Gels 2023, 9, 143. https://doi.org/10.3390/gels9020143 www.mdpi.com/journal/gels Article Pluronics‐Based Drug Delivery Systems for Flavonoids Anticancer Treatment Sylwia Ronka 1, *, Aleksandra Kowalczyk 1 , Dagmara Baczyńska 2 and Anna K. Żołnierczyk 3 1 Department of Polymer Engineering and Technology, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50‐370 Wrocław, Poland 2 Department of Molecular and Cellular Biology, Faculty of Pharmacy with Division of Laboratory Diagnostics, Wrocław Medical University, Borowska 211A, 50‐556 Wrocław, Poland 3 Department of Food Chemistry and Biocatalysis, Faculty of Biotechnology and Food Science, Wrocław University of Environmental and Life Sciences, Norwida 25, 50‐375 Wrocław, Poland * Correspondence: sylwia.ronka@pwr.edu.pl; Tel.: +48‐713‐203‐826; Fax: +48‐713‐202‐152 Abstract: This research concerns the investigation of the preparation of polymeric nanocarriers con‐ taining a flavonoid—naringenin, xanthohumol or isoxanthohumol—based on Pluronics by the thin‐ film formation method. The size of the formed micelles and their stability upon dilution were eval‐ uated using Dynamic light scattering (DLS) analysis; the high values of the drug loading and the encapsulation efficiency confirmed that the proposed systems of flavonoids delivery consisting of Pluronic P123 and F127 nanomicelles could effectively distribute the drug into tumour tissues, which makes these nanocarriers ideal candidates for passive targeting of cancer cells by the en‐ hanced permeation and retention (EPR) effect. The in vitro cytotoxicity of proposed flavonoids in the Pluronic formulations was investigated by the SRB assay with human colon cancer cells. We designed mixed polymeric micelles, which was a successful drug delivery system for the case of naringenin not being able to enhance the bioavailability and cytotoxic activity of xanthohumol and isoxanthohumol. Furthermore, it was observed that the higher amount of polymer in the formula‐ tion achieved better cytotoxic activity. Keywords: amphiphilic copolymers; flavonoids; cancer therapy; drug delivery systems; nanostructures 1. Introduction Many clinical studies revealed that conventional anticancer agents’ therapeutic effi‐ cacy is insufficient, despite promising in vitro experiments. The reduced efficacy of the chemotherapy arises from poor solubility of compounds in an aqueous environment, in‐ appropriate pharmacokinetic characteristics, insufficient penetration of tumour vessels, activation of multidrug resistance (MDR) in cancer cells, and toxic effects towards normal cells. Therefore, several approaches have been applied to overcome these problems, e.g., investigating new alternative anticancer agents, and developing targeted nanoscale drug delivery systems [1]. Compounds of natural origin are of great interest to researchers, due to their diverse biological activities. Among them, natural flavonoids and their synthetic derivatives pos‐ sess high anticancer abilities. Naringenin (NG) and prenylated flavonoids such as xan‐ thoumol (XH) and isoxanthohumol (IXH) are very attractive compounds because of their high bioactivity, accompanied by easy and inexpensive access [2–4]. Naringenin exerts an anti‐inflammatory effect by inhibiting the production of nitric oxide and prostaglandin E2 [5]. In addition, antiproliferative and proapoptotic effects of naringenin have been con‐ firmed in many human cancer cell lines, i.e., breast, colon, uterus, melanoma, and Citation: Ronka, S.; Kowalczyk, A.; Baczyńska, D.; Żołnierczyk, A.K. Pluronics‐Based Drug Delivery Systems for Flavonoids Anticancer Treatment. Gels 2023, 9, 143. https://doi.org/10.3390/gels9020143 Academic Editor: Filippo Rossi Received: 21 January 2023 Revised: 3 February 2023 Accepted: 6 February 2023 Published: 8 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/license s/by/4.0/).