Spatiotemporal Activation of a Quercetin-Based Prodrug via Two-Photon Excitation of Its Intrinsic ESIPT Chromophore

Spatiotemporal Activation of a Quercetin-Based Prodrug via Two-Photon Excitation of Its Intrinsic ESIPT Chromophore | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Spatiotemporal Activation of a Quercetin-Based Prodrug via Two-Photon Excitation of Its Intrinsic ESIPT Chromophore Moses Udoisoh, Temitope Esther Olajide, Boniface Anthony Ale, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8432877/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The precise and spatiotemporally confined activation of therapeutic agents in living tissue remains a major challenge in drug delivery. Existing photopharmacological systems suffer from poor tissue penetration, phototoxicity, and the scarcity of biocompatible chromophores with robust nonlinear optical response. Here we introduce and theoretically validate a natural, biocompatible platform for two-photon drug activation based on quercetin’s intrinsic excited-state intramolecular proton-transfer (ESIPT) chromophore. Using a fully quantum-mechanical framework, we simulate the ultrafast cascade triggered by simultaneous absorption of two NIR photons, which promotes quercetin to its first excited state. Within tens of femtoseconds, the nuclear wavepacket undergoes ESIPT, forming a high-energy keto tautomer that dramatically reshapes the potential-energy surface along the linker coordinate. This electronic reorganization lowers the bond-dissociation barrier by ~ 68% and elongates the equilibrium bond length by ~ 38%, funnelling the system into a barrierless dissociative channel. Time-dependent Schrödinger equation simulations reveal sub-100-fs proton-transfer kinetics, picosecond-scale bond rupture, and an overall cleavage yield exceeding 80%. The mechanism is further validated by a pronounced kinetic isotope effect (KIE ≈ 3.2) and strong spectral selectivity, with optimal activation centered at 800 nm. By integrating natural ESIPT reactivity, two-photon nonlinear optics, and prodrug chemistry, this work establishes a theoretical foundation for a new class of biocompatible, quantum-controlled phototherapeutics capable of deep-tissue activation with unprecedented spatiotemporal precision, bridging a longstanding gap between molecular photophysics and precision medicine. Two-photon activated prodrug Quercetin ESIPT photophysics Nonlinear optical response in biomolecules Deep-tissue photopharmacology Quantum-controlled phototherapeutics Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8432877","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":575483891,"identity":"ab2a5de6-96f5-41c6-88c8-e9dfba98dc42","order_by":0,"name":"Moses Udoisoh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYBADxgZmBgZmhgoJCJeHeC1nSNICJJgZ2xgIa9Ftb3/48AfDYdl+dvaHjwvnWcgbHG9gfPC2jSFP3gG7FrMzZ4yNeRgOG89s5jE2nrlNwnDDmQPMhnPbGIoND+DQciOHTZqB4XDihsM8bNK82yQYN9xIADLaGBI3NuDSkv785w+wFvZn0rxzJOw33H/A/hu/lgQzoGdBWhjMpHkbJBI33GBgYwZpmY/D+yC/SPMYpEP8wnNMInnmmcRmyTnngHpxaTne/vDjjwpr2X7+4w8f89TU2fYdP3zww5sym8T5OBwGAQYoPHAcSTAYHMCnBSuQx2vLKBgFo2AUjCAAAC0RWnHUrJp6AAAAAElFTkSuQmCC","orcid":"","institution":"Ignatius Ajuru University of Education","correspondingAuthor":true,"prefix":"","firstName":"Moses","middleName":"","lastName":"Udoisoh","suffix":""},{"id":575483892,"identity":"0d4499d0-5cd9-4c4c-9082-6be0e563a795","order_by":1,"name":"Temitope Esther Olajide","email":"","orcid":"","institution":"William V.S. 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Chromophore","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Two-photon activated prodrug, Quercetin ESIPT photophysics, Nonlinear optical response in biomolecules, Deep-tissue photopharmacology, Quantum-controlled phototherapeutics","lastPublishedDoi":"10.21203/rs.3.rs-8432877/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8432877/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe precise and spatiotemporally confined activation of therapeutic agents in living tissue remains a major challenge in drug delivery. Existing photopharmacological systems suffer from poor tissue penetration, phototoxicity, and the scarcity of biocompatible chromophores with robust nonlinear optical response. Here we introduce and theoretically validate a natural, biocompatible platform for two-photon drug activation based on quercetin\u0026rsquo;s intrinsic excited-state intramolecular proton-transfer (ESIPT) chromophore. Using a fully quantum-mechanical framework, we simulate the ultrafast cascade triggered by simultaneous absorption of two NIR photons, which promotes quercetin to its first excited state. Within tens of femtoseconds, the nuclear wavepacket undergoes ESIPT, forming a high-energy keto tautomer that dramatically reshapes the potential-energy surface along the linker coordinate. This electronic reorganization lowers the bond-dissociation barrier by ~\u0026thinsp;68% and elongates the equilibrium bond length by ~\u0026thinsp;38%, funnelling the system into a barrierless dissociative channel. Time-dependent Schr\u0026ouml;dinger equation simulations reveal sub-100-fs proton-transfer kinetics, picosecond-scale bond rupture, and an overall cleavage yield exceeding 80%. The mechanism is further validated by a pronounced kinetic isotope effect (KIE\u0026thinsp;\u0026asymp;\u0026thinsp;3.2) and strong spectral selectivity, with optimal activation centered at 800 nm. By integrating natural ESIPT reactivity, two-photon nonlinear optics, and prodrug chemistry, this work establishes a theoretical foundation for a new class of biocompatible, quantum-controlled phototherapeutics capable of deep-tissue activation with unprecedented spatiotemporal precision, bridging a longstanding gap between molecular photophysics and precision medicine.\u003c/p\u003e","manuscriptTitle":"Spatiotemporal Activation of a Quercetin-Based Prodrug via Two-Photon Excitation of Its Intrinsic ESIPT Chromophore","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-19 05:46:03","doi":"10.21203/rs.3.rs-8432877/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d9561c92-734c-4e5d-af0d-ea1b9bac8d1d","owner":[],"postedDate":"January 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-01T19:24:12+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-19 05:46:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8432877","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8432877","identity":"rs-8432877","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}