and characterize CDR oxidation variants in mAb-A by using a Proteomix Butyl-NP5 column. The HIC analysis revealed oxidation variants that eluted earlier than the main species with weaker hydrophobicity. It was found that Met105 in the CDR was more susceptible to oxidation. Additionally, it was noted that the oxidation of Met105 on a single heavy chain resulted in elution at a distinct position compared to the oxidation on two heavy chains. This observation led to the fractionation and enrichment of the oxidized variants for further evaluation of their biofunction. The study also demonstrated that the oxidation of Met105 did not impact the antigen-binding capacity but significantly reduced the PD-1/PD-L1 blockade activity of mAb-A. The HIC method, which was employed to quantify CDR oxidation, underwent validation and was subsequently utilized for stability studies as well as for assessing the similarity between mAb-A and its reference product.
单克隆抗体（mAb）中互补决定区（CDR）的氧化是影响重组 mAb 疗法临床疗效和安全性的关键质量属性。本研究利用 Proteomix Butyl-NP5 色谱柱开发了一种稳健的疏水相互作用色谱（HIC）方法，用于定量和定性 mAb-A 中的 CDR 氧化变体。通过 HIC 分析发现，氧化变体的疏水性较弱，比主变体更早洗脱。研究发现，CDR 中的 Met105 更容易被氧化。此外，研究人员还注意到，与两条重链上的氧化相比，单条重链上的 Met105 氧化导致洗脱位置不同。根据这一观察结果，对氧化变体进行了分馏和富集，以进一步评估其生物功能。研究还表明，Met105 的氧化不会影响抗原结合能力，但会显著降低 mAb-A 的 PD-1/PD-L1 阻断活性。用于量化 CDR 氧化的 HIC 方法经过了验证，随后被用于稳定性研究以及评估 mAb-A 与其参考品之间的相似性。
{"title":"In-Depth Characterization for Methionine Oxidization in Complementary Domain Region by Hydrophobic Interaction Chromatography","authors":"Liu Tang, Huiliang Geng, Lei Zhang, Xinyi Wang, Mengdan Fei, Boyuan Yang, Haijie Sun, Zhongli Zhang","doi":"10.1021/acsptsci.4c00296","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00296","url":null,"abstract":"The oxidation of the complementarity-determining region (CDR) in monoclonal antibodies (mAbs) is a critical quality attribute that can affect the clinical efficacy and safety of recombinant mAb therapeutics. In this study, a robust hydrophobic interaction chromatography (HIC) method was developed to quantify and characterize CDR oxidation variants in mAb-A by using a Proteomix Butyl-NP5 column. The HIC analysis revealed oxidation variants that eluted earlier than the main species with weaker hydrophobicity. It was found that Met<sub>105</sub> in the CDR was more susceptible to oxidation. Additionally, it was noted that the oxidation of Met<sub>105</sub> on a single heavy chain resulted in elution at a distinct position compared to the oxidation on two heavy chains. This observation led to the fractionation and enrichment of the oxidized variants for further evaluation of their biofunction. The study also demonstrated that the oxidation of Met<sub>105</sub> did not impact the antigen-binding capacity but significantly reduced the PD-1/PD-L1 blockade activity of mAb-A. The HIC method, which was employed to quantify CDR oxidation, underwent validation and was subsequently utilized for stability studies as well as for assessing the similarity between mAb-A and its reference product.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141785272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-18DOI: 10.1021/acsptsci.4c00186
Youyi Peng, Allen H. Zhang, Liping Wei, William J. Welsh
The global prevalence of diabetes is steadily rising, with an estimated 537 million adults affected by diabetes in 2021, projected to reach 783 million by 2045. A severe consequence of diabetes is the development of painful diabetic neuropathy (PDN), afflicting approximately one in every three diabetic patients and significantly compromising their quality of life. Current pharmacotherapies for PDN provide inadequate pain relief for many patients, underscoring the need for novel treatments that are both safe and effective. The Sigma 1 Receptor (S1R) is a ligand-operated chaperone protein that resides at the mitochondria-associated membrane of the endoplasmic reticulum. The S1R has been shown to play crucial roles in regulating cellular processes implicated in pain modulation. This study explores the potential of PW507, a novel S1R antagonist, as a therapeutic candidate for PDN. PW507 exhibited promising in vitro and in vivo properties in terms of ADME, toxicity, pharmacokinetics, and safety. In preclinical rat models of Streptozotocin-induced diabetic neuropathy, PW507 demonstrated significant efficacy in alleviating mechanical allodynia and thermal hyperalgesia following both acute and chronic (2-week) administration, without inducing tolerance and visual evidence of toxicity. To the best of our knowledge, this is the first report to evaluate an S1R antagonist in STZ-induced diabetic rats following both acute and 2-week chronic administration, offering compelling preclinical evidence for the potential use of PW507 as a promising therapeutic option for PDN.
