Citation: Francis, A.P.; Ahmad, A.; Nagarajan, S.D.D.; Yogeeswarakannan, H.S.; Sekar, K.; Khan, S.A.; Meenakshi, D.U.; Husain, A.; Bazuhair, M.A.; Selvasudha, N. Development of a Novel Red Clay-Based Drug Delivery Carrier to Improve the Therapeutic Efficacy of Acyclovir in the Treatment of Skin Cancer. Pharmaceutics 2023, 15, 1919. https://doi.org/10.3390/ pharmaceutics15071919 Academic Editors: Rafael Prado-Gotor, Elia M. Grueso and Rosa María Giráldez-Pérez Received: 27 May 2023 Revised: 1 July 2023 Accepted: 3 July 2023 Published: 10 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). pharmaceutics Article Development of a Novel Red Clay-Based Drug Delivery Carrier to Improve the Therapeutic Efficacy of Acyclovir in the Treatment of Skin Cancer Arul Prakash Francis 1 , Aftab Ahmad 2,3 , Sri Durga Devi Nagarajan 4 , Harish Sundar Yogeeswarakannan 4 , Krishnaraj Sekar 4 , Shah Alam Khan 1,5 , Dhanalekshmi Unnikrishnan Meenakshi 1,5, *, Asif Husain 6 , Mohammed A. Bazuhair 7 and Nandakumar Selvasudha 8, * 1 Centre of Molecular Medicine and Diagnostics (COMMAND), Saveetha Dental College and Hospitals, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600077, India; fdapharma@gmail.com (A.P.F.); shahalam@nu.edu.om (S.A.K.) 2 Health Information Technology Department, The Applied College, King Abdulaziz University, Jeddah 21589, Saudi Arabia; abdulsalam@kau.edu.sa 3 Pharmacovigilance and Medication Safety Unit, Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia 4 Department of Pharmaceutical Technology, Anna University, Chennai 600025, India; durga.elango10@gmail.com (S.D.D.N.); harishsundar2407@gmail.com (H.S.Y.); s.krishnapharma25@gmail.com (K.S.) 5 College of Pharmacy, National University of Science and Technology, Muscat PC 130, Oman 6 Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India; ahusain@jamiahamdard.ac.in 7 Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; obazohair@kau.edu.sa 8 Department of Biotechnology, Pondicherry University, Puducherry 605014, India * Correspondence: dhanalekshmi@nu.edu.om (D.U.M.); nkselvasudha@gmail.com (N.S.) Abstract: Acyclovir (ACV) is a promising candidate for drug repurposing because of its potential to provide an effective treatment for viral infections and non-viral diseases, such as cancer, for which limited treatment options exist. However, its poor physicochemical properties limit its application. This study aimed to formulate and evaluate an ACV-loaded red clay nanodrug delivery system exhibiting an effective cytotoxicity. The study focused on the preparation of a complex between ACV and red clay (RC) using sucrose stearate (SS) (nanocomplex F1) as an immediate-release drug-delivery system for melanoma treatment. The synthesized nanocomplex, which had nanosized dimensions, a negative zeta potential and the drug release of approximately 85% after 3 h, was found to be promising. Characterization techniques, including FT-IR, XRD and DSC-TGA, confirmed the effective encapsulation of ACV within the nanocomplex and its stability due to intercalation. Cytotoxicity experiments conducted on melanoma cancer cell lines SK-MEL-3 revealed that the ACV release from the nanocomplex formulation F1 effectively inhibited the growth of melanoma cancer cells, with an IC 50 of 25 ± 0.09 μg/mL. Additionally, ACV demonstrated a significant cytotoxicity at approximately 20 μg/mL in the melanoma cancer cell line, indicating its potential repurposing for skin cancer treatment. Based on these findings, it can be suggested that the RC-SS complex could be an effective drug delivery carrier for localized cancer therapy. Furthermore, the results of an in silico study suggested the addition of chitosan to the formulation for a more effective drug delivery. Energy and interaction analyses using various modules in a material studio demonstrated the high stability of the composite comprising red clay, sucrose stearate, chitosan and ACV. Thus, it could be concluded that the utilization of the red clay-based drug delivery system is a promising strategy to improve the effectiveness of targeted cancer therapy. Keywords: acyclovir; red clay; drug release; cytotoxicity; in silico Pharmaceutics 2023, 15, 1919. https://doi.org/10.3390/pharmaceutics15071919 https://www.mdpi.com/journal/pharmaceutics