{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T06:10:13Z","timestamp":1789798213150,"version":"4.0.1"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,9]],"date-time":"2020-04-09T00:00:00Z","timestamp":1586390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>The goal of this study is to develop optimized chitosan-coated Simvastatin (SIM) nanoparticles (NPs) loaded in an in situ gel (ISG) formulation via a face-centered central composite design (FCCCD). Coated SIM-NPs were doped with Quercetin (QRC) using a modified nanoprecipitation method. The concentrations of poloxamer 188 (A) and chitosan (B) at five different levels, plus\/minus alpha (+1.414 and \u22121.414: axial points), plus\/minus 1 (factorial points) and the center point were optimized for particle size (PS-Y1), entrapment efficacy (EE-Y2) and stability index (SI-Y3). Based on the desirability approach, a formulation containing poloxamer 188 0.24% and chitosan 0.43% renders the prerequisites of optimum formulation for preparing SIM\u2013QRC NP-loaded ISG. Scanning microscopy showed spherical SIM-NPs, indicating monodispersity in the range of 0.50 \u00b1 0.04 nm with a charge of +32.42 mV. The optimized formulation indicated the highest EE 79.67% and better stability at 4 \u00b0C. Drug release from SIM\u2013QRC NP-loaded ISG was slower to plateau by up to 96 h and, at the end of 168 h, only 65.12% of SIM was released in a more controlled manner in comparison to SIM\u2013QRC NPs and plain SIM. ISG formulation showed a considerable increase in apoptosis occurrence through caspase-3 mediation and it also enhanced the tumor suppressor protein levels. Enhanced biological activity of SIM was observed due to QRC enabling promising drug and polymer synergistic interaction. The proposed formulation can provide a breakthrough in localized therapy, overcoming the potential drawbacks of systemic chemotherapy for tongue carcinoma.<\/jats:p>","DOI":"10.3390\/md18040201","type":"journal-article","created":{"date-parts":[[2020,4,9]],"date-time":"2020-04-09T14:42:03Z","timestamp":1586443323000},"page":"201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["In Situ Gel Loaded with Chitosan-Coated Simvastatin Nanoparticles: Promising Delivery for Effective Anti-Proliferative Activity against Tongue Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Mallesh","family":"Kurakula","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, The University of Memphis, Memphis, TN 38152, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. Raghavendra","family":"Naveen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Annamacharya College of Pharmacy, New Boyanapalli, Rajampet, Andhra Pradesh 516126, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1758-3284-3-43","article-title":"Modern surgical treatment of tongue carcinoma A clinical retrospective research over a 12 years period","volume":"3","author":"Majeed","year":"2011","journal-title":"Head Neck Oncol."},{"key":"ref_2","first-page":"24","article-title":"The World Oral Health Report 2003: Continuous improvement of oral health in the 21st century\u2014The approach of the WHO Global Oral Health Programme","volume":"31","author":"Pekka","year":"2003","journal-title":"Community Dent. Oral Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1007\/s12663-013-0566-8","article-title":"New Management Stratergies of Oral Tongue Cancer in Bangladesh","volume":"13","author":"Sultana","year":"2014","journal-title":"J. Maxillofac. Oral Surg."},{"key":"ref_4","unstructured":"(2020, February 18). Tongue Cancer or Cancer of the Tongue (2008) Its Various Causes Along with Symptoms and Treatments. (Internet). Available online: http:\/\/www.cancer-infoguidecom\/tongue-cancer.Html."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"450","DOI":"10.4103\/jomfp.JOMFP_118_19","article-title":"Meta-analysis on risk factors of squamous cell carcinoma of the tongue in young adults","volume":"23","author":"Mohideen","year":"2020","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_6","first-page":"1","article-title":"Squamous Cell Carcinoma of the Tongue in a 21-Year Old Female: A Case Report with Review of the Literature","volume":"3","author":"Cameron","year":"2016","journal-title":"Int. J. Dent. Oral Health"},{"key":"ref_7","first-page":"309","article-title":"Global epidemiology of oral and oropharnyngeal cancer","volume":"45","author":"Saman","year":"2008","journal-title":"Oral Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s40902-017-0139-8","article-title":"Analysis of the outcome of young age tongue squamous cell carcinoma","volume":"39","author":"Jae","year":"2017","journal-title":"Maxillofac. Plast. Reconstr. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1166\/jbn.2016.2228","article-title":"Functional Chitosan Nanoparticles in Cancer Treatment","volume":"12","author":"Fu","year":"2016","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_10","first-page":"879","article-title":"Nanostructured chitosan composites for cancer therapy: A review","volume":"67","author":"Kalyani","year":"2017","journal-title":"Int. J. Polym. Mater."