{"title":"Preclinical Evaluation of Sigma 1 Receptor Antagonists as a Novel Treatment for Painful Diabetic Neuropathy","authors":"Youyi Peng, Allen H. Zhang, Liping Wei, William J. Welsh","doi":"10.1021/acsptsci.4c00186","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00186","url":null,"abstract":"The global prevalence of diabetes is steadily rising, with an estimated 537 million adults affected by diabetes in 2021, projected to reach 783 million by 2045. A severe consequence of diabetes is the development of painful diabetic neuropathy (PDN), afflicting approximately one in every three diabetic patients and significantly compromising their quality of life. Current pharmacotherapies for PDN provide inadequate pain relief for many patients, underscoring the need for novel treatments that are both safe and effective. The Sigma 1 Receptor (S1R) is a ligand-operated chaperone protein that resides at the mitochondria-associated membrane of the endoplasmic reticulum. The S1R has been shown to play crucial roles in regulating cellular processes implicated in pain modulation. This study explores the potential of PW507, a novel S1R antagonist, as a therapeutic candidate for PDN. PW507 exhibited promising <i>in vitro</i> and <i>in vivo</i> properties in terms of ADME, toxicity, pharmacokinetics, and safety. In preclinical rat models of Streptozotocin-induced diabetic neuropathy, PW507 demonstrated significant efficacy in alleviating mechanical allodynia and thermal hyperalgesia following both acute and chronic (2-week) administration, without inducing tolerance and visual evidence of toxicity. To the best of our knowledge, this is the first report to evaluate an S1R antagonist in STZ-induced diabetic rats following both acute and 2-week chronic administration, offering compelling preclinical evidence for the potential use of PW507 as a promising therapeutic option for PDN.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.1021/acsptsci.4c00314
Kenan Aloss, Pedro Henrique Leroy Viana, Syeda Mahak Zahra Bokhari, Nino Giunashvili, Csaba András Schvarcz, Dániel Bócsi, Zoltán Koós, Zoltán Benyó, Péter Hamar
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options. Modulated electro-hyperthermia (mEHT) is a novel adjuvant cancer therapy that induces selective cancer damage. However, mEHT upregulates heat shock protein beta 1 (HSPB1), a cancer-promoting stress chaperone molecule. Thus, we investigated whether ivermectin (IVM), an anthelmintic drug, may synergize with mEHT and enhance its anticancer effects by inhibiting HSPB1 phosphorylation. Isogenic 4T1 TNBC cells were inoculated into BALB/c mice and treated with mEHT, IVM, or a combination of both. IVM synergistically improved the tumor growth inhibition achieved by mEHT. Moreover, IVM downregulated mEHT-induced HSPB1 phosphorylation. Thus, the strongest cancer tissue damage was observed in the mEHT + IVM-treated tumors, coupled with the strongest apoptosis induction and proliferation inhibition. In addition, there was no significant body weight loss in mice treated with mEHT and IVM, indicating that this combination was well-tolerated. In conclusion, mEHT combined with IVM is a new, effective, and safe option for the treatment of TNBC.
