A Novel Multi-target Drug with Nanoparticle Precision for Triple-Negative Breast Cancer

A Novel Multi-target Drug with Nanoparticle Precision for Triple-Negative Breast 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 A Novel Multi-target Drug with Nanoparticle Precision for Triple-Negative Breast Cancer Nikila Swaminathan, Venkata Naga Goutham Davuluri This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7588411/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 16 You are reading this latest preprint version Abstract Triple-negative breast cancer (TNBC) is a clinically aggressive subtype characterized by hypoxia-driven metabolic reprogramming, contributing to therapeutic resistance and poor prognosis. Two key metabolic enzymes, lactate dehydrogenase A (LDHA) and carbonic anhydrase IX (CAIX), are consistently overexpressed in TNBC and represent actionable targets for disrupting tumor adaptation under hypoxia. This study presents the computational design and in silico validation of Inhibitron-LC, a novel dual inhibitor that targets both LDHA and CAIX and aims to overcome the limitations of existing single-target agents such as FX11 and acetazolamide. Structure-based molecular docking demonstrated the high binding affinity of Inhibitron-LC for both targets. ADMET profiling indicated favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. A comparative evaluation against vorinostat, a clinically approved epigenetic modulator, revealed the potential for enhanced metabolic disruption and synergistic efficacy. To improve delivery and tumor targeting, PEGylated pH-responsive liposomal nanoparticles were designed for encapsulating Inhibitron-LC. Physiologically based pharmacokinetic (PBPK) modeling predicted improved tumor accumulation, reduced systemic toxicity, and an increased circulation half-life. These findings provide a compelling computational framework for a multitarget therapeutic strategy in TNBC, combining metabolic pathway inhibition with nanoparticle delivery. Future directions include in vitro cytotoxicity assays and translational preclinical studies. Triple-Negative Breast Cancer (TNBC) Hypoxia Metabolic Networks and Pathways Lactate Dehydrogenase A Carbonic Anhydrases Drug Design Molecular Docking Simulation Pharmacokinetics Nanoparticles Drug Delivery Systems Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 25 Nov, 2025 Reviews received at journal 22 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviewers agreed at journal 13 Nov, 2025 Reviews received at journal 13 Nov, 2025 Reviewers agreed at journal 13 Nov, 2025 Reviews received at journal 20 Oct, 2025 Reviews received at journal 14 Oct, 2025 Reviewers agreed at journal 12 Oct, 2025 Reviewers agreed at journal 10 Oct, 2025 Reviewers agreed at journal 10 Oct, 2025 Reviewers agreed at journal 10 Oct, 2025 Reviewers invited by journal 10 Oct, 2025 Editor assigned by journal 07 Oct, 2025 Submission checks completed at journal 07 Oct, 2025 First submitted to journal 06 Oct, 2025 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-7588411","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":532435781,"identity":"314b974c-bd72-4ab0-99a3-6770d159d5af","order_by":0,"name":"Nikila Swaminathan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYFACHhBxAIgZmxkSKoA0M3MDEVoSYFrOgLQwEq2FgZmBsQ1EE9DC33/22GfeH3fkGaSbmw0ezquN5m8HavlRsQ2nFokbecmzeRKeGTbIHGxOSNx2PHfGYcYGxp4zt3Fbc4PHmJknAahMIrH5QOK2Y7kNQDYzYxtuLfLnz4C12EO0zDmWO5+QFoMDOWAtiSAtCYkNNbkbCGkxvJFjzDgn7XByG1CLQcKxA7kbgVoO4vOLHNBhDG9sDtv2S6Q/lvxRU5c77/zhgw9+VODxPgywQajDYPIAYfUIUEeK4lEwCkbBKBghAADcQl1UXKwuQwAAAABJRU5ErkJggg==","orcid":"","institution":"Allen High School","correspondingAuthor":true,"prefix":"","firstName":"Nikila","middleName":"","lastName":"Swaminathan","suffix":""},{"id":532435782,"identity":"0ad8441d-1163-47dc-b717-cf7fc4432df2","order_by":1,"name":"Venkata Naga Goutham Davuluri","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Venkata","middleName":"Naga Goutham","lastName":"Davuluri","suffix":""}],"badges":[],"createdAt":"2025-09-11 06:38:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7588411/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7588411/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94392088,"identity":"199d9eda-4647-43e6-9c40-f0b0db42f252","added_by":"auto","created_at":"2025-10-27 13:53:17","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6665317,"visible":true,"origin":"","legend":"","description":"","filename":"ResearchManuscriptInhibitronLCBMCCancerVersion1.2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/953f544b0b3915588c3b3f07.docx"},{"id":94391719,"identity":"ab073f6c-c452-46df-bef0-4aa7acd9afb4","added_by":"auto","created_at":"2025-10-27 13:53:05","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5269,"visible":true,"origin":"","legend":"","description":"","filename":"c81078d1a1624b229fad61819c60f0a2.json","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/93fff4d3d88c56f3b64d5505.json"},{"id":94391312,"identity":"41e21925-fcd6-4ce7-b0cd-249504db5196","added_by":"auto","created_at":"2025-10-27 13:52:44","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":172656,"visible":true,"origin":"","legend":"","description":"","filename":"c81078d1a1624b229fad61819c60f0a21enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/a327c340d7680a281fa646fc.xml"},{"id":94489552,"identity":"f36a8227-b2c9-4ae8-8a47-4fc7323935e5","added_by":"auto","created_at":"2025-10-27 