Development and in Vivo Evaluation of Sunitinib-loaded Cubosomes for Enhanced Oral Bioavailability and Lymphatic Uptake

Development and in Vivo Evaluation of Sunitinib-loaded Cubosomes for Enhanced Oral Bioavailability and Lymphatic Uptake | 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 Development and in Vivo Evaluation of Sunitinib-loaded Cubosomes for Enhanced Oral Bioavailability and Lymphatic Uptake Shiva Rama Krishna Muppalla, Kishore Babu Bonige This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9348532/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Sunitinib (SUNI) is a small-molecule tyrosine kinase inhibitor with limited water solubility, extensive first-pass metabolism, and low oral bioavailability, restricting its therapeutic efficacy. This study aimed to enhance SUNI solubility, sustain its release, and improve oral bioavailability through cubosome-based nanoparticulate delivery. Glyceryl monooleate (GMO) cubosomes were prepared using high-pressure homogenization (HPH) and optimized via a Box-Behnken Design (BBD) to evaluate the effects of formulation and process variables—including GMO/Pluronic F-127 ratio, drug concentration, homogenization pressure, and homogenization cycles on particle size (PS), polydispersity index (PDI), and entrapment efficiency (%EE). Characterization using ATR-FTIR, DSC, XRD, and TEM confirmed the absence of drug-excipient interactions, successful drug incorporation in an amorphous form, and nanostructured morphology. The optimized cubosomes, containing 5.07% w/w lipid, 0.7% w/w stabilizer, 500 MPa homogenization pressure, and 8 cycles, exhibited PS of 77.8 ± 3.43 nm, PDI 0.241 ± 0.004, %EE 71.46 ± 2.01%, and zeta potential − 31.2 ± 2.34 mV. In vitro release studies demonstrated sustained drug release for over 12 hours compared to the pure drug. Pharmacokinetic evaluation in vivo revealed significant enhancement, with C max and AUC₀–∞ increased 3.78- and 5.58-fold, respectively, and oral bioavailability improved 5.6-fold relative to SUNI suspension. These findings suggest that SUNI-cubosomes represent a promising oral drug delivery system, combining enhanced absorption and prolonged release, which may improve the therapeutic performance of sunitinib. Sunitinib Cubosomes Box Benkhen design GMO Bioavailability Full Text Additional Declarations No competing interests reported. Supplementary Files Tables.docx Supplementarytables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 28 Apr, 2026 Reviewers agreed at journal 17 Apr, 2026 Reviewers invited by journal 15 Apr, 2026 Editor assigned by journal 15 Apr, 2026 Submission checks completed at journal 14 Apr, 2026 First submitted to journal 07 Apr, 2026 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-9348532","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":624787720,"identity":"b29a8ca8-ffd1-47eb-9f94-11848951e24f","order_by":0,"name":"Shiva Rama Krishna Muppalla","email":"","orcid":"","institution":"A.U. 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This study aimed to enhance SUNI solubility, sustain its release, and improve oral bioavailability through cubosome-based nanoparticulate delivery. Glyceryl monooleate (GMO) cubosomes were prepared using high-pressure homogenization (HPH) and optimized via a Box-Behnken Design (BBD) to evaluate the effects of formulation and process variables\u0026mdash;including GMO/Pluronic F-127 ratio, drug concentration, homogenization pressure, and homogenization cycles on particle size (PS), polydispersity index (PDI), and entrapment efficiency (%EE). Characterization using ATR-FTIR, DSC, XRD, and TEM confirmed the absence of drug-excipient interactions, successful drug incorporation in an amorphous form, and nanostructured morphology. The optimized cubosomes, containing 5.07% w/w lipid, 0.7% w/w stabilizer, 500 MPa homogenization pressure, and 8 cycles, exhibited PS of 77.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.43 nm, PDI 0.241\u0026thinsp;\u0026plusmn;\u0026thinsp;0.004, %EE 71.46\u0026thinsp;\u0026plusmn;\u0026thinsp;2.01%, and zeta potential\u0026thinsp;\u0026minus;\u0026thinsp;31.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.34 mV. In vitro release studies demonstrated sustained drug release for over 12 hours compared to the pure drug. Pharmacokinetic evaluation in vivo revealed significant enhancement, with C \u003csub\u003emax\u003c/sub\u003e and AUC₀\u0026ndash;\u0026infin; increased 3.78- and 5.58-fold, respectively, and oral bioavailability improved 5.6-fold relative to SUNI suspension. These findings suggest that SUNI-cubosomes represent a promising oral drug delivery system, combining enhanced absorption and prolonged release, which may improve the therapeutic performance of sunitinib.\u003c/p\u003e","manuscriptTitle":"Development and in Vivo Evaluation of Sunitinib-loaded Cubosomes for Enhanced Oral Bioavailability and Lymphatic Uptake","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-22 05:42:18","doi":"10.21203/rs.3.rs-9348532/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"337927563526617688885237255693277772782","date":"2026-04-28T08:45:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"36533114122276094322851166956716344294","date":"2026-04-17T07:52:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-15T06:40:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-15T06:36:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-14T08:45:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"BioNanoScience","date":"2026-04-07T18:16:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bionanoscience","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnsc","sideBox":"Learn more about [BioNanoScience](http://link.springer.com/journal/12668)","snPcode":"12668","submissionUrl":"https://submission.nature.com/new-submission/12668/3","title":"BioNanoScience","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f2924d37-59e6-4795-b2e7-f52a8a7fc70b","owner":[],"postedDate":"April 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-22T05:42:19+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-22 05:42:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9348532","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9348532","identity":"rs-9348532","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}