{"title":"Ivermectin Synergizes with Modulated Electro-hyperthermia and Improves Its Anticancer Effects in a Triple-Negative Breast Cancer Mouse Model","authors":"Kenan Aloss, Pedro Henrique Leroy Viana, Syeda Mahak Zahra Bokhari, Nino Giunashvili, Csaba András Schvarcz, Dániel Bócsi, Zoltán Koós, Zoltán Benyó, Péter Hamar","doi":"10.1021/acsptsci.4c00314","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00314","url":null,"abstract":"Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options. Modulated electro-hyperthermia (mEHT) is a novel adjuvant cancer therapy that induces selective cancer damage. However, mEHT upregulates heat shock protein beta 1 (HSPB1), a cancer-promoting stress chaperone molecule. Thus, we investigated whether ivermectin (IVM), an anthelmintic drug, may synergize with mEHT and enhance its anticancer effects by inhibiting HSPB1 phosphorylation. Isogenic 4T1 TNBC cells were inoculated into BALB/c mice and treated with mEHT, IVM, or a combination of both. IVM synergistically improved the tumor growth inhibition achieved by mEHT. Moreover, IVM downregulated mEHT-induced HSPB1 phosphorylation. Thus, the strongest cancer tissue damage was observed in the mEHT + IVM-treated tumors, coupled with the strongest apoptosis induction and proliferation inhibition. In addition, there was no significant body weight loss in mice treated with mEHT and IVM, indicating that this combination was well-tolerated. In conclusion, mEHT combined with IVM is a new, effective, and safe option for the treatment of TNBC.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141719932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.1021/acsptsci.4c00284
Jing Wang, Muqing Zhang, Hu Wang
Mesenchymal stem cells (MSCs) hold significant promise for regenerative medicine and tissue engineering due to their unique multipotent differentiation ability and immunomodulatory properties. MSC therapy is widely discussed and utilized in clinical treatment. However, during both invitro expansion and in vivo transplantation, MSCs are prone to senescence, an irreversible growth arrest characterized by morphological, gene expression, and functional changes in genomic regulation. The microenvironment surrounding MSCs plays a crucial role in modulating their senescence phenotype, influenced by factors such as hypoxia, inflammation, and aging status. Numerous strategies targeting MSC senescence have been developed, including senolytics and senomorphic agents, antioxidant and exosome therapies, mitochondrial transfer, and niche modulation. Novel approaches addressing replicative senescence have also emerged. This paper comprehensively reviews the current molecular manifestations of MSC senescence, addresses the environmental impact on senescence, and highlights potential therapeutic strategies to mitigate senescence in MSC-based therapies. These insights aim to enhance the efficacy and understanding of MSC therapies.
{"title":"Emerging Landscape of Mesenchymal Stem Cell Senescence Mechanisms and Implications on Therapeutic Strategies","authors":"Jing Wang, Muqing Zhang, Hu Wang","doi":"10.1021/acsptsci.4c00284","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00284","url":null,"abstract":"Mesenchymal stem cells (MSCs) hold significant promise for regenerative medicine and tissue engineering due to their unique multipotent differentiation ability and immunomodulatory properties. MSC therapy is widely discussed and utilized in clinical treatment. However, during both <i>in</i> <i>vitro</i> expansion and <i>in vivo</i> transplantation, MSCs are prone to senescence, an irreversible growth arrest characterized by morphological, gene expression, and functional changes in genomic regulation. The microenvironment surrounding MSCs plays a crucial role in modulating their senescence phenotype, influenced by factors such as hypoxia, inflammation, and aging status. Numerous strategies targeting MSC senescence have been developed, including senolytics and senomorphic agents, antioxidant and exosome therapies, mitochondrial transfer, and niche modulation. Novel approaches addressing replicative senescence have also emerged. This paper comprehensively reviews the current molecular manifestations of MSC senescence, addresses the environmental impact on senescence, and highlights potential therapeutic strategies to mitigate senescence in MSC-based therapies. These insights aim to enhance the efficacy and understanding of MSC therapies.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141719931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.1021/acsptsci.4c00282
