Pub Date : 2024-07-08DOI: 10.1021/acsptsci.4c00257
Nobuki Kazuta, Kazuma Nakashima, Hiroyuki Watanabe, Masahiro Ono
In the field of radiopharmaceutical development targeting cancer, an albumin binder (ALB) is commonly used to improve accumulation of radioligands in tumors because it has high binding affinity for albumin and extends the circulation time of radioligands. The further development of ALB-containing radioligands is also expected to regulate their pharmacokinetics. In this study, we newly designed and synthesized [111In]In-PNT-DA1 derivatives, prostate-specific membrane antigen (PSMA)-targeting radioligands including a functional linker (d-glutamic acid or 4-(aminomethyl)benzoic acid), and evaluated the relationships among the structure, albumin-binding affinity, and pharmacokinetics. These derivatives showed a different binding affinity for albumin by the introduction of a linker. Biodistribution studies revealed that the introduction of a linker affects the pharmacokinetics of each derivative. The biodistribution studies also suggested that moderate albumin-binding affinity enhances the tumor/kidney ratio of the derivative. SPECT imaging using [111In]In-PNT-DA3 with the highest tumor/kidney ratio among [111In]In-PNT-DA1 derivatives led to clear visualization of a PSMA-positive LNCaP tumor. The results suggest that the appropriate introduction of linker entities may be necessary to improve the pharmacokinetics of PSMA-targeting radioligands.
{"title":"Effect of Linker Entities on Pharmacokinetics of 111In-Labeled Prostate-Specific Membrane Antigen-Targeting Ligands with an Albumin Binder","authors":"Nobuki Kazuta, Kazuma Nakashima, Hiroyuki Watanabe, Masahiro Ono","doi":"10.1021/acsptsci.4c00257","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00257","url":null,"abstract":"In the field of radiopharmaceutical development targeting cancer, an albumin binder (ALB) is commonly used to improve accumulation of radioligands in tumors because it has high binding affinity for albumin and extends the circulation time of radioligands. The further development of ALB-containing radioligands is also expected to regulate their pharmacokinetics. In this study, we newly designed and synthesized [<sup>111</sup>In]In-PNT-DA1 derivatives, prostate-specific membrane antigen (PSMA)-targeting radioligands including a functional linker (<span>d</span>-glutamic acid or 4-(aminomethyl)benzoic acid), and evaluated the relationships among the structure, albumin-binding affinity, and pharmacokinetics. These derivatives showed a different binding affinity for albumin by the introduction of a linker. Biodistribution studies revealed that the introduction of a linker affects the pharmacokinetics of each derivative. The biodistribution studies also suggested that moderate albumin-binding affinity enhances the tumor/kidney ratio of the derivative. SPECT imaging using [<sup>111</sup>In]In-PNT-DA3 with the highest tumor/kidney ratio among [<sup>111</sup>In]In-PNT-DA1 derivatives led to clear visualization of a PSMA-positive LNCaP tumor. The results suggest that the appropriate introduction of linker entities may be necessary to improve the pharmacokinetics of PSMA-targeting radioligands.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141609474","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}
This Review explores how tumor-associated regulatory cells (Tregs) affect cancer immunotherapy. It shows how Tregs play a role in keeping the immune system in check, how cancers grow, and how well immunotherapy work. Tregs use many ways to suppress the immune system, and these ways are affected by the tumor microenvironment (TME). New approaches to cancer therapy are showing promise, such as targeting Treg checkpoint receptors precisely and using Fc-engineered antibodies. It is important to tailor treatments to each patient’s TME in order to provide personalized care. Understanding Treg biology is essential for creating effective cancer treatments and improving the long-term outcomes of immunotherapy.
