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Sonidegib (SDB) is a therapeutic option for the treatment of BCSC by inhibiting hedgehog signaling. The problems with SDB\u2019s low solubility, poor bioavailability, resistance, poor targeting, and first-pass action make it less effective when taken orally. This investigation set out to design an intratumoral in situ pH-sensitive hydrogel of SDB-invasomes (IPHS-INV) that can effectively treat BCSC by improving SDB\u2019s bioavailability, sustainability, targeting, and efficacy while also reducing its resistance and undesirable side effects. Methods: Numerous S-INV formulations were developed using Box\u2013Behnken Design Expert and tested before settling on the optimum S-INV formulation. An experimental 7, 12-dimethylbenzanthracene (DMBA) carcinoma rat model was used for in vivo studies of the IPHS-INV formulation after it was combined with chitosan. Results: Phospholipids (1.72% w\/w), cholesterol (0.15% w\/w), ethanol (1% v\/v), and cineole (1.5% v\/v) were shown to be the optimal components in the SDB-invasome formulation. The IPHS-INV formulation outperformed the permeation and bioavailability of free SDB by 7.14 and 6 times, respectively, and sustained its release by 57.41%. The IPHS-INV formulation showed a decrease in tumor volume of 99.05% and a reduction of hypercellular tumors, indicating its anti-cancer activity. The intratumoral IPHS-INV formulation maintained a higher concentration of SDB in tumors, indicating its targeting activity. Conclusions: These findings support the use of the intratumoral IPHS-INV formulation as an effective strategy for the treatment of BCSC.<\/jats:p>","DOI":"10.3390\/ph18010031","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T12:37:19Z","timestamp":1735648639000},"page":"31","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Fabrication and In Vivo Evaluation of In Situ pH-Sensitive Hydrogel of Sonidegib\u2013Invasomes via Intratumoral Delivery for Basal Cell Skin Cancer Management"],"prefix":"10.3390","volume":"18","author":[{"given":"Maha M.","family":"Ghalwash","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics and Drug Manufacturing, Faculty of Pharmacy, Modern University for Technology and Information, Cairo 11435, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0082-4160","authenticated-orcid":false,"given":"Amr Gamal","family":"Fouad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nada H.","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Deraya University, Minya 61768, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4508-9497","authenticated-orcid":false,"given":"Marwa M.","family":"Nagib","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Misr International University, Cairo 11435, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherif Faysal Abdelfattah","family":"Khalil","sequence":"additional","affiliation":[{"name":"Pharmacology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany","family":"Belal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2813-245X","authenticated-orcid":false,"given":"Samar F.","family":"Miski","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Department, College of Pharmacy, Taibah University,  Madina 42278, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisreen Khalid Aref","family":"Albezrah","sequence":"additional","affiliation":[{"name":"Department of Obstetric & Gynecology, College of Medicine, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amani","family":"Elsayed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Taif University, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1048-6281","authenticated-orcid":false,"given":"Ahmed H. E.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1368-3133","authenticated-orcid":false,"given":"Eun Joo","family":"Roh","sequence":"additional","affiliation":[{"name":"Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea"},{"name":"Division of Bio-Medical Science & Technology, University of Science and Technology, Daejeon 34113, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaimaa","family":"El-Housiny","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Drug Manufacturing, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11435, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,30]]},"reference":[{"key":"ref_1","first-page":"94","article-title":"Pathological diagnosis in malignant skin tumors","volume":"42","author":"An","year":"2023","journal-title":"Dermatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"781","DOI":"10.57239\/PJLSS-2024-22.2.0056","article-title":"Differentiation of the DMBA Signaling Pathway on the Development of Skin Tumor Based on Histopathological Changing","volume":"22","author":"Rifai","year":"2024","journal-title":"Pak. 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