Chandra Choudhury, James E. Egleton, Neville J. Butcher, Angela J. Russell, Rodney F. Minchin
Arylamine N-acetyltransferase 1 (NAT1) expression has been shown to attenuate mitochondrial function, suggesting it is a promising drug target in diseases of mitochondrial dysfunction. Here, several second-generation naphthoquinones have been investigated as small molecule inhibitors of NAT1. The results show that the compounds inhibit both in vitro and in whole cells. A lead compound (Cmp350) was further investigated for its ability to alter mitochondrial metabolism in MDA-MB-231 cells. At concentrations that inhibited NAT1 by over 85%, no overt toxicity was observed. Moreover, the inhibitor decreased basal respiration and reserve respiratory capacity without affecting ATP production. Cells treated with Cmp350 were almost exclusively dependent on glucose as a fuel source. We postulate that Cmp350 is an excellent lead compound for the development of NAT1-targeted inhibitors as both experimental tools and therapeutics in the treatment of hypermetabolic diseases such as amyotrophic lateral sclerosis, cancer cachexia, and sepsis.
{"title":"Small Molecule Inhibitors of Arylamine N-Acetyltransferase 1 Attenuate Cellular Respiration","authors":"Chandra Choudhury, James E. Egleton, Neville J. Butcher, Angela J. Russell, Rodney F. Minchin","doi":"10.1021/acsptsci.4c00282","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00282","url":null,"abstract":"Arylamine N-acetyltransferase 1 (NAT1) expression has been shown to attenuate mitochondrial function, suggesting it is a promising drug target in diseases of mitochondrial dysfunction. Here, several second-generation naphthoquinones have been investigated as small molecule inhibitors of NAT1. The results show that the compounds inhibit both <i>in vitro</i> and in whole cells. A lead compound (Cmp350) was further investigated for its ability to alter mitochondrial metabolism in MDA-MB-231 cells. At concentrations that inhibited NAT1 by over 85%, no overt toxicity was observed. Moreover, the inhibitor decreased basal respiration and reserve respiratory capacity without affecting ATP production. Cells treated with Cmp350 were almost exclusively dependent on glucose as a fuel source. We postulate that Cmp350 is an excellent lead compound for the development of NAT1-targeted inhibitors as both experimental tools and therapeutics in the treatment of hypermetabolic diseases such as amyotrophic lateral sclerosis, cancer cachexia, and sepsis.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141719930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-11DOI: 10.1021/acsptsci.4c00250
Ozlem Ozbek, Destina Ekingen Genc, Kutlu O. Ulgen
Nanoparticles (NPs) have been widely used to improve the pharmacokinetic properties and tissue distribution of small molecules such as targeting to a specific tissue of interest, enhancing their systemic circulation, and enlarging their therapeutic properties. NPs have unique and complicated in vivo disposition properties compared to small molecule drugs due to their complex multifunctionality. Physiologically based pharmacokinetic (PBPK) modeling has been a powerful tool in the simulation of the absorption, distribution, metabolism, and elimination (ADME) characteristics of the materials, and it can be used in the characterization and prediction of the systemic disposition, toxicity, efficacy, and target exposure of various types of nanoparticles. In this review, recent advances in PBPK model applications related to the nanoparticles with unique properties, and dispositional features in the biological systems, ADME characteristics, the description of transport processes of nanoparticles in the PBPK model, and the challenges in PBPK model development of nanoparticles are delineated and juxtaposed with those encountered in small molecule models. Nanoparticle related, non-nanoparticle-related, and interspecies-scaling methods applied in PBPK modeling are reviewed. In vitro to in vivo extrapolation (IVIVE) methods being a promising computational tool to provide in vivo predictions from the results of in vitro and in silico studies are discussed. Finally, as a recent advancement ML/AI-based approaches and challenges in PBPK modeling in the estimation of ADME parameters and pharmacokinetic (PK) analysis results are introduced.
