ACS Pharmacology and Translational Science最新文献

{"title":"Off-Target Activation of CatSper Limits the Utility of a Novel Small Molecule Slo3 Inhibitor and its Derivatives in Human Sperm","authors":"Teresa Mittermair,&nbsp;Jens Münchow,&nbsp;Timo Strünker,&nbsp;Louisa Temme,&nbsp;Christoph Brenker","doi":"10.1021/acsptsci.6c00091","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00091","url":null,"abstract":"<p>The sperm-specificK⁺ channel Slo3 is requiredfor spermfunction and fertilization in mice and humans. Due to the lack ofselective pharmacological tools, its molecular and cellular physiologyin human sperm has remained only ill-defined, though. The compoundVU0546110 (<strong>1</strong>) was recently introduced as the first selectiveSlo3 inhibitor and is now being used to study the channel’srole in human sperm. Whether the compound may have off-target actionsin sperm is however unknown. Here, using kinetic Ca²⁺ fluorimetry,patch-clamp recordings, and sperm from infertile men with a homozygousdeletion of the <em>CATSPER</em>2 gene as experimental model,we show that VU0546110 simultaneously inhibits Slo3 and activatesthe sperm-specific Ca²⁺ channel CatSper. This demonstratesthat the utility of the drug is limited: it is difficult to decipherif its action on human sperm is due to inhibition of Slo3, activationof CatSper, or a combination of both. We also introduce derivativesof VU0546110 that show a reduced potency and efficacy for CatSperactivation, while preserving the inhibitory action on Slo3.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2469–2481"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950842","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}

{"title":"The Lipid Switch: Ultra-High Dose Omega Fatty Acids Determine MYCN Neuroblastoma Fate and Implicate Substrate-Level Oxylipin Competition","authors":"Vishwa Patel,&nbsp;Yan Ning Li,&nbsp;Xin Shen,&nbsp;J. Thomas Brenna,&nbsp;John T. Powers","doi":"10.1021/acsptsci.6c00098","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00098","url":null,"abstract":"<p>Pediatric neuroblastomaexhibits puzzling biological heterogeneity─sometumors regress spontaneously while high-risk cases resist intensivemultimodal therapy─suggesting modifiable determinants of tumorfate beyond genes and proteins. Using a syngeneic MYCN-driven mousemodel, we show that lipid composition acts as a switch, creating chemicalenvironments that determine neuroblastoma progression implicatingcompeting oxylipin signaling pathways. Ultrahigh dose oral arachidonicacid (ARA, ω6, 4.7 g/day human equivalent) dramatically acceleratedtumorigenesis, producing 100% tumor incidence with solid non-necroticmasses 4-fold larger than controls. Conversely, docosahexaenoic acid(DHA, ω3, 24 g/day equivalent) profoundly suppressed tumor progression:half of the tumors regressed completely, while the remainder grewslowly, averaging 22% the size of controls and 6% the size of ARAtumors. Comprehensive oxylipin profiling via LC-MS/MS revealed divergentoxylipin profiles: ARA metabolism via cyclooxygenase, lipoxygenase,and cytochrome P450 pathways generated pro-tumorigenic eicosanoids(PGE2, TXB2, EETs) that drive angiogenesis, tumor cell proliferation,and invasion. In contrast, DHA competitively suppressed ARA-derivedeicosanoid synthesis while enriching tissues with anti-inflammatory,pro-resolving mediators (17,18-EpETE, 18-HEPE, 14-HDHA) that inhibitpathological angiogenesis and tumor growth. Both treatments were welltolerated in our model at projected doses safe in adult humans forother indications. Because COX/LOX/CYP450-mediated oxylipin signalingoperates across solid tumors, these findings support dietary highlyunsaturated fatty acid composition as a candidate, modifiable determinantof cancer progression, suggesting ultrahigh dose omega-3 fatty acidsas a low-toxicity adjunct to conventional therapies.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2482–2496"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950703","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}