17:05:05","extension":"jpeg","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":865510,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/d8f9329b5ac02b807c60f919.jpeg"},{"id":94391308,"identity":"58548427-17a9-4d98-a73a-be182eeb86a3","added_by":"auto","created_at":"2025-10-27 13:52:43","extension":"jpeg","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":651801,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/4165e868f81e9fc2ed7c5f97.jpeg"},{"id":94390306,"identity":"a23ca414-f066-4ddb-9d16-1931e8ab7c2c","added_by":"auto","created_at":"2025-10-27 13:52:12","extension":"jpeg","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6296,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage11.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/e26a6d028fce028028afda74.jpeg"},{"id":94392155,"identity":"1d46442f-0db9-45ee-a556-359086a0ee34","added_by":"auto","created_at":"2025-10-27 13:53:22","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":783940,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage12.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/cf72d9d446022dcbb143058f.png"},{"id":94390187,"identity":"7d8cfd1a-e3ef-4abf-b756-f1b31e979399","added_by":"auto","created_at":"2025-10-27 13:52:05","extension":"jpeg","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":617332,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage13.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/e358336fb302048cb54d801d.jpeg"},{"id":94389680,"identity":"6045c3f3-677e-4536-aa65-8d24840c28cc","added_by":"auto","created_at":"2025-10-27 13:51:49","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1059182,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/3cef05a5cb4c942d58dc1ffa.png"},{"id":94390845,"identity":"722535de-68c2-4d58-a4e2-5c20a9fe2194","added_by":"auto","created_at":"2025-10-27 13:52:30","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":502758,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage15.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/07399d8434abb0aebeb395e5.png"},{"id":94391661,"identity":"6fcfc268-4d3a-46cb-96bb-7d40d0749ed1","added_by":"auto","created_at":"2025-10-27 13:53:01","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":473265,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage16.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/06c10fd08938f0a71bc64748.png"},{"id":94391311,"identity":"08498c5b-a84f-4c4a-8bfc-6934a968aa54","added_by":"auto","created_at":"2025-10-27 13:52:44","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":111713,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage17.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/74321db3cee5a0180abca6eb.png"},{"id":94391533,"identity":"2bb6c92b-c3e6-4a14-afe0-14cea749ac31","added_by":"auto","created_at":"2025-10-27 13:52:55","extension":"jpeg","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6769,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/1332651b30a8a25939133ef2.jpeg"},{"id":94489920,"identity":"5873742e-2436-418f-8300-a21790506d70","added_by":"auto","created_at":"2025-10-27 17:06:32","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":272592,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/1d58b7f51bcfcdf178dde02f.png"},{"id":94391350,"identity":"cf5260cb-1d08-49ca-955d-f8d4a50283b8","added_by":"auto","created_at":"2025-10-27 13:52:47","extension":"jpeg","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":293555,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/4af948e9a5c8cb29995fcf3f.jpeg"},{"id":94390667,"identity":"fb70e34d-bad0-4972-a226-944051579492","added_by":"auto","created_at":"2025-10-27 13:52:25","extension":"jpeg","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":481445,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/e9dc0bb84452bdbb39e42cdd.jpeg"},{"id":94390266,"identity":"065b5b09-ea75-4087-ad1d-bb3bfe69fee7","added_by":"auto","created_at":"2025-10-27 13:52:10","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":102369,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/4d6182a690e80d1d04f919a0.png"},{"id":94392132,"identity":"cccd294b-0cf1-40d2-83f0-91fe11f0381b","added_by":"auto","created_at":"2025-10-27 13:53:21","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":143010,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/491fd9a3dfb4057912c3b9d6.png"},{"id":94391908,"identity":"195e6421-21e6-43df-8a3f-bc4f1994b5d9","added_by":"auto","created_at":"2025-10-27 13:53:11","extension":"jpeg","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":622208,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage8.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/c1e4176d99c168510cece59c.jpeg"},{"id":94391757,"identity":"ac533fa8-b6cf-4f32-8caf-a56370818145","added_by":"auto","created_at":"2025-10-27 13:53:07","extension":"jpeg","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":221628,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage9.