{"title":"Advances in Physiologically Based Pharmacokinetic (PBPK) Modeling of Nanomaterials","authors":"Ozlem Ozbek, Destina Ekingen Genc, Kutlu O. Ulgen","doi":"10.1021/acsptsci.4c00250","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00250","url":null,"abstract":"Nanoparticles (NPs) have been widely used to improve the pharmacokinetic properties and tissue distribution of small molecules such as targeting to a specific tissue of interest, enhancing their systemic circulation, and enlarging their therapeutic properties. NPs have unique and complicated <i>in vivo</i> disposition properties compared to small molecule drugs due to their complex multifunctionality. Physiologically based pharmacokinetic (PBPK) modeling has been a powerful tool in the simulation of the absorption, distribution, metabolism, and elimination (ADME) characteristics of the materials, and it can be used in the characterization and prediction of the systemic disposition, toxicity, efficacy, and target exposure of various types of nanoparticles. In this review, recent advances in PBPK model applications related to the nanoparticles with unique properties, and dispositional features in the biological systems, ADME characteristics, the description of transport processes of nanoparticles in the PBPK model, and the challenges in PBPK model development of nanoparticles are delineated and juxtaposed with those encountered in small molecule models. Nanoparticle related, non-nanoparticle-related, and interspecies-scaling methods applied in PBPK modeling are reviewed. <i>In vitro</i> to <i>in vivo</i> extrapolation (IVIVE) methods being a promising computational tool to provide <i>in vivo</i> predictions from the results of <i>in vitro</i> and <i>in silico</i> studies are discussed. Finally, as a recent advancement ML/AI-based approaches and challenges in PBPK modeling in the estimation of ADME parameters and pharmacokinetic (PK) analysis results are introduced.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"79 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141609471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1021/acsptsci.4c00261
Yinlong Li, Kenneth Dahl, Peter Johnström, Katarina Varnäs, Lars Farde, Christer Halldin, Amy Medd, Donna Maier, Mark E. Powell, Jiahui Chen, Richard Van, Jimmy Patel, Ahmad Chaudhary, Yabiao Gao, Zhendong Song, Ahmed Haider, Yihan Shao, Charles S. Elmore, Steven Liang, Magnus Schou
The metabotropic glutamate receptor 2 (mGluR2) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR2-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR2 positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity (Ki mGluR2 = 1.31 nM) and an excellent in vitro binding specificity of 89% while demonstrating selectivity over other mGluR subtypes (>4000-fold). Autoradiography with the radiolabeled counterpart, [3H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR2-rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR2 PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [11C]AZ12559322 (6a) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR2 PAMs with improved brain exposure.
{"title":"Radiosynthesis and Evaluation of 11C-Labeled Isoindolone-Based Positive Allosteric Modulators for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor 2","authors":"Yinlong Li, Kenneth Dahl, Peter Johnström, Katarina Varnäs, Lars Farde, Christer Halldin, Amy Medd, Donna Maier, Mark E. Powell, Jiahui Chen, Richard Van, Jimmy Patel, Ahmad Chaudhary, Yabiao Gao, Zhendong Song, Ahmed Haider, Yihan Shao, Charles S. Elmore, Steven Liang, Magnus Schou","doi":"10.1021/acsptsci.4c00261","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00261","url":null,"abstract":"The metabotropic glutamate receptor 2 (mGluR<sub>2</sub>) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR<sub>2</sub>-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR<sub>2</sub> positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity (<i>K</i><sub>i</sub> mGluR<sub>2</sub> = 1.31 nM) and an excellent in vitro binding specificity of 89% while demonstrating selectivity over other mGluR subtypes (>4000-fold). Autoradiography with the radiolabeled counterpart, [<sup>3</sup>H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR<sub>2</sub>-rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR<sub>2</sub> PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [<sup>11</sup>C]AZ12559322 (<b>6a</b>) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR<sub>2</sub> PAMs with improved brain exposure.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-09DOI: 10.1021/acsptsci.4c00228
