Chitosan Based thermosensitive In Situ Hydrogel for localized Delivery of Exemestane loaded micelles: A Novel Strategy for Enhanced Breast Cancer Therapy

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Chitosan Based thermosensitive In Situ Hydrogel for localized Delivery of Exemestane loaded micelles: A Novel Strategy for Enhanced Breast Cancer Therapy | 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 Chitosan Based thermosensitive In Situ Hydrogel for localized Delivery of Exemestane loaded micelles: A Novel Strategy for Enhanced Breast Cancer Therapy Gurdeep Singh, Sharabjit Singh, Ajeet Singh, Shashank K. Singh, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6975303/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Mar, 2026 Read the published version in Journal of Pharmaceutical Innovation → Version 1 posted You are reading this latest preprint version Abstract Targeted delivery of therapeutic agents to specific sites holds promise for enhancing drug concentration at the intended location. This study aims to develop novel micelles formulated using a Chrysin-Pluronic L121 conjugated polymer for the encapsulation of exemestane. Additionally, the micellar formulation is incorporated into thermosensitive injectable hydrogels to facilitate its localized administration and improve the therapeutic efficacy in the treatment of breast cancer. The prepared thermosensitive hydrogels demonstrated favorable gelation properties in terms of both time and temperature. In vitro release studies revealed a gradual and sustained release of EXE and CHS over a period of 72 h. Evaluation through in vitro cytotoxicity assays, confocal microscopy, and western blot analysis revealed a superior synergistic effect of EXE with CHS Additionally, the in situ thermosensitive hydrogel facilitated enhanced accumulation of EXE and CHS at the injection site. In vivo studies conducted on BALB/c mice bearing tumors demonstrated tumor inhibition, highlighting the potential of this localized delivery system. Overall, the incorporation of in situ hydrogel presents a promising strategy for effectively treating hormone-related breast cancer, offering improved therapeutic efficacy and safety. Exemestane chrysin in situ hydrogel mixed micelles localized delivery breast cancer Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 17 Mar, 2026 Read the published version in Journal of Pharmaceutical Innovation → 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-6975303","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":529121092,"identity":"79c18a89-f91f-4abd-941f-71d78bb73a1d","order_by":0,"name":"Gurdeep Singh","email":"","orcid":"","institution":"Guru Nanak Dev University","correspondingAuthor":false,"prefix":"","firstName":"Gurdeep","middleName":"","lastName":"Singh","suffix":""},{"id":529121093,"identity":"5415d1a0-3b47-49a1-8a91-f148e699c075","order_by":1,"name":"Sharabjit Singh","email":"","orcid":"","institution":"Guru Nanak Dev University","correspondingAuthor":false,"prefix":"","firstName":"Sharabjit","middleName":"","lastName":"Singh","suffix":""},{"id":529121094,"identity":"a840644f-d643-4cfb-8af7-357277024c9a","order_by":2,"name":"Ajeet Singh","email":"","orcid":"","institution":"Indian Institute of Integrative Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ajeet","middleName":"","lastName":"Singh","suffix":""},{"id":529121095,"identity":"c9f5875b-8f0e-45f2-8ecb-0969dcb7380c","order_by":3,"name":"Shashank K. 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