{"title":"Insights into the Mechanism of Action of Phosphoantigen Prodrugs on Vγ9Vδ2 T Cell Activation","authors":"Maria Sharif,&nbsp;Claudia M. A. Pinna,&nbsp;Kamila Rakhimova,&nbsp;Taher E. Taher,&nbsp;Andrew D. Beggs,&nbsp;Youcef Mehellou,&nbsp;Benjamin E. Willcox","doi":"10.1021/acsptsci.6c00264","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00264","url":null,"abstract":"<p>The activation ofVγ9Vδ2 T cells has emergedas a promisingmodality in cancer immunotherapy. Phosphate and phosphonate prodrugsof Vγ9Vδ2 T cell phosphoantigens have been developed aspotent activators of Vγ9Vδ2 T cells that are capable ofeffectively facilitating lysis of a range of cancer cells <em>in vitro</em>. In this work, we show that phosphonate prodrugsof the phosphoantigen derivative, HMBP, enter cells in an energy-independentmanner and produce their pharmacological activity independently ofthe mevalonate pathway, a target of the widely used bisphosphonateand Vγ9Vδ2 T cell activator, zoledronate. Interestingly,these prodrugs, termed HMBP ProPAgens, induced an enhanced and moreuniversal Vγ9Vδ2 T cell cytotoxicity against diverse cancercell lines <em>in vitro</em> compared to zoledronate, an effectalso observed in patient-derived colorectal cancer organoids. Together,the data presented in this work further support the development ofHMBP ProPAgens as a novel class of cancer immunotherapeutic agents.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2585–2594"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950864","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}

{"title":"Cross-Sectional Plasma Proteomic Phenotypes Associated with Prolonged Intermittent Levosimendan Exposure in Advanced Heart Failure","authors":"José Mesquita Bastos,&nbsp;Ines Cruz,&nbsp;Luis Santos,&nbsp;Rui Vitorino","doi":"10.1021/acsptsci.6c00195","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00195","url":null,"abstract":"<p>Levosimendan is intermittentlyadministered in selected patientswith advanced heart failure, but data on prolonged exposure and associatedcirculating molecular profiles remain limited. We conducted a retrospectiveobservational study of 41 patients with heart failure with reducedejection fraction, including eight patients exposed to ≥22intermittent levosimendan infusions and 33 nonexposed controls followedin the same specialist heart failure setting. Baseline clinical characteristics,follow-up outcomes, and plasma proteomic profiles were assessed usinglabel-free data-independent acquisition mass spectrometry. Patientsexposed to prolonged intermittent levosimendan were older and hadmore advanced heart failure at baseline, including lower left ventricularejection fraction and higher NT-proBNP concentrations. During clinicalfollow-up from the first specialist cardiology observation to plasmasampling, cardiovascular hospitalization occurred in 3/8 levosimendan-exposedpatients and 1/33 controls, while cardiovascular death occurred in2/8 and 0/33, respectively; these outcomes are reported descriptivelybecause of baseline imbalance, retrospective treatment allocation,and the small exposed-group size. These outcomes are reported descriptivelybecause of baseline imbalance and the small exposed-group size. Plasmaproteomic analysis identified cross-sectional differences betweengroups. Control patients showed higher representation of immune andinflammatory proteins, whereas levosimendan-exposed patients showedhigher abundance of proteins related to antioxidant defense, redoxregulation, coagulation/hemostasis, and metabolic adaptation, includingGPX3, SELENOP, PROS1, F2, AHSG, and ALDOA. These findings define anexploratory plasma proteomic phenotype associated with prolonged intermittentlevosimendan exposure in real-world advanced heart failure. Prospectivecontrolled studies with baseline and serial proteomic sampling arerequired to determine whether these molecular differences reflecttreatment-associated adaptation or underlying clinical differences.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2513–2524"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950804","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}