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/a26858a73e70713d609c0b52.jpeg"},{"id":94391692,"identity":"6bdab55c-bb5a-4af6-ad06-b6db95b53d0f","added_by":"auto","created_at":"2025-10-27 13:53:03","extension":"png","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":204602,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/12b68c9c5f282f759a3dca69.png"},{"id":94391529,"identity":"8a6ab59d-342d-4363-9c81-a83388280bc6","added_by":"auto","created_at":"2025-10-27 13:52:54","extension":"png","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":114143,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/2a3f307f126320f7a172f6c8.png"},{"id":94391690,"identity":"a3d95f92-3a6c-485a-90a1-12a7608b84b7","added_by":"auto","created_at":"2025-10-27 13:53:03","extension":"png","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2229,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/63c51ffb822e745ee83aea95.png"},{"id":94392126,"identity":"6f165975-92ad-4470-ace9-375abc2a0609","added_by":"auto","created_at":"2025-10-27 13:53:20","extension":"png","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":138560,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage12.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/fcf2bef8adc38895cb48000b.png"},{"id":94391070,"identity":"761b94ba-3f27-4405-b879-fe65e45a5cbd","added_by":"auto","created_at":"2025-10-27 13:52:38","extension":"png","order_by":24,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":106319,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage13.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/de863663687ee2aeac6c71f1.png"},{"id":94392078,"identity":"0c5c2032-10de-40a9-903d-d702cde8ff62","added_by":"auto","created_at":"2025-10-27 13:53:16","extension":"png","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":142825,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/154a12dbcef63b39c5f7580c.png"},{"id":94391324,"identity":"38f50459-642a-4ffb-8de3-b6d13878fc43","added_by":"auto","created_at":"2025-10-27 13:52:46","extension":"png","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":90103,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage15.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/06902be3cfd776e5a97357b8.png"},{"id":94389678,"identity":"af56515c-a6f2-4203-81de-105e19b1b94b","added_by":"auto","created_at":"2025-10-27 13:51:49","extension":"png","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":118621,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage16.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/15c87241796e941867683bd4.png"},{"id":94390311,"identity":"a1d1f14f-8bdd-4601-924e-e22227e910ea","added_by":"auto","created_at":"2025-10-27 13:52:13","extension":"png","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":32724,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage17.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/ffc5ef4f18630dcc2fa61f7b.png"},{"id":94392302,"identity":"d1526c94-19c8-44ca-968d-97d6c53df775","added_by":"auto","created_at":"2025-10-27 13:53:25","extension":"png","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2278,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/10cc71ba2e3330524c68658a.png"},{"id":94391716,"identity":"c04d5d5b-1d77-423a-b0f6-3d287923e74a","added_by":"auto","created_at":"2025-10-27 13:53:05","extension":"png","order_by":30,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":60612,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/cc6fa72a77346556e24c6be6.png"},{"id":94391646,"identity":"5dcb333d-d214-4583-9fa0-610de501e8e2","added_by":"auto","created_at":"2025-10-27 13:53:00","extension":"png","order_by":31,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54012,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/7411ee9e28aa59318e1c25b9.png"},{"id":94392429,"identity":"9fa75be7-1456-44dc-a68d-42be6b1b7ad1","added_by":"auto","created_at":"2025-10-27 13:53:29","extension":"png","order_by":32,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":156047,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/62b7b925ed1b04798b4ae46d.png"},{"id":94391328,"identity":"1c2816bb-9229-468f-a3e5-cdb976d3b63f","added_by":"auto","created_at":"2025-10-27 13:52:47","extension":"png","order_by":33,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":26237,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/b23328153c8c3cc5eced7b5a.png"},{"id":94390305,"identity":"560dddcf-89d0-4a4b-bb5a-538cf2722443","added_by":"auto","created_at":"2025-10-27 13:52:12","extension":"png","order_by":34,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":76636,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/dc6734109192a03cc5937ad8.png"},{"id":94392423,"identity":"366dd1b8-4292-4a9f-8ba8-4cfb2357e14d","added_by":"auto","created_at":"2025-10-27 13:53:28","extension":"png","order_by":35,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":141469,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/0ea5c296faf4000321e05dde.png"},{"id":94392150,"identity":"b7f7c344-fc9b-4306-864d-689d715686f5","added_by":"auto","created_at":"2025-10-27 13:53:22","extension":"png","order_by":36,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54060,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/6730807cc1aa64e7e591174b.png"},{"id":94390275,"identity":"fb1e94fe-cd27-4982-894c-864ae16d899a","added_by":"auto","created_at":"2025-10-27 