Gels 2022, 8, 103. https://doi.org/10.3390/gels8020103 www.mdpi.com/journal/gels Article QbD Supported Optimization of the Alginate-Chitosan Nanoparticles of Simvastatin in Enhancing the Anti-Proliferative Activity against Tongue Carcinoma Waleed Y. Rizg 1,2 , N. Raghavendra Naveen 3 , Mallesh Kurakula 4, *, Haitham A. Bukhary 5 , Awaji Y Safhi 6 , Eman Alfayez 7 , Amal M. Sindi 8 , Sarah Ali 8 and Samar S. Murshid 9 and Khaled M. Hosny 1,2 1 Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; wrizq@kau.edu.sa (W.Y.R.); kmhomar@kau.edu.sa (K.M.H.) 2 Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia 3 Department of Pharmaceuticsม Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B.G.Nagar, Karnataka 571448, India; raghavendra.naveen@gmail.com 4 Product Development Department, CURE Pharmaceutical, Oxnard, CA 93033, USA 5 Department of Pharmaceutics, Collage of Pharmacy, Umm Al-Qura University, Makkah 24381, Saudi Arabia; habukhary@uqu.edu.sa 6 Department of Pharmaceutics, Faculty of Pharmacy, Jazan University, Jazan 82817, Saudi Arabia; asafhi@jazanu.edu.sa 7 Department of Oral Biology, Faculty of Dentistry, King Abdulaziz University, Jeddah 21589, Saudi Arabia; ealfayez@kau.edu.sa 8 Department of Oral Diagnostic Sciences, Faculty of Dentistry, King Abdulaziz University, Jeddah 21589, Saudi Arabia.; amsindi@kau.edu.sa (A.M.S.); samali@kau.edu.sa (S.A.) 9 Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; samurshid@kau.edu.sa (S.S.A.M.) * Correspondence: mallesh_kurakula@yahoo.com (M.K.) Abstract: The goal of the current study is to develop a chitosan alginate nanoparticle system encap- sulating the model drug, simvastatin (SIM-CA-NP) using a novel polyelectrolytic complexation method. The formulation was optimized using the central composite design by considering the con- centrations of chitosan and alginate at five different levels (coded as +1.414, +1, 0, −1, and −1.414) in achieving minimum particle size (PS-Y1) and maximum entrapment efficiency (EE-Y2). A total of 13 runs were formulated (as projected by the Design-Expert software) and evaluated accordingly for the selected responses. On basis of the desirability approach (D = 0.880), a formulation containing 0.258 g of chitosan and 0.353 g of alginate could fulfill the prerequisites of optimum formulation in achieving 142.56 nm of PS and 75.18% EE. Optimized formulation (O-SIM-CAN) was further eval- uated for PS and EE to compare with the theoretical results, and relative error was found to be within the acceptable limits, thus confirming the accuracy of the selected design. SIM release from O-SIM-CAN was retarded significantly even beyond 96 h, due to the encapsulation in chitosan al- ginate carriers. The cell viability study and Caspase-3 enzyme assay showed a notable difference in contrast to that of plain SIM and control group. All these stated results confirm that the alginate- chitosan nanoparticulate system enhanced the anti-proliferative activity of SIM. Keywords: simvastatin; chitosan; alginate; central composite design; caspase-3-enzyme assay 1. Introduction Nanoparticles have gained huge attention as drug carriers. In particular, the poly- mer-based on nanoparticles [1,2], lipid-based [3,4], magnetic nanoparticles [5,6], and lip- osomes [7] are broadly studied under nanoformulations. Amongst them, the polymeric nanoparticles seemed to be particularly explored on account of their distinct Citation: Rizg, W.Y.; Naveen, R.; Kurakula, M.; Bukhary, H.A.; Safhi, A.Y.; Alfayez, E.; Sindi, A.M.; Ali, S.; Samar S. Murshid QbD Supported Optimization of the Alginate-Chitosan Nanoparticles of Simvastatin in Enhancing the Anti-Proliferative Activity against Tongue Carcinoma. Gels 2022, 8, 103. https://doi.org/10.3390/gels8020103 Academic Editor: Alejandro Sosnik Received: 16 January 2022 Accepted: 4 February 2022 Published: 9 February 2022 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institu- tional affiliations. Copyright: © 2022 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://cre- ativecommons.org/licenses/by/4.0/).