Pharmacology Research & Perspectives最新文献

{"title":"The TAAR1 Agonist PCC0105004 Regulates Amygdala Synaptic Plasticity to Alleviate Anxiety-Like Behaviors in Rats.","authors":"Yingtian Zhang, Wei Zhang, Linyao Yu, Yaoqin Shi, Min Xu, Hui Wang, Chunmei Li, Jingwei Tian","doi":"10.1002/prp2.70068","DOIUrl":"10.1002/prp2.70068","url":null,"abstract":"<p><p>Anxiety disorder is a persistent, widespread, and intractable mood disorder, and the available pharmacotherapies have limited efficacy with significant side effects. Trace amine-associated receptor 1 (TAAR1) is an emerging drug target for neuropsychiatric disorders. This study examined the effects and underlying mechanisms of a novel TAAR1 agonist, PCC0105004, in a rat model of CUMS-induced anxiety-like behavior. The elevated zero maze and open field tests test were employed to evaluate the anti-anxiety-like activity of PCC0105004. PCC0105004 dose-dependently attenuated anxiety-like behaviors in rats without affecting spontaneous activity. Morphologically, PCC0104005 decreased the density of dendritic spines in the amygdala. For the mechanistic studies, whole-genome transcriptomic analysis revealed significant differences in the patterns of amygdala gene expression in the CUMS-induced anxiety rat model. These transcriptomic data were further confirmed by using RT-qPCR and western blotting, further revealing alterations associated with genes (Col1a1, DCN, Ewsr1) known to regulate synaptic plasticity, and PCC0105004 was able to reverse these changes. These results suggest that PCC0105004 is a promising anxiolytic candidate for pharmacotherapy of anxiety and warrants further examination and development.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 2","pages":"e70068"},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Cordycepin as a Neuroprotective Agent in Huntington's Disease: In Vitro and In Vivo Insights.","authors":"Chih-Wei Tung, Siew Chin Chan, Pei-Hsun Cheng, Yi-Ching Chen, Po-Ming Wu, Wei-Chen Lin, Rong-Jane Chen, Bu-Miin Huang, Shang-Hsun Yang","doi":"10.1002/prp2.70091","DOIUrl":"https://doi.org/10.1002/prp2.70091","url":null,"abstract":"<p><p>Huntington's disease (HD) is a challenging neurodegenerative disorder linked to Huntingtin (HTT) gene mutation, lacking an effective cure despite numerous therapeutic attempts. Cordyceps sinensis, recognized for its health benefits, particularly its constituent cordycepin, exhibits neuroprotective effects in various neurodegenerative diseases. However, the neuroprotective potential of cordycepin in HD remains insufficiently explored. In this study, in vitro experiments using HD cell models demonstrate that cordycepin treatment enhances cell survival, slightly diminishes mutant HTT aggregates, and improves neuronal formation. In vivo investigations on R6/2 HD transgenic mice reveal a modest increase in body weight and a slight amelioration in pathological aggregates following cordycepin administration, although behavioral changes are not significant. While the underlying mechanisms remain unexplored, the findings suggest cordycepin's promise as a supplementary therapeutic for HD, providing neuroprotective effects and reducing mutant protein aggregates.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 2","pages":"e70091"},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved Clinical Outcomes With Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Lung Disease: Real-World Evidence From an Italian Single-Center Study.","authors":"Nicola Perrotta, Luigi Angelo Fiorito, Gianfranco Casini, Rossella Gentile, Roberta Vescovo, Alfonso Piciocchi, Roberta Lobello, Carlo Cappelli, Roberto Poscia, Giuseppe Cimino","doi":"10.1002/prp2.70083","DOIUrl":"10.1002/prp2.70083","url":null,"abstract":"<p><p>The combination of Elexacaftor/Tezacaftor/Ivacaftor (ETI) has resulted in a significant improvement in lung function and global clinical parameters, which have not been previously achieved with other CFTR modulators. However, there is a paucity of evidence in the literature on the long-term use of ETI in adolescents and patients with severe pulmonary impairment. Furthermore, the response to ETI may differ between homozygotes and heterozygotes, as well as between naïve patients and those previously treated with other CFTR modulators. A retrospective study was conducted to examine changes in percent predicted forced expiratory volume in 1 s (ppFEV₁), body-mass index (BMI), and sweat chloride concentration (SwCl) at baseline and at 6, 12 and 24 months after the initiation of ETI. Secondary outcomes included the number of pulmonary exacerbations, Cystic Fibrosis Questionnaire-Revised (CFQ-R) score, adverse events, mortality and transplantation rates. 139 subjects were included and followed up for up to 2 years after starting ETI. The results demonstrated a significant improvement in ppFEV₁ and BMI after 12 months of therapy (respectively, 16%, p < 0.001; +1.5 kg/m², p = 0.005), with a slight decline in the values after 24 months. This effect was independent of genotype and showed a different degree of response in naïve subjects compared to patients previously treated with other CFTR modulators. SwCl decreased from 84 to 37 mmol/L over 24 months (p < 0.001). 