Nav Raj Phulara, Apurv Rege, Charles J. Bieberich, Herana Kamal Seneviratne
Efavirenz (EFV) is a commonly used drug to treat human immunodeficiency virus infection and is known to exert adverse effects on the brain. Although it is known that EFV is associated with abnormal plasma lipid levels, the changes in the spatial localization of individual lipid molecules in brain tissue following EFV treatment are yet to be explored. In this study, we employed a matrix-assisted laser desorption/ionization mass spectrometry imaging approach to determine region-specific lipid alterations in mouse brains following EFV treatment. We detected unique spatial localization patterns of phosphatidylcholine (PC), sphingomyelin (SM), ceramide phosphoinositol (PI-Cer), and hexosylceramide (HexCer) molecules in the mouse brain. Interestingly, PC(32:0), PC(38:5), and SM(36:1;O2) showed high abundance in the hippocampus region, whereas PI-Cer(38:8) exhibited low abundance in the hippocampus region of the EFV-treated mouse brains. Additionally, we observed low abundance of PC(38:6), PC(40:6), and PI-Cer(40:3) in the thalamus region of the EFV-treated mouse brains. Furthermore, SM(40:1;O2), SM(42:2;O2), SM(42:1;O2), SM(43:2;O2), and SM(43:1;O2) exhibited their accumulation in the corpus callosum region of the EFV-treated mouse brains as compared to controls. However, HexCer(42:1;O3) exhibited depletion in the corpus callosum region in response to EFV treatment. To characterize the expression patterns of proteins, including lipid metabolizing enzymes, in response to EFV treatment, mass spectrometry-based proteomics was utilized. From these, the expression levels of 12 brain proteins were found to be significantly decreased following EFV treatment. Taken together, these multiomics data provide important insights into the effects of EFV on brain lipid metabolism.
{"title":"Mass Spectrometry Imaging Reveals Region-Specific Lipid Alterations in the Mouse Brain in Response to Efavirenz Treatment","authors":"Nav Raj Phulara, Apurv Rege, Charles J. Bieberich, Herana Kamal Seneviratne","doi":"10.1021/acsptsci.4c00228","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00228","url":null,"abstract":"Efavirenz (EFV) is a commonly used drug to treat human immunodeficiency virus infection and is known to exert adverse effects on the brain. Although it is known that EFV is associated with abnormal plasma lipid levels, the changes in the spatial localization of individual lipid molecules in brain tissue following EFV treatment are yet to be explored. In this study, we employed a matrix-assisted laser desorption/ionization mass spectrometry imaging approach to determine region-specific lipid alterations in mouse brains following EFV treatment. We detected unique spatial localization patterns of phosphatidylcholine (PC), sphingomyelin (SM), ceramide phosphoinositol (PI-Cer), and hexosylceramide (HexCer) molecules in the mouse brain. Interestingly, PC(32:0), PC(38:5), and SM(36:1;O2) showed high abundance in the hippocampus region, whereas PI-Cer(38:8) exhibited low abundance in the hippocampus region of the EFV-treated mouse brains. Additionally, we observed low abundance of PC(38:6), PC(40:6), and PI-Cer(40:3) in the thalamus region of the EFV-treated mouse brains. Furthermore, SM(40:1;O2), SM(42:2;O2), SM(42:1;O2), SM(43:2;O2), and SM(43:1;O2) exhibited their accumulation in the corpus callosum region of the EFV-treated mouse brains as compared to controls. However, HexCer(42:1;O3) exhibited depletion in the corpus callosum region in response to EFV treatment. To characterize the expression patterns of proteins, including lipid metabolizing enzymes, in response to EFV treatment, mass spectrometry-based proteomics was utilized. From these, the expression levels of 12 brain proteins were found to be significantly decreased following EFV treatment. Taken together, these multiomics data provide important insights into the effects of EFV on brain lipid metabolism.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141609473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-08DOI: 10.1021/acsptsci.4c00269