{"title":"Proteolysis Targeting Chimera (PROTAC) Linkerology Enhances the CDK-Degradation Selectivity Profile of a Multi-CDK Inhibitor: Discovery of Potent, Anti-Leukemic CDK9 Degraders","authors":"Alexandria M. Chan,&nbsp;Christian Eberly,&nbsp;Christopher C. Goodis,&nbsp;Erik B. Nordquist,&nbsp;Mehari Weldemariam,&nbsp;Brandon A. Carter-Cooper,&nbsp;Sarah Pogash,&nbsp;Rena Lapidus,&nbsp;Maureen A. Kane,&nbsp;Alexander D. MacKerell, Jr.,&nbsp;Curt I. Civin,&nbsp;Steven Fletcher","doi":"10.1021/acsptsci.6c00232","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00232","url":null,"abstract":"<p>The degradation efficiencyof a PROTAC─bivalent compoundsthat link together a ligand for a protein of interest with a ligandfor an E3 ligase─is governed, in part, by the length and flexibilityof its linker (“linkerology”), as well as the accessibilityof ubiquitinatable surface lysines. Based on the prior serendipitousdiscovery of the cyclin-dependent kinase 9 (CDK9)-selective PROTACdegrader “THAL-SNS-032”, developed from the multi-CDK2/CDK7/CDK9inhibitor SNS-032, we speculated that other multi-CDK inhibitors mightlikewise be transformed into CDK9-selective PROTACs, establishinga “linkerology” platform approach to enhancing CDK familymember specificity (and beyond). We tested this hypothesis using AT7519,a multi-CDK2/CDK5/CDK9 inhibitor, and employing cereblon as the targetedE3 ligase. Accordingly, we built candidate PROTACs by linking AT7519to one of two thalidomide derivatives; those molecules in which AT7519and the thalidomide derivative were coupled via rigid linkers causedgreater degradation of the CDK9 protein than those with more flexiblelinkers. Western blotting of human acute myeloid leukemia (AML) cellstreated with AMC-3-221, our most CDK9-selective PROTAC, resulted inalmost-complete reduction of the CDK9 protein, with no detectabledegradation of CDK1, CDK2, or CDK5, and minimal degradation of CDK4and CDK6, corroborated by global proteomics analysis. Subtle shorteningor lengthening of AMC-3-221’s rigid linker altered the CDKdegradation selectivity profile, suggesting that continued linkervariation may further enhance selectivity. Molecular modeling providedinsight into the observed selectivity through the analyses of ternarycomplex stabilities. AMC-3-221 treatment rapidly decreased RNA andprotein levels of oncogenic downstream targets of CDK9─MCL-1and c-/N-MYC─and potently inhibited human AML and other typesof human cancer cell lines, with less inhibition of a non-transformedcell line, via an on-target mechanism of apoptosis. AMC-3-221’sCDK9 degradation potency (DC₅₀ &lt; 10 nM) approximatedits antileukemic inhibitory potency (IC₅₀ &lt; 50 nM).The maximum tolerated dose in mice of AMC-3-221 was higher than thatof another PROTAC, AMC-3-225, consistent with AMC-3-221’s moreselective CDK degradation profile. In summary, we demonstrate thatconverting a multi-CDK inhibitor into a PROTAC with selectivity forCDK9 over other family members is not an isolated phenomenon. Ourfindings further support the concept that PROTAC linkerology may serveas a platform for enhancing kinase selectivity.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2560–2584"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950994","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}

{"title":"Adenosine A2A and A2B Receptors as Therapeutic Targets in Cardiovascular Diseases: Mechanistic Insights and Clinical Prospects","authors":"Warisara Parichatikanond,&nbsp;Ratchanee Duangrat,&nbsp;Narawat Nuamnaichati,&nbsp;Sarawuth Phosri,&nbsp;Hnin Ei Ei Khine,&nbsp;Supachoke Mangmool","doi":"10.1021/acsptsci.6c00184","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00184","url":null,"abstract":"<p>Adenosine is a ubiquitous endogenous modulator that coordinatesdiverse physiological processes by binding to specific adenosine receptors(ARs). Among the four known AR subtypes, A_2ARs and A_2BRs are critical determinants of cardiovascular homeostasis.This narrative review comprehensively synthesizes current knowledgeon the molecular mechanisms, signaling pathways, and cardiovasculareffects of A_2ARs and A_2BRs, evaluating theirtherapeutic potential in the management of cardiovascular pathologies.Both receptor subtypes are widely distributed across cardiac and vasculartissues, where their activation engages multiple signaling cascades,including G protein-, PKC-, MAPK-, and PI3K/Akt-dependent cascades,to mediate beneficial effects in cardioprotection and vascular regulation.In ischemic heart disease, stimulation of A_2ARs and A_2BRs confers potent anti-ischemic, anti-inflammatory, and antifibroticactions, collectively reducing infarct size and attenuating pathologicalmyocardial fibrosis and remodeling. Additionally, A_2ARsand A_2BRs contribute to the regulation of vascular toneand function by promoting vasodilation, angiogenesis, and an improvedendothelial function. Overall, this review underscores the multifacetedand critical roles of A_2AR and A_2BR in the cardiovascularsystem and highlights their emerging potential as promising therapeutictargets for cardiovascular diseases.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2358–2378"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950693","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}