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/j.1582-4934.2001.tb00172.x","article-title":"Statins: Mechanism of action and effects","volume":"5","author":"Stancu","year":"2007","journal-title":"J. Cell. Mol. Med."},{"key":"ref_12","first-page":"205","article-title":"Non-lipid-related effects of statins","volume":"5","author":"Stefano","year":"2002","journal-title":"J. Clin. Basic Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3211","DOI":"10.2147\/DDDT.S114724","article-title":"Rapid disintegrating tablets of simvastatin dispersions in polyoxyethylene\u2013polypropylene block copolymer for maximized disintegration and dissolution","volume":"10","author":"Balata","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ijpharm.2003.12.028","article-title":"Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs","volume":"274","author":"Kang","year":"2004","journal-title":"Int. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1002\/pros.23089","article-title":"A mitochondrial DNA mutation influences the apoptotic effect of statins on prostate cancer","volume":"75","author":"Sun","year":"2015","journal-title":"Prostate"},{"key":"ref_16","first-page":"1","article-title":"Quercetin: A natural compound for ovarian cancer treatment","volume":"12","author":"Rana","year":"2019","journal-title":"J. Ovarian Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.fitote.2015.09.018","article-title":"Quercetin: A flavanol with multifaceted therapeutic applications?","volume":"106","author":"Gabriele","year":"2015","journal-title":"Fitoterapia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1093\/jn\/135.3.525","article-title":"Low Concentrations of Flavanoids Are Protective in Rat H4IIE Cells Whereas High Concentrations Cause DNA Damage and Apoptosis","volume":"135","author":"Wim","year":"2005","journal-title":"J. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"826","DOI":"10.2174\/1871520614666140521122932","article-title":"Nanoparticle-delivered quercetin for cancer therapy","volume":"14","author":"Men","year":"2014","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_20","first-page":"111","article-title":"Nanotechnology for cancer treatment","volume":"3","author":"William","year":"2015","journal-title":"Nanotechnol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1166\/jnn.2015.9189","article-title":"Curcumin-Loaded Chitosan-Coated Nanoparticles as a New Approach for the Local Treatment of Oral Cavity Cancer","volume":"15","author":"Mazzarino","year":"2015","journal-title":"J. Nanosci. Nanotechnol."},{"key":"ref_22","first-page":"1398","article-title":"In-Situ gel: New trends in controlled and Sustained Drug Delivery System","volume":"2","author":"Nirmala","year":"2010","journal-title":"Int. J. Pharm Tech Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s10847-009-9605-y","article-title":"Encapsulation of cyclodextrin complexed simvastatin in chitosan nanocarriers: A novel technique for oral delivery","volume":"66","author":"Vyas","year":"2009","journal-title":"J. Incl. Phenom. Macrocycl. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.ajps.2017.04.003","article-title":"Formulation optimization of scutellarin-loaded HP-\u03b2-CD\/chitosan nanoparticles using response surface methodology with Box-Behnken design","volume":"12","author":"Liu","year":"2017","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1567201813666151109102718","article-title":"Co-Delivery of Atorvastatin Nanocrystals in PLGA based in situ Gel for Anti-Hyperlipidemic Efficacy","volume":"13","author":"Kurakula","year":"2016","journal-title":"Curr. Drug Deliv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1002\/jps.24448","article-title":"Quality by Design Coupled with Near Infrared in Formulation of Transdermal Glimepiride Liposomal Films","volume":"104","author":"Ahmed","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_27","first-page":"140","article-title":"Design expert supported mathematical optimization of repaglinide gastro retentive floating tablets: In vitro and in vivo evaluation","volume":"2","author":"Naveen","year":"2017","journal-title":"Fut. J. Pharm. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1208\/s12249-019-1496-7","article-title":"Preparation, Optimization, and Evaluation of Hyaluronic Acid-Based Hydrogel Loaded with Miconazole Self-Nanoemulsion for the Treatment of Oral Thrush","volume":"20","author":"Hosny","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/08982104.2015.1117490","article-title":"Solid lipid nanoparticles for transdermal delivery of avanafil: Optimization, formulation, in-vitro and ex-vivo studies","volume":"26","author":"Kurakula","year":"2016","journal-title":"J. Liposome Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"101528","DOI":"10.1016\/j.bcab.2020.101528","article-title":"Statistical modelling and optimization of protease production by an autochthonous Bacillus aryabhattai Ab15-ES: A response surface methodology approach","volume":"24","author":"Adetunji","year":"2020","journal-title":"Biocatal. Agric. Biotechnol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"321","DOI":"10.2147\/IJN.S77731","article-title":"Chitosan based atorvastatin nanocrystals: Effect of cationic charge on particle size, formulation stability, and in-vivo efficacy","volume":"10","author":"Kurakula","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_32","first-page":"5","article-title":"Etoposide-loaded nanoparticles made from poly-e-caprolactone (PCL): Formulation, characterization, in vitro drug release for controlled drug delivery system","volume":"5","author":"Mallamma","year":"2014","journal-title":"Int. J. Biopharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1002\/pros.20845","article-title":"The dietary bioflavonoid, quercetin, selectively induces apoptosis of prostate cancer cells by down-regulating the expression of heat shock protein 90","volume":"68","author":"Aalinkeel","year":"2008","journal-title":"Prostate"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.jpba.2008.02.009","article-title":"Compatibility studies between mannitol and omeprazole sodium isomers","volume":"48","author":"Markovic","year":"2008","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s12046-015-0451-x","article-title":"Optimum culture medium composition for lipopeptide production by Bacillus subtilis using response surface model-based ant colony optimization","volume":"41","author":"Eswari","year":"2016","journal-title":"Sadhana"},{"key":"ref_36","unstructured":"Naveen, N.R., Kurakula, M., and Gowthami, B. (2020). Process optimization by response surface methodology for preparation and evaluation of methotrexate loaded chitosan nanoparticles. Mater. Today Proc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.lwt.2014.12.020","article-title":"Development and evaluation of biodegradable polymeric nanoparticles for the effective delivery of quercetin using a quality by design approach","volume":"61","author":"Kumar","year":"2015","journal-title":"LWT"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0378-5173(95)04286-5","article-title":"Crystallization tendency and polymorphic transitions in triglyceride nanoparticles","volume":"129","author":"Heike","year":"1996","journal-title":"Int. J. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.ijbiomac.2014.08.051","article-title":"Psyllium arabinoxylan: Carboxymethylation, characterization and evaluation for nanoparticulate drug delivery","volume":"72","author":"Meenakshi","year":"2015","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0378-5173(82)90114-4","article-title":"Effect of poloxamer 407 gel on the miotic activity of pilocarpine nitrate in rabbits","volume":"12","author":"Miller","year":"1982","journal-title":"Int. J. Pharm."},{"key":"ref_41","first-page":"1","article-title":"Formulation and evaluation of sumatriptan succinate nasal in-situ gel using Fulvic acid as novel permeation enhancer","volume":"2","author":"Shyam","year":"2010","journal-title":"Int. J. Res. Dev. Pharm. Life Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3109\/10717544.2010.490247","article-title":"Formulation development of smart gel periodontal drug delivery system for local delivery of chemotherapeutic agents with application of experimental design","volume":"17","author":"Dabhi","year":"2010","journal-title":"Drug Deliv."},{"key":"ref_43","first-page":"193","article-title":"Formulation and Evaluation of Stomach Specific In-situ Gel of Metoclopramide Using Natural, Bio-Degradable Polymers","volume":"2","author":"Vinay","year":"2011","journal-title":"Int. J. Pharm. Biomed. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.powtec.2009.09.004","article-title":"Formulation optimization of dihydrartemisinin nanostructured lipid carrier using response surface methodology","volume":"197","author":"Zhang","year":"2010","journal-title":"Powder Technol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Naveen, N.R., Gopinath, C., and Kurakula, M. (2020). Okra-Thioglycolic Acid Conjugate\u2014Synthesis, Characterization, and Evaluation as a Mucoadhesive Polymer. Processes, 8.","DOI":"10.3390\/pr8030316"},{"key":"ref_46","first-page":"3371","article-title":"Berberine induces apoptosis in human HSC-3 oral cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway","volume":"27","author":"Lin","year":"2007","journal-title":"Anticancer Res."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/18\/4\/201\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:16:59Z","timestamp":1760174219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/18\/4\/201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,9]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["md18040201"],"URL":"https:\/\/doi.org\/10.3390\/md18040201","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,9]]}}}