这篇综述探讨了肿瘤相关调节细胞（Tregs）如何影响癌症免疫疗法。它说明了Tregs如何在控制免疫系统、癌症如何生长以及免疫疗法如何发挥作用。肿瘤调节细胞通过多种方式抑制免疫系统，而这些方式会受到肿瘤微环境（TME）的影响。癌症治疗的新方法正显示出希望，例如精确靶向 Treg 检查点受体和使用 Fc 工程抗体。重要的是要根据每位患者的 TME 量身定制治疗方案，以提供个性化治疗。了解 Treg 的生物学特性对于创造有效的癌症疗法和改善免疫疗法的长期疗效至关重要。
{"title":"Deciphering Regulatory T-Cell Dynamics in Cancer Immunotherapy: Mechanisms, Implications, and Therapeutic Innovations","authors":"Sankha Bhattacharya, Gaurav Paraskar, Megha Jha, Girdhari Lal Gupta, Bhupendra G. Prajapati","doi":"10.1021/acsptsci.4c00156","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00156","url":null,"abstract":"This Review explores how tumor-associated regulatory cells (Tregs) affect cancer immunotherapy. It shows how Tregs play a role in keeping the immune system in check, how cancers grow, and how well immunotherapy work. Tregs use many ways to suppress the immune system, and these ways are affected by the tumor microenvironment (TME). New approaches to cancer therapy are showing promise, such as targeting Treg checkpoint receptors precisely and using Fc-engineered antibodies. It is important to tailor treatments to each patient’s TME in order to provide personalized care. Understanding Treg biology is essential for creating effective cancer treatments and improving the long-term outcomes of immunotherapy.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551514","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 : 2024-07-03DOI: 10.1021/acsptsci.4c00363
Yuxi Zhang, Luke Kuo, Kimberly A. Woodhouse, Lindsay E. Fitzpatrick
Continuous subcutaneous insulin infusion for Type 1 diabetes relies upon insulin infusion sets (IIS) to reliably deliver insulin to a subcutaneous depot, where it is absorbed into systemic circulation. However, IIS are plagued by short wear times and high failure rates, due in part to inconsistent insulin absorption that can arise over time. While emerging evidence suggests that the local inflammatory response to the IIS cannula may impact both wear times and unreliable insulin adsorption, the mechanisms are poorly understood. Here, we investigated the effects of local infused insulin concentrations on the biomaterial host response to better understand the underlying factors that limit the IIS performance. We first modeled the insulin concentration for a constant basal infusion rate to select a relevant insulin concentration range of 0.1–10 U/mL within the infusion site. We then examined the influence of a commercial insulin analogue (Humulin-N) using an in vitro macrophage-material model, which uses adsorbed fibroblast lysate (containing damage-associated molecular patterns) to activate macrophages and recapitulates macrophage responses on implanted biomaterials. RAW-Blue macrophages cultured on lysate-adsorbed surfaces had increased nuclear factor-κB (NF-κB) and activating protein 1 (AP-1) activity and intracellular reactive oxygen species (ROS) accumulation compared to control surfaces. Humulin-N concentration (0.5–10 U/mL) enhanced the NF-κB/AP-1 activity and ROS accumulation in macrophages on lysate-adsorbed surfaces. However, Humulin-N had no effect on NF-κB/AP-1 or ROS in the absence of the inflammatory stimulus. Additionally, high insulin concentrations arising from therapeutic doses induced macrophage apoptosis with and without adsorbed lysate. This study contributes to emerging evidence that infused insulin affects the tissue response to IIS.
{"title":"Therapeutic Insulin Analogue Concentrations at Infusion Sites Enhanced the Pro-Inflammatory Response and Apoptosis in an In Vitro Macrophage-Material Interaction Model","authors":"Yuxi Zhang, Luke Kuo, Kimberly A. Woodhouse, Lindsay E. Fitzpatrick","doi":"10.1021/acsptsci.4c00363","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00363","url":null,"abstract":"Continuous subcutaneous insulin infusion for Type 1 diabetes relies upon insulin infusion sets (IIS) to reliably deliver insulin to a subcutaneous depot, where it is absorbed into systemic circulation. However, IIS are plagued by short wear times and high failure rates, due in part to inconsistent insulin absorption that can arise over time. While emerging evidence suggests that the local inflammatory response to the IIS cannula may impact both wear times and unreliable insulin adsorption, the mechanisms are poorly understood. Here, we investigated the effects of local infused insulin concentrations on the biomaterial host response to better understand the underlying factors that limit the IIS performance. We first modeled the insulin concentration for a constant basal infusion rate to select a relevant insulin concentration range of 0.1–10 U/mL within the infusion site. We then examined the influence of a commercial insulin analogue (Humulin-N) using an in vitro macrophage-material model, which uses adsorbed fibroblast lysate (containing damage-associated molecular patterns) to activate macrophages and recapitulates macrophage responses on implanted biomaterials. RAW-Blue macrophages cultured on lysate-adsorbed surfaces had increased nuclear factor-κB (NF-κB) and activating protein 1 (AP-1) activity and intracellular reactive oxygen species (ROS) accumulation compared to control surfaces. Humulin-N concentration (0.5–10 U/mL) enhanced the NF-κB/AP-1 activity and ROS accumulation in macrophages on lysate-adsorbed surfaces. However, Humulin-N had no effect on NF-κB/AP-1 or ROS in the absence of the inflammatory stimulus. Additionally, high insulin concentrations arising from therapeutic doses induced macrophage apoptosis with and without adsorbed lysate. This study contributes to emerging evidence that infused insulin affects the tissue response to IIS.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551515","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 : 2024-06-26DOI: 10.1021/acsptsci.4c00006
Sohui Park, Jisu Shin, Kyeonghwan Kim, Darong Kim, Won Seok Lee, Jusuk Lee, Illhwan Cho, In Wook Park, Soljee Yoon, Songmin Lee, Hye Yun Kim, Ji Hoon Lee, Ki Bum Hong, YoungSoo Kim
Aggregation of misfolded amyloid-β (Aβ) and hyperphosphorylated tau proteins to plaques and tangles, respectively, is the major drug target of Alzheimer’s disease (AD), as the former is an onset biomarker and the latter is associated with neurodegeneration. Thus, we report a small molecule drug candidate, DN5355, with a dual-targeting function toward aggregates of both Aβ and tau. DN5355 was selected through a series of four screenings assessing 52 chemicals for their functions to inhibit and reverse the aggregation of Aβ and tau by utilizing thioflavin T. When orally administered to AD transgenic mouse model 5XFAD, DN5355 significantly reduced cerebral Aβ plaques and hyperphosphorylated tau tangles. In Y-maze spontaneous alteration and contextual fear conditioning tests, 5XFAD mice showed amelioration of cognitive deficits upon the oral administration of DN5355.