{"title":"Modulatory Effects of Buspirone on Psychostimulant-Induced Behavioral Alterations under Chronic Restraint Stress in Rats","authors":"Nausheen Alam,&nbsp;Shagufta Abbasi","doi":"10.1021/acsptsci.6c00316","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00316","url":null,"abstract":"<p>Psychostimulantssuch as methylphenidate (MPH) and modafinil (MOD)are effective in attention-deficit/hyperactivity disorder and narcolepsybut may induce behavioral activation, anxiety-like responses, andcognitive alterations, particularly under stress. Buspirone (BUS),a nonsedative anxiolytic acting as a partial 5-HT₁A receptoragonist, may influence stimulant-related behavioral effects. Thisstudy evaluated whether BUS modifies behavioral outcomes induced bychronic MPH and MOD administration in rats exposed to repeated restraintstress. Adult male Sprague–Dawley rats received oral MPH (10mg/kg), MOD (75 mg/kg), BUS (10 mg/kg), or their combinations for35 days under restrained or nonrestrained conditions. Behavioral assessmentsincluded locomotor activity, exploratory performance (open-field andhead-dip tests), and memory evaluation using passive avoidance andMorris water maze paradigms. MPH and MOD alone increased locomotoractivity and altered exploratory behavior, with effects influencedby stress conditions. BUS coadministration attenuated stimulant-inducedhyperactivity and modulated exploratory responses. BUS alone reducedpassive avoidance latency, which may reflect anxiolytic effects ratherthan impaired memory, while combined treatment indicated modulationof stimulant-associated cognitive outcomes. BUS may reduce stimulant-inducedbehavioral activation under stress, suggesting its potential as anadjunct to improve the behavioral tolerability of psychostimulanttherapy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2606–2616"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950775","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}

{"title":"Sinigrin Mitigates Pulmonary Inflammation and Fibrosis Partly through Adenosine Monophosphate-Activated Protein Kinase (AMPK) Signaling","authors":"Suriya Panneerselvam,&nbsp;Jeyasankari S,&nbsp;Anoop Kishore,&nbsp;Sai Balaji Andugulapati","doi":"10.1021/acsptsci.5c00826","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00826","url":null,"abstract":"<p>Idiopathic pulmonary fibrosis (IPF)is a progressiveinterstitiallung disease characterized by aberrant fibroblast activation and excessiveextracellular matrix accumulation, predominantly collagen, leadingto irreversible lung remodeling. Sinigrin (SNG), a naturally occurringglucosinolate with reported anti-inflammatory and antioxidant activities,has not been investigated in the context of pulmonary fibrosis. Inthe present study, we evaluated the therapeutic activity of SNG usingcomplementary <em>in vitro</em> and <em>in vivo</em> models of IPF. In the current investigation, inflammatory responseswere induced by lipopolysaccharide (LPS) in RAW 264.7 macrophagesand precision-cut lung slices (PCLS), whereas fibrotic activationwas elicited by TGF-β in LL29, DHLF cells, and PCLS. Treatmentwith sinigrin and dexamethasone significantly suppressed LPS-inducedinflammatory mediators (IL-6, TNF-α, IL-1β, CCL2, MMP-9,and COX-2). In TGF-β-stimulated fibroblasts/PCLS, SNG and pirfenidonemarkedly attenuated collagen accumulation and downregulated the expressionof key fibrotic markers (FN-1, α-SMA, TIMP-1, TIMP-3, COL1α1,and COL3α1). SNG administration in a bleomycin-induced pulmonaryfibrosis mouse model significantly improved body weight, survivalrate, and pulmonary index. Histopathological analyses revealed reducedcollagen deposition and lowered Ashcroft scores, accompanied by decreasedoxidative stress and improved lung function in SNG treatment comparedto BLM and PFD groups. Consistently, gene and protein expression analysesdemonstrated that SNG dose-dependently attenuated the bleomycin-inducedinflammatory and fibrotic marker expression. Further mechanistic investigations,including an AMPK siRNA-based approach, demonstrated that SNG exertsits anti-inflammatory and antifibrotic effects partly through activationof AMPK signaling. Collectively, these findings suggest that SNG mayrepresent a therapeutic candidate for the treatment of IPF.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2438–2453"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950612","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}

