Polylactide-tethered SN38 prodrugs in polymeric nanoparticles as reliable nanomedicines for the treatment of cervical cancer

Polylactide-tethered SN38 prodrugs in polymeric nanoparticles as reliable nanomedicines for the treatment of cervical cancer | 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 Polylactide-tethered SN38 prodrugs in polymeric nanoparticles as reliable nanomedicines for the treatment of cervical cancer Xiaomin Yu, Mingzhu Zhong, Qian Kang, Kaiwen Wu, Xiaoyan Xiang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8484219/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 Background Cervical cancer remains a major global health burden, and current chemotherapeutic options are limited by poor efficacy and severe toxicity. Irinotecan (CPT-11) exerts its antitumor activity via its active metabolite, SN38, a topoisomerase I inhibitor that disrupts DNA synthesis. However, the clinical utility of CPT-11 is compromised by its poor aqueous solubility, low in vivo conversion efficiency to SN38, and significant systemic toxicity. Although nanotechnology has been used to improve the delivery of SN38, the existing nanocartors still have the defects of insufficient tumor targeting and low cellular uptake, highlighting the need to optimize the drug delivery system. This study aims to develop 2SN38-PLA@PEG1 0k -PLA 20k nanodrugs and evaluate their in vitro and in vivo antitumor efficacy against cervical cancer, in order to provide new insights into optimizing drug delivery systems and improving clinical outcomes in cervical cancer therapy. Methods We synthesized and characterized 2SN38-PLA prodrugs, then prepared three poly(ethylene glycol)-polylactic acid (PEG-PLA) copolymers with varying chain lengths (PEG 2k -PLA 2k , PEG 5k -PLA 8k , and PEG10k-PLA 20k ) via nanoprecipitation to screen the optimal formulation. We then determined the physicochemical properties of these nanodrugs. In vitro evaluations were carried out to assess cellular uptake, cytotoxicity, apoptosis, and cell cycle distribution, while in vivo therapeutic efficacy and biosafety were evaluated using a TC-1 cell-derived subcutaneous xenograft model established in C57BL/6 mice. Results 2SN38-PLA@PEG 10k -PLA 20k nanoparticles exhibited stable physicochemical stability. In vitro, the nanodrugs were efficiently internalized by cervical cancer cells, showing lower IC 50 values against cervical cancer cell lines and reduced toxicity compared to CPT11. Mechanistically, the nanodrugs induced DNA damage, which in turn triggered cell cycle arrest and apoptotic cell death. In vivo experiments, the nanodrugs significantly inhibited xenograft tumor growth, prolonged the mouse survival, and showed no obvious systemic toxicity, confirming the favorable biosafety. Conclusion 2SN38-PLA@PEG 10k -PLA 20k nanoparticles emerge as a highly efficient and biocompatible nanodrug with robust antitumor activity against cervical cancer, validated both in vitro and in vivo. This study provides a solid preclinical foundation for the translational application of the nanodrug, thereby facilitating the optimization of cervical cancer therapeutic outcomes. 2SN38-dsPLA prodrug Nanomedicine Drug Delivery Cervical Cancer Therapeutic potential Full Text 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-8484219","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":571479950,"identity":"fd7a4dcd-a5cf-4186-b06e-48af6a6f2286","order_by":0,"name":"Xiaomin Yu","email":"","orcid":"","institution":"Department of Clinical Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000,China","correspondingAuthor":false,"prefix":"","firstName":"Xiaomin","middleName":"","lastName":"Yu","suffix":""},{"id":571479954,"identity":"da6cc66a-1d4d-49f2-b244-289921b49b5d","order_by":1,"name":"Mingzhu 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cancer","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":"2SN38-dsPLA prodrug, Nanomedicine, Drug Delivery, Cervical Cancer, Therapeutic potential","lastPublishedDoi":"10.21203/rs.3.rs-8484219/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8484219/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCervical cancer remains a major global health burden, and current chemotherapeutic options are limited by poor efficacy and severe toxicity. Irinotecan (CPT-11) exerts its antitumor activity via its active metabolite, SN38, a topoisomerase I inhibitor that disrupts DNA synthesis. However, the clinical utility of CPT-11 is compromised by its poor aqueous solubility, low in vivo conversion efficiency to SN38, and significant systemic toxicity. Although nanotechnology has been used to improve the delivery of SN38, the existing nanocartors still have the defects of insufficient tumor targeting and low cellular uptake, highlighting the need to optimize the drug delivery system. This study aims to develop 2SN38-PLA@PEG1\u003csub\u003e0k\u003c/sub\u003e-PLA\u003csub\u003e20k\u003c/sub\u003e nanodrugs and evaluate their in vitro and in vivo antitumor efficacy against cervical cancer, in order to provide new insights into optimizing drug delivery systems and improving clinical outcomes in cervical cancer therapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe synthesized and characterized 2SN38-PLA prodrugs, then prepared three poly(ethylene glycol)-polylactic acid (PEG-PLA) copolymers with varying chain lengths (PEG\u003csub\u003e2k\u003c/sub\u003e-PLA\u003csub\u003e2k\u003c/sub\u003e, PEG\u003csub\u003e5k\u003c/sub\u003e-PLA\u003csub\u003e8k\u003c/sub\u003e, and PEG10k-PLA\u003csub\u003e20k\u003c/sub\u003e) via nanoprecipitation to screen the optimal formulation. We then determined the physicochemical properties of these nanodrugs. In vitro evaluations were carried out to assess cellular uptake, cytotoxicity, apoptosis, and cell cycle distribution, while in vivo therapeutic efficacy and biosafety were evaluated using a TC-1 cell-derived subcutaneous xenograft model established in C57BL/6 mice.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e2SN38-PLA@PEG\u003csub\u003e10k\u003c/sub\u003e-PLA\u003csub\u003e20k\u003c/sub\u003e nanoparticles exhibited stable physicochemical stability. In vitro, the nanodrugs were efficiently internalized by cervical cancer cells, showing lower IC\u003csub\u003e50\u003c/sub\u003e values against cervical cancer cell lines and reduced toxicity compared to CPT11. Mechanistically, the nanodrugs induced DNA damage, which in turn triggered cell cycle arrest and apoptotic cell death. In vivo experiments, the nanodrugs significantly inhibited xenograft tumor growth, prolonged the mouse survival, and showed no obvious systemic toxicity, confirming the favorable biosafety.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003e2SN38-PLA@PEG\u003csub\u003e10k\u003c/sub\u003e-PLA\u003csub\u003e20k\u003c/sub\u003e nanoparticles emerge as a highly efficient and biocompatible nanodrug with robust antitumor activity against cervical cancer, validated both in vitro and in vivo. This study provides a solid preclinical foundation for the translational application of the nanodrug, thereby facilitating the optimization of cervical cancer therapeutic outcomes.\u003c/p\u003e","manuscriptTitle":"Polylactide-tethered SN38 prodrugs in polymeric nanoparticles as reliable nanomedicines for the treatment of cervical cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 19:44:47","doi":"10.21203/rs.3.rs-8484219/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":"0f912686-6e97-48fe-acfc-be223942f372","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-26T18:11:17+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 19:44:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8484219","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8484219","identity":"rs-8484219","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}