错误折叠的淀粉样蛋白-β（Aβ）和过度磷酸化的tau蛋白分别聚集成斑块和缠结，是阿尔茨海默病（AD）的主要药物靶点，因为前者是发病的生物标志物，后者与神经变性有关。因此，我们报告了一种候选小分子药物 DN5355，它对 Aβ 和 tau 的聚集体具有双重靶向功能。DN5355 是通过对 52 种化学物质进行一系列四次筛选而筛选出来的，这些化学物质利用硫黄素 T 抑制和逆转 Aβ 和 tau 的聚集。在Y迷宫自发改变和情境恐惧条件反射测试中，5XFAD小鼠口服DN5355后认知缺陷有所改善。
{"title":"Modulation of Amyloid and Tau Aggregation to Alleviate Cognitive Impairment in a Transgenic Mouse Model of Alzheimer’s Disease","authors":"Sohui Park, Jisu Shin, Kyeonghwan Kim, Darong Kim, Won Seok Lee, Jusuk Lee, Illhwan Cho, In Wook Park, Soljee Yoon, Songmin Lee, Hye Yun Kim, Ji Hoon Lee, Ki Bum Hong, YoungSoo Kim","doi":"10.1021/acsptsci.4c00006","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00006","url":null,"abstract":"Aggregation of misfolded amyloid-β (Aβ) and hyperphosphorylated tau proteins to plaques and tangles, respectively, is the major drug target of Alzheimer’s disease (AD), as the former is an onset biomarker and the latter is associated with neurodegeneration. Thus, we report a small molecule drug candidate, DN5355, with a dual-targeting function toward aggregates of both Aβ and tau. DN5355 was selected through a series of four screenings assessing 52 chemicals for their functions to inhibit and reverse the aggregation of Aβ and tau by utilizing thioflavin T. When orally administered to AD transgenic mouse model 5XFAD, DN5355 significantly reduced cerebral Aβ plaques and hyperphosphorylated tau tangles. In Y-maze spontaneous alteration and contextual fear conditioning tests, 5XFAD mice showed amelioration of cognitive deficits upon the oral administration of DN5355.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141513861","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 : 2024-05-27DOI: 10.1021/acsptsci.4c00158
Ingrid Marie Heyns, Alina Farah Faunce, Mercy Ngosa Mumba, M. N. V. Ravi Kumar, Meenakshi Arora
Opioids are commonly prescribed to address intense, ongoing pain associated with cancer, as well as long-lasting noncancer-related pain when alternative methods have proven ineffective. Individuals who exhibit both chronic pain and misuse of opioids face a significant danger of experiencing adverse health outcomes and the potential loss of life related to opioid use. Thus, there is a current movement to prescribe naloxone to those considered high-risk for opioid overdose. Naloxone has been explored as an antidote to reverse acute respiratory depression. Conversely, naloxone can give rise to other problems, including hypertension and cardiac arrhythmias. Thus, the importance of nanotechnology-enabled drug delivery strategies and their role in mitigating naloxone side-effects are significant. In this review, we explore the latest advancements in nanotechnology-enabled naloxone and alternative methods for addressing the opioid crisis through the utilization of non-opioid natural alternatives for chronic pain management.