58.3% reduction of PEx rate was observed compared to the number of exacerbations prior to ETI. Overall, lung function, SwCl, PEx rate, CFQ-R scores and BMI improved after 24 months of ETI treatment. ETI was well tolerated, and none of the patients interrupted the treatment due to toxicity.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 2","pages":"e70083"},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143773048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soluble Guanylate Cyclase Stimulator, BAY41-8543: A Promising Approach for the Treatment of Chronic Heart Failure Caused by Pressure and Volume Overload.","authors":"Adriana Martišková, Matúš Sýkora, Natália Andelová, Miroslav Ferko, Olga Gawrys, Katarína Andelová, Petr Kala, Luděk Červenka, Barbara Szeiffová Bačová","doi":"10.1002/prp2.70087","DOIUrl":"10.1002/prp2.70087","url":null,"abstract":"<p><p>Heart failure (HF) is a leading cause of morbidity and mortality, often driven by prolonged exposure to pathological stimuli such as pressure and volume overload. These factors contribute to excessive oxidative stress, adverse cardiac remodeling, and dysregulation of the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway. Given the urgent need for effective treatments, this study investigated the potential of sGC stimulators to mitigate HF progression. We utilized male hypertensive Ren-2 transgenic (TGR) rats and a volume-overload HF model induced by an aortocaval fistula (ACF). Rats received the sGC stimulator BAY 41-8543 (3 mg/kg/day) for 30 weeks, while normotensive Hannover Sprague-Dawley rats served as controls. At the study endpoint (40 weeks of age), left ventricular tissue was analyzed using mass spectrometry, Western blotting, and histological assessment. TGR rats treated with sGC stimulators exhibited a significant increase in key antioxidant proteins (SOD1, CH10, ACSF2, NDUS1, DHE3, GSTM2, and PCCA), suggesting enhanced resistance to oxidative stress. However, sGC stimulator treatment also upregulated extracellular matrix remodeling markers (MMP-2, TGF-β, and SMAD2/3), which are typically associated with fibrosis. Despite this, Masson's trichrome staining revealed reduced collagen deposition in both TGR and TGR-ACF rats receiving sGC stimulators. Notably, all untreated TGR-ACF rats succumbed before the study endpoint, preventing direct assessment of sGC stimulator effects in advanced HF. These findings highlight the therapeutic potential of sGC stimulators in HF, particularly through their antioxidant effects. However, their concurrent influence on fibrosis warrants further investigation to optimize treatment strategies.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 2","pages":"e70087"},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11955242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Absorption, Distribution, Metabolism, and Excretion of Binimetinib Following a Single Oral Dose of [¹⁴C]Binimetinib 45 mg in Healthy Male Participants.","authors":"Dustin Huynh, Erik Hahn, Micaela B Reddy, Renae Chavira, Lance Wollenberg","doi":"10.1002/prp2.70061","DOIUrl":"10.1002/prp2.70061","url":null,"abstract":"<p><p>Binimetinib is a MEK1/2 inhibitor particularly active in cells harboring activating mutations in the MAP kinase pathway, especially in BRAF and NRAS. Binimetinib, in combination with encorafenib, has received marketing approval in several jurisdictions for the treatment of patients with BRAF V600E or V600K mutant melanoma. The absorption, distribution, metabolism, and excretion of binimetinib were evaluated by administering a carbon 14-labeled binimetinib 45 mg dose (containing 40 μCi of radiolabeled material) to 6 healthy male participants. A total of 62.3% of the radioactivity was eliminated in the feces, while 31.4% was eliminated in the urine. The overall recovery of radioactivity in the excreta for all 6 participants was 93.6% (3.27%), indicating that good mass balance was achieved. The total percentage of the dose in the excreta of all metabolites containing the N-demethylation clearance of binimetinib by CYP1A2 and CYP2C19 was approximately 17.8%. The contribution of direct glucuronidation to the clearance of binimetinib was estimated to be 61.2% and represented the majority of the clearance. Additionally, excretion of unchanged binimetinib into the urine was estimated to have contributed 6.9% to the overall clearance. Based on study results, binimetinib is at least ≈ 50% absorbed, but based on its PK properties and because its glucuronide conjugates are unstable in the GI tract, absorption is thought to be significantly higher.