{"title":"Injectable Hydrogels for Local Pharmacokinetic Control in Solid Tumors: From Passive Reservoirs to Stimulus-Responsive Exposure Systems","authors":"Shiva Yaripour,&nbsp;Epiphane K. Silli,&nbsp;Muneeba Khalid,&nbsp;Huixia Lv","doi":"10.1021/acsptsci.6c00327","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00327","url":null,"abstract":"<p>Solid tumors remain difficult therapeutic targets becauseinadequateand heterogeneous intratumoral exposure, rapid local clearance, andpostoperative recurrence can limit durable tumor control. Injectablehydrogels provide locoregional platforms that prolong drug residencewithin tumors or resection cavities while reducing systemic distribution.However, prolonged retention alone does not justify classifying thesesystems as pharmacokinetic organlike regulators. Here, we synthesizethe literature on injectable hydrogels for solid tumor therapy anddistinguish passive long-acting reservoirs from stimulus-responsivelocal pharmacokinetic regulators using three operational criteria:partial decoupling of local exposure from systemic circulation, context-dependentrelease or degradation in response to tumor cues, and measurable pharmacokineticoutputs linked to the tissue state or therapeutic response. Preclinicalevidence indicates that hydrogel depots can increase local residencetime, reduce systemic exposure, remodel the tumor immune microenvironment,and suppress recurrence. Nevertheless, most systems remain bettersupported as sustained local reservoirs than as fully validated systemswith PK organ-like potential. Key gaps include limited matched tumorand plasma pharmacokinetic data, insufficient PK/PD modeling, nonstandardizedrecurrence end points, and limited clinical validation. This reviewprovides an exposure-centered framework for defining evidence requiredto support PK-organ-like claims.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2396–2418"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950624","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}

{"title":"Fibrinogen–Drug Nanoparticles Achieve Durable Responses in Pancreatic and Breast Cancer Murine Models","authors":"Rose Razavi,&nbsp;Michael O’Connor,&nbsp;James F. Hainfeld","doi":"10.1021/acsptsci.6c00337","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00337","url":null,"abstract":"<p>Inadequate targeting,short-lived therapeutic exposure,drug resistance,and toxicities limit effective cancer treatments. We developed a strategythat redirects an evolutionarily optimized clotting cascade to achieveselective, sustained drug deposition within solid tumors. A vasculardisrupting agent induces tumor-specific endothelial injury, activatingplatelets and exposing fibrinogen-binding sites. Systemically administeredfibrinogen–drug nanoparticles (FDNs) bind activated plateletswith multivalent avidity, amplify thrombus formation, and become immobilizedwithin tumor vessels, creating an intratumoral drug depot that maintainsdrug concentrations far above cytotoxic levels for over 10 days. Asingle 20 min treatment induced durable complete remissions in mostmice bearing subcutaneous triple-negative breast or pancreatic tumors.This novel vascular-targeted approach enhances selective intratumoraldrug localization through multivalent platelet binding, embolization,and sustained drug release to combat refractory cancers.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2628–2638"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950635","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}