Citation: Alkholifi, F.K.; Alam, A.; Foudah, A.I.; Yusufoglu, H.S. Phospholipid-Based Topical Nano-Hydrogel of Mangiferin: Enhanced Topical Delivery and Improved Dermatokinetics. Gels 2023, 9, 178. https://doi.org/10.3390/ gels9030178 Academic Editors: Lan Xiao, Chun Xu and Wendong Gao Received: 19 January 2023 Revised: 17 February 2023 Accepted: 20 February 2023 Published: 24 February 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/). gels Article Phospholipid-Based Topical Nano-Hydrogel of Mangiferin: Enhanced Topical Delivery and Improved Dermatokinetics Faisal K. Alkholifi 1 , Aftab Alam 2, * , Ahmed I. Foudah 2 and Hasan S. Yusufoglu 3 1 Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia 2 Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia 3 Department of Pharmacognosy & Pharmaceutical Chemistry, College of Dentistry & Pharmacy, Buraydah Private Colleges, Buraydah 51418, Saudi Arabia * Correspondence: a.alam@psau.edu.sa Abstract: Mangiferin is a herbal drug that has proven anticancer potential. Owing to its lower aqueous solubility and poor oral bioavailability, the full pharmacological potential of this bioactive drug has not fully been explored. In the present study, phospholipid-based microemulsion systems were developed to bypass oral delivery. The globule size of the developed nanocarriers was less than 150 nm and the drug entrapment was >75% with a drug loading ~25%. The developed system offered a controlled release pattern following the Fickian drug release. This enhanced mangiferin’s in vitro anticancer activity by four-fold, the cellular uptake was observed to be improved by three-fold on the MCF-7 cells. Ex vivo dermatokinetic studies showed substantial topical bioavailability with a prolonged residence time. The findings provide a simple technique to administer mangiferin via a topical route promising a safer, topically bioavailable and effective treatment option for breast cancer. Such scalable carriers with immense topical delivery potential may provide a better option for present-day topical products of a conventional nature. Keywords: dermal bioavailability; dermal pharmacokinetics; topical administration; nanoemulsion; microemulsion; anticancer; breast cancer 1. Introduction Mangiferin, chemically known as 2-β-D-glucopyranosyl-1,3,6,7-tetrahydroxy-9H- xanthen-9-one, is extracted from the seed, peel and kernel of Mangifera indica and other plants of higher order. This plant possesses immense potential for managing breast cancer, as reported in the literature. Recent scientific studies have established the beneficial effects of mangiferin, not only limited to immunomodulation, lipid-lowering, anticancer, antioxi- dant, antidiabetic, antiallergic and antimicrobial effects, but have been further reported for many lifestyle-related disorders [1–3]. The anticancer potential of this bioactive molecule has been explored by researchers all over the globe for benefits in breast, colon, lung and neuronal cancers. This phytoconstituent acts by various mechanisms ranging from free radical scavenging to the induction of apoptosis [4]. It is an acceptable trend that phyto- chemicals are explored for multiple therapeutic benefits [5,6], but numerous challenges are associated with the delivery of phytochemicals [7,8]. Like most phytochemicals, mangiferin is associated with problems such as higher lipophilicity, lesser solubility in biological fluids and poor bioavailability [9]. The oral bioavailability of mangiferin is reported to be lower than 2% [10]. Numerous reports are available where emulsifying systems have enhanced the bioavailability of poorly bioavail- able drugs [11]. Drug delivery carriers such as adhesive nanocarriers [12], PEGylated carbon nanotubes [10], injectable hydrogels [13], nano-mixed micelles [14] and nanostruc- Gels 2023, 9, 178. https://doi.org/10.3390/gels9030178 https://www.mdpi.com/journal/gels