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70061"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDAC4/5 Inhibitor, LMK-235 Improves Animal Voluntary Movement in MPTP-Induced Parkinson's Disease Model.","authors":"Heejin Lee, Hyun-Jin Kim, Ju-Sik Min, Eunhye Lee, Dong Kyu Choi, Jae-Hyeog Choi, Yohan Seo, Sion Lee, Chun Young Im, Gi Hun Bae, Yoojin Oh, Eun-A Ko, Sung-Cherl Jung, Soong-Hyun Kim, Oh-Bin Kwon","doi":"10.1002/prp2.70057","DOIUrl":"10.1002/prp2.70057","url":null,"abstract":"<p><p>Oxidation of dopamine can cause various side effects, which ultimately leads to cell death and contributes to Parkinson's disease (PD). To counteract dopamine oxidation, newly synthesized dopamine is quickly transported into vesicles via vesicular monoamine transporter 2 (VMAT2) for storage. VMAT2 expression is reduced in patients with PD, and studies have shown increased accumulation of dopamine oxidation byproducts and α-synuclein in animals with low VMAT2 expression. Conversely, animals that overexpress VMAT2 show better protection for dopamine neurons. Based on these findings, this study used histone deacetylase inhibitors (HDACi) to increase VMAT2 expression, reduce dopamine-induced oxidative stress, and evaluate the resulting behavioral improvements in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. LMK-235 not only increased VMAT2 expression at various concentrations in the SH-SY5Y cell line differentiated into dopaminergic cells but also demonstrated effective cytoprotective properties in several toxicity assays. It significantly raised VMAT2 expression in both the striatum and the ventral tegmental area of an MPTP-induced PD model, supporting its role in reversing behavioral abnormalities linked to PD. In addition to these results, coadministration of LMK-235 with L-DOPA, a standard therapy for PD, restored typical behavioral patterns, highlighting the potential of HDACi in alleviating PD symptoms. The expression of VMAT2 induced by LMK-235, an inhibitor of Class IIa histone deacetylases primarily found in the nervous system, aids in sequestering dopamine into vesicles, potentially enhancing cell survival by inhibiting dopamine oxidation. Additionally, upregulation of VMAT2 has been shown to offer effective protection against MPTP-induced toxicity and significantly improve behavioral abnormalities associated with PD. Coadministration with L-DOPA produced the most notable improvement in behavioral outcomes. Altogether, these findings suggest that the overexpression of VMAT2 may offer a promising strategy for developing treatments for PD by mitigating dopaminergic neuron death resulting from dopamine oxidation.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70057"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposed Medicines: A Scan of the Non-commercial Clinical Research Landscape.","authors":"Sola Akinbolade, Ross Fairbairn, Alex Inskip, Rhiannon Potter, Aoife Oliver, Dawn Craig","doi":"10.1002/prp2.70049","DOIUrl":"10.1002/prp2.70049","url":null,"abstract":"<p><p>Medicine repurposing is a strategy to identify new uses for the existing medicines for the purpose of addressing areas of unmet medical need. This paper aims to provide horizon scanning intelligence on repurposed medicines that are evaluated by non-commercial organizations such as academia and highlights opportunities for further research to improve patient health outcomes. A scan of the clinical landscape of non-commercially sponsored repurposed medicines is routinely conducted by the NIHR Innovation Observatory (IO). This ongoing project involves a horizon scan of clinical trial registries and the IO's internal horizon scanning Medicines Innovation Database to identify potential candidate medicines used as monotherapy or in combination to treat new indications outside the scope of their licensed indication. In addition to making these data publicly available, the output also supports the NHS England Medicines Repurposing Programme. The snapshot scan reported here (trials completing April 2020-March 2023) identified a total of 528 technologies (meaning, a single product or combination of medicinal products targeting a specific indication in one or more related trials). The technologies were classified according to their characteristics and targeted therapeutic indications as well as revealing the least treated disease conditions. The candidate medicines identified in this scan could potentially receive tailored support toward adoption into practice and policy. The NIHR IO regularly provides this scan as a source of intelligence on repurposed medicines. This provides valuable insights into innovation trends, gaps, and areas of unmet clinical need.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70049"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142838727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are We Estimating the Mean and Variance Correctly in the Presence of Observations Outside of Measurable Range?","authors":"Markéta Janošová, Stanislav Katina, Jozef Hanes","doi":"10.1002/prp2.70048","DOIUrl":"10.1002/prp2.70048","url":null,"abstract":"<p><p>Laboratory measurements used for safety assessments in clinical trials are subject to the limits of the used laboratory equipment. These limits determine the range of values which the equipment can accurately measure. When observations fall outside the measurable range, this creates a problem in estimating parameters of the normal distribution. It may be tempting to use methods of estimation that are easy to implement, however selecting an incorrect method may lead to biased estimates (under- or overestimation) and change the research outcomes, for example, incorrect result of two-sample test about means when comparing two populations or biased estimation of regression line. In this