13:52:11","extension":"xml","order_by":37,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":171518,"visible":true,"origin":"","legend":"","description":"","filename":"c81078d1a1624b229fad61819c60f0a21structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/c6c13fe77d82ee52974c5c96.xml"},{"id":94391357,"identity":"811bfa0b-ce9f-4603-a069-5269c974b7b2","added_by":"auto","created_at":"2025-10-27 13:52:47","extension":"html","order_by":38,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":189273,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1/3ad18d26ad70750b5dcfa367.html"},{"id":94491383,"identity":"58005a06-1aa3-4685-b17a-e430ce2fb0aa","added_by":"auto","created_at":"2025-10-27 17:24:39","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2148081,"visible":true,"origin":"","legend":"","description":"","filename":"ResearchManuscriptInhibitronLCBMCCancerVersion1.2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7588411/v1_covered_d883440b-41bc-4bdf-859c-49285dd864a1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Novel Multi-target Drug with Nanoparticle Precision for Triple-Negative Breast Cancer","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Triple-Negative Breast Cancer (TNBC), Hypoxia, Metabolic Networks and Pathways, Lactate Dehydrogenase A, Carbonic Anhydrases, Drug Design, Molecular Docking Simulation, Pharmacokinetics, Nanoparticles, Drug Delivery Systems","lastPublishedDoi":"10.21203/rs.3.rs-7588411/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7588411/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTriple-negative breast cancer (TNBC) is a clinically aggressive subtype characterized by hypoxia-driven metabolic reprogramming, contributing to therapeutic resistance and poor prognosis. Two key metabolic enzymes, lactate dehydrogenase A (LDHA) and carbonic anhydrase IX (CAIX), are consistently overexpressed in TNBC and represent actionable targets for disrupting tumor adaptation under hypoxia.\u003c/p\u003e\u003cp\u003eThis study presents the computational design and in silico validation of Inhibitron-LC, a novel dual inhibitor that targets both LDHA and CAIX and aims to overcome the limitations of existing single-target agents such as FX11 and acetazolamide.\u003c/p\u003e\u003cp\u003eStructure-based molecular docking demonstrated the high binding affinity of Inhibitron-LC for both targets. ADMET profiling indicated favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. A comparative evaluation against vorinostat, a clinically approved epigenetic modulator, revealed the potential for enhanced metabolic disruption and synergistic efficacy.\u003c/p\u003e\u003cp\u003eTo improve delivery and tumor targeting, PEGylated pH-responsive liposomal nanoparticles were designed for encapsulating Inhibitron-LC. Physiologically based pharmacokinetic (PBPK) modeling predicted improved tumor accumulation, reduced systemic toxicity, and an increased circulation half-life.\u003c/p\u003e\u003cp\u003eThese findings provide a compelling computational framework for a multitarget therapeutic strategy in TNBC, combining metabolic pathway inhibition with nanoparticle delivery. Future directions include in vitro cytotoxicity assays and translational preclinical studies.\u003c/p\u003e","manuscriptTitle":"A Novel Multi-target Drug with Nanoparticle Precision for Triple-Negative Breast Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-25 15:44:02","doi":"10.21203/rs.3.rs-7588411/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-11-25T18:56:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-23T03:22:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"187998393757699753228915019261326306620","date":"2025-11-15T05:49:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"175792006408330338349409918573084610146","date":"2025-11-14T01:55:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-13T16:03:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"106374963931091484373208060866530008161","date":"2025-11-13T14:23:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-20T16:34:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-14T09:04:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"217691754120105627743934692430648069123","date":"2025-10-12T17:30:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"119882852864212439545968693152902686586","date":"2025-10-11T01:11:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"280292089969992162417742561080970388677","date":"2025-10-10T10:44:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47616570607822784769979935834137916474","date":"2025-10-10T10:20:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-10T10:06:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-07T10:42:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-07T07:45:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-10-07T02:07:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"74854a6c-be55-4287-aa7e-3d87adb051c4","owner":[],"postedDate":"October 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-25T15:44:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-25 15:44:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7588411","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7588411","identity":"rs-7588411","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}