{"title":"Nanotechnology-Enhanced Naloxone and Alternative Treatments for Opioid Addiction","authors":"Ingrid Marie Heyns, Alina Farah Faunce, Mercy Ngosa Mumba, M. N. V. Ravi Kumar, Meenakshi Arora","doi":"10.1021/acsptsci.4c00158","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00158","url":null,"abstract":"Opioids are commonly prescribed to address intense, ongoing pain associated with cancer, as well as long-lasting noncancer-related pain when alternative methods have proven ineffective. Individuals who exhibit both chronic pain and misuse of opioids face a significant danger of experiencing adverse health outcomes and the potential loss of life related to opioid use. Thus, there is a current movement to prescribe naloxone to those considered high-risk for opioid overdose. Naloxone has been explored as an antidote to reverse acute respiratory depression. Conversely, naloxone can give rise to other problems, including hypertension and cardiac arrhythmias. Thus, the importance of nanotechnology-enabled drug delivery strategies and their role in mitigating naloxone side-effects are significant. In this review, we explore the latest advancements in nanotechnology-enabled naloxone and alternative methods for addressing the opioid crisis through the utilization of non-opioid natural alternatives for chronic pain management.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141171098","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 : 2024-03-21DOI: 10.1021/acsptsci.4c00068
Sydney Risen, Breonna Kusick, Sadhana Sharma, Vincenzo S. Gilberto, Stephen Brindley, Mikayla Aguilar, Jared M. Brown, Stephanie McGrath, Anushree Chatterjee, Julie A. Moreno, Prashant Nagpal
Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions and multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids can offer limited relief for systemic inflammation for some organs, many patients never achieve remission, and such drugs do not cross the blood–brain barrier, making them ineffective for tackling neuroinflammation. Especially in the brain, unintended activation of microglia and astrocytes is hypothesized to be directly or indirectly responsible for multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. Recent studies have also shown that targeting inflammasomes and specific immune targets can be beneficial for these diseases. Furthermore, our previous studies have shown targeting NF-κB and NLRP3 through brain penetrant Nanoligomer cocktail SB_NI_112 (abbreviated as NI112) can be therapeutic for several neurodegenerative diseases. Here, we show safety-toxicity studies, followed by pharmacokinetics and biodistribution in small- (mice) and large-animal (dog) studies of this inflammasome-targeting Nanoligomer cocktail NI112. We conducted studies using four different routes of administration: intravenous, subcutaneous, intraperitoneal, and intranasal, and identified the drug concentration over time using inductively coupled plasma mass spectrometry in the blood serum, the brain (including different brain regions), and other target organs such as liver, kidney, and colon. Our results indicate that the Nanoligomer cocktail has a strong safety profile and shows high biodistribution (F ∼ 0.98) and delivery across multiple routes of administration. Further analysis showed high brain bioavailability with a ratio of NI112 in brain tissue to blood serum of ∼30%. Our model accurately shows dose scaling, translation between different routes of administration, and interspecies scaling. These results provide an excellent platform for human clinical translation and prediction of therapeutic dosage between different routes of administration.
{"title":"Large- and Small-Animal Studies of Safety, Pharmacokinetics, and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs","authors":"Sydney Risen, Breonna Kusick, Sadhana Sharma, Vincenzo S. Gilberto, Stephen Brindley, Mikayla Aguilar, Jared M. Brown, Stephanie McGrath, Anushree Chatterjee, Julie A. Moreno, Prashant Nagpal","doi":"10.1021/acsptsci.4c00068","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00068","url":null,"abstract":"Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions and multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids can offer limited relief for systemic inflammation for some organs, many patients never achieve remission, and such drugs do not cross the blood–brain barrier, making them ineffective for tackling neuroinflammation. Especially in the brain, unintended activation of microglia and astrocytes is hypothesized to be directly or indirectly responsible for multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. Recent studies have also shown that targeting inflammasomes and specific immune targets can be beneficial for these diseases. Furthermore, our previous studies have shown targeting NF-κB and NLRP3 through brain penetrant Nanoligomer cocktail SB_NI_112 (abbreviated as NI112) can be therapeutic for several neurodegenerative diseases. Here, we show safety-toxicity studies, followed by pharmacokinetics and biodistribution in small- (mice) and large-animal (dog) studies of this inflammasome-targeting Nanoligomer cocktail NI112. We conducted studies using four different routes of administration: intravenous, subcutaneous, intraperitoneal, and intranasal, and identified the drug concentration over time using inductively coupled plasma mass spectrometry in the blood serum, the brain (including different brain regions), and other target organs such as liver, kidney, and colon. Our results indicate that the Nanoligomer cocktail has a strong safety profile and shows high biodistribution (<i>F</i> ∼ 0.98) and delivery across multiple routes of administration. Further analysis showed high brain bioavailability with a ratio of NI112 in brain tissue to blood serum of ∼30%. Our model accurately shows dose scaling, translation between different routes of administration, and interspecies scaling. These results provide an excellent platform for human clinical translation and prediction of therapeutic dosage between different routes of administration.","PeriodicalId":501473,"journal":{"name":"ACS Pharmacology & Translational Science","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140196925","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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