article, we consider the use of four methods: ignoring unmeasured observations, replacing unmeasured observations with a multiple of the limit, using a truncated normal distribution, and using a normal distribution with censored observations. To compare these methods we designed a simulation study and measured their accuracy in several different situations using relative error <math> <semantics> <mrow> <mfrac> <mrow><mover><mi>μ</mi> <mo>̂</mo></mover> <mo>-</mo> <mi>μ</mi></mrow> <mi>μ</mi></mfrac> </mrow> <annotation>$$ frac{hat{mu}-mu }{mu } $$</annotation></semantics> </math> , ratio <math> <semantics> <mrow> <mfrac><mover><mi>σ</mi> <mo>̂</mo></mover> <mi>σ</mi></mfrac> </mrow> <annotation>$$ frac{hat{sigma}}{sigma } $$</annotation></semantics> </math> , and mean square errors of both parameters. Based on the results of this simulation study, if the amount of observations outside of measurable range is below 40%, we recommend using a normal distribution with censored observations in practice. These recommendations should be incorporated into guidelines for good statistical practice. If the amount of observations outside of measurable range exceeds 40%, we advise not to use the data for any statistical analysis. To illustrate how the choice of method can affect the estimates, we applied the methods to real-life laboratory data.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70048"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Part 2: Drug Interactions Involving Cannabis Products in Persons Aged 18 and Over: A Summary of Published Case Reports and Analysis of the FDA Adverse Event Reporting System.","authors":"Maryann R Chapin, Sandra L Kane-Gill, Xiaotong Li, Kojo Abanyie, Sanya B Taneja, Susan Egbert, Mary F Paine, Richard D Boyce","doi":"10.1002/prp2.70047","DOIUrl":"10.1002/prp2.70047","url":null,"abstract":"<p><p>The increasing utilization of cannabis products combined with lack of data regarding potential cannabis-prescription drug interactions is concerning. This study aimed to review published case reports and FDA Adverse Event Reporting System (FAERS) spontaneous reports to assess cannabis-drug interactions in persons aged 18 and over. A literature search identified 20 case reports that were each assessed for drug interaction causality using the Drug Interaction Probability Scale. Data collected from the FAERS revealed a greater proportion of reports mentioning serious outcomes, including death, when cannabis was used concomitantly with controlled substances compared to noncontrolled substances. Fisher's exact test showed a statistically significant difference between the controlled and noncontrolled groups (p = 0.043). Overall, these findings emphasize the need for additional research and vigilant monitoring of cannabis use when combined with other medications.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70047"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A549 Alveolar Carcinoma Spheroids as a Cytotoxicity Platform for Carboxyl- and Amine-Polyethylene Glycol Gold Nanoparticles.","authors":"Melissa Petzer, Seth-Frerich Fobian, Mary Gulumian, Vanessa Steenkamp, Werner Cordier","doi":"10.1002/prp2.70051","DOIUrl":"10.1002/prp2.70051","url":null,"abstract":"<p><p>Gold nanoparticles (AuNPs) present with unique physicochemical features and potential for functionalization as anticancer agents. Three-dimensional spheroid models can be used to afford greater tissue representation due to their heterogeneous phenotype and complex molecular architecture. This study developed an A549 alveolar carcinoma spheroid model for cytotoxicity assessment and mechanistic evaluation of functionalized AuNPs. A549 spheroids were generated using an agarose micro-mold and were characterized (morphology, acid phosphatase activity, protein content) over 21 culturing days. The 72-h cytotoxicity of carboxyl-polyethylene glycol- (PCOOH-) and amine-polyethylene glycol- (PNH₂-) functionalized AuNPs against Day 7 spheroids was assessed by determining spheroid morphology, acid phosphatase activity, protein content, caspase-3/7 activity, and cell cycle kinetics. Spheroids remained stable over the experimental period. Although the A549 spheroids' volume increased while remaining viable over the culturing period, structural integrity decreased from Day 14 onwards. The PCOOH-AuNPs lacked cytotoxicity at a maximum concentration of 1.2 × 10¹² nanoparticles/mL with no prominent alteration to the cellular processes investigated, while the PNH₂-AuNPs (at a maximum of 4.5 × 10¹² nanoparticles/mL) displayed dose- and time-dependent cytotoxicity with associated loss of spheroid compactness, debris formation, DNA fragmentation, and a 75% reduction in acid phosphatase activity. Differentiation between cytotoxic and non-cytotoxic AuNPs was achieved, with preliminary elucidation of cytotoxicity endpoints. The PNH₂-AuNPs promote cytotoxicity by modulating cellular kinetics while destabilizing the spheroid ultrastructure. The model serves as a proficient platform for more in-depth elucidation of NP cytotoxicity at the preclinical investigation phase.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70051"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}