Andrea Chicca, Daniel Bátora, Christoph Ullmer, Antonello Caruso, Sabine Grüner, Jürgen Fingerle, Thomas Hartung, Roland Degen, Matthias Müller, Uwe Grether, Pal Pacher, Jürg Gertsch
The cannabinoid CB2 receptor (CB2R) is a potential therapeutic target for distinct forms of tissue injury and inflammatory diseases. To thoroughly investigate the role of CB2R in pathophysiological conditions and for target validation in vivo, optimal pharmacological tool compounds are essential. Despite the sizable progress in the generation of potent and selective CB2R ligands, pharmacokinetic parameters are often neglected for in vivo studies. Here, we report the generation and characterization of a tetra-substituted pyrazole CB2R full agonist named RNB-61 with high potency (Ki 0.13–1.81 nM, depending on species) and a peripherally restricted action due to P-glycoprotein-mediated efflux from the brain. 3H and 14C labeled RNB-61 showed apparent Kd values of <4 nM toward human CB2R in both cell and tissue experiments. The 6,800-fold selectivity over CB1 receptors and negligible off-targets in vitro, combined with high oral bioavailability and suitable systemic pharmacokinetic (PK) properties, prompted the assessment of RNB-61 in a mouse ischemia-reperfusion model of acute kidney injury (AKI) and in a rat model of chronic kidney injury/inflammation and fibrosis (CKI) induced by unilateral ureteral obstruction. RNB-61 exerted dose-dependent nephroprotective and/or antifibrotic effects in the AKI/CKI models. Thus, RNB-61 is an optimal CB2R tool compound for preclinical in vivo studies with superior biophysical and PK properties over generally used CB2R ligands.
{"title":"A Highly Potent, Orally Bioavailable Pyrazole-Derived Cannabinoid CB2 Receptor- Selective Full Agonist for In Vivo Studies","authors":"Andrea Chicca, Daniel Bátora, Christoph Ullmer, Antonello Caruso, Sabine Grüner, Jürgen Fingerle, Thomas Hartung, Roland Degen, Matthias Müller, Uwe Grether, Pal Pacher, Jürg Gertsch","doi":"10.1021/acsptsci.4c00269","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00269","url":null,"abstract":"The cannabinoid CB2 receptor (CB2R) is a potential therapeutic target for distinct forms of tissue injury and inflammatory diseases. To thoroughly investigate the role of CB2R in pathophysiological conditions and for target validation <i>in vivo</i>, optimal pharmacological tool compounds are essential. Despite the sizable progress in the generation of potent and selective CB2R ligands, pharmacokinetic parameters are often neglected for <i>in vivo</i> studies. Here, we report the generation and characterization of a tetra-substituted pyrazole CB2R full agonist named RNB-61 with high potency (<i>K</i><sub>i</sub> 0.13–1.81 nM, depending on species) and a peripherally restricted action due to <i>P</i>-glycoprotein-mediated efflux from the brain. <sup>3</sup>H and <sup>14</sup>C labeled RNB-61 showed apparent <i>K</i><sub>d</sub> values of <4 nM toward human CB2R in both cell and tissue experiments. The 6,800-fold selectivity over CB1 receptors and negligible off-targets <i>in vitro</i>, combined with high oral bioavailability and suitable systemic pharmacokinetic (PK) properties, prompted the assessment of RNB-61 in a mouse ischemia-reperfusion model of acute kidney injury (AKI) and in a rat model of chronic kidney injury/inflammation and fibrosis (CKI) induced by unilateral ureteral obstruction. RNB-61 exerted dose-dependent nephroprotective and/or antifibrotic effects in the AKI/CKI models. Thus, RNB-61 is an optimal CB2R tool compound for preclinical <i>in vivo</i> studies with superior biophysical and PK properties over generally used CB2R ligands.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141609472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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