Colloids and Surfaces B: Biointerfaces 204 (2021) 111778 Available online 20 April 2021 0927-7765/© 2021 Elsevier B.V. All rights reserved. Apigenin-loaded galactose tailored PLGA nanoparticles: A possible strategy for liver targeting to treat hepatocellular carcinoma Soumya Ganguly a , Saikat Dewanjee b , Ramkrishna Sen a , Dipankar Chattopadhyay c , Shantanu Ganguly d , Raghuvir Gaonkar a , Mita Chatterjee Debnath a, * a Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India b Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India c Department of Polymer Science & Technology, University College of Science & Technology, University of Calcutta, Kolkata, India d Regional Radiation Medicine Centre, Saroj Gupta Cancer Centre and Research Institute, Kolkata, India A R T I C L E INFO Keywords: Apigenin Galactosylated-PLGA HCC HepG2 cell Therapeutic effcacy Scintigraphic imaging ABSTRACT Hepatocellular carcinoma (HCC) is the most common hepatic malignancy worldwide. Recent reports focusing on the effcacy of apigenin-loaded nanoparticles (NPs) in combating the progress of HCC encouraged us to develop galactose-tailored PLGA NPs loaded with apigenin (API-GAL-NPs) for active liver targeting to treat HCC. Two kinds of apigenin NPs, such as apigenin-PLGA NPs (API-NPs) and API-GAL-NPs were fabricated and characterized by size, surface morphology, encapsulation effcacy, and in vitro drug release kinetics. In vitro assays were per- formed on HepG2 cells to check the cellular internalization, cytotoxic potential, and apoptotic potential of free apigenin (API), API-NPs, and API-GAL-NPs. In this stdy, API-GAL-NPs exhibited improved cellular internalization of API resulting in signifcantly high cytotoxic and apoptotic potentials to HepG2 cells over API and API-NPs. In in vivo studies, API-GAL-NPs exhibited a better protective effect against DEN-induced HCC in rats evidenced by the signifcant reduction of nodule formation, downregulation of matrix metalloproteinases (MMP-2 and MMP- 9), and induction of apoptosis in the liver than API and API-NPs. Histopathological studies and scintigraphic imaging also confrmed that API-GAL-NPs treatment achieved better therapeutic effcacy against DEN-induced HCC in rats over API-NPs. In conclusion, API-GAL-NPs may serve as a potential therapeutic agent against HCC in the future by achieving improved liver targeting. 1. Introduction HCC is one of the leading causes of cancer-associated death around the world [1]. It is the ffth most typical malignancy in men and seventh amongst women [2]. Over a half-million of newly diagnosed cases of HCC appear per year [2]. An extremely poor prognosis worsens the re- covery of this disease. Early diagnosis of HCC can have some therapeutic options, such as surgical liver resection, liver transplantation, and chemotherapy [3]. However, HCC is mostly diagnosed at an advanced stage, where chemotherapy remains the only therapeutic option [1]. Thus, target-specifc delivery of chemotherapeutic agents is a primary therapeutic requirement in its therapeutic management. API is an edible naturally occurring favonoid that exhibited signifcant anticancer po- tential in preclinical studies without imparting toxic effects to normal cells [4]. It is an excellent apoptosis inducer to liver cancer cells, and can exhibit signifcant chemo-preventive and/or tumor-suppressive effects against HCC [4]. API induces apoptosis to liver cancer cells by increasing cellular ROS production mediated through NADPH oxidase activation Abbreviations: Akt, protein kinase B; ALP, alkaline phosphatase; ALT, alanine transaminase; API, apigenin; API-GAL-NPs, apigenin galactose nanoparticles; API- NPs, Apigenin nanoparticles; ASGP-R, asialoglycoprotein receptors; AST, aspartate transaminase; AUC, area under the curve; b.w., body weight; DAPI, 4 ′ ,6-dia- midino-2-phenylindole; DEN, diethylnitrosamine; FESEM, feld emission scanning electron microscope; FITC, fuorescein isothiocyanate; FTIR, Fourier transform infrared spectroscopy; GAL-PLGA, galactosylated PLGA; HCC, hepatocellular carcinoma; HPLC, high pressure liquid chromatography; IL-4R, interleukin 4 receptor; i. p., intraparetoneal; i.v., intravenous; MMP, matrix metalloproteinases; NMR, nuclear magnetic resonance; NPs, nanoparticles; Nrf-2, nuclear factor erythroid 2- related factor 2; PBS, phosphate buffered saline; PDI, polydispersity index; PI3K, phosphoinositide 3-kinase; PLGA, poly (Lactic-co-glycolic acid); TEM, trans- mission electron microscope; USFDA, United States Food and Drug Administration; USP-18, ubiquitin-specifc peptidase 18. * Corresponding author at: Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, 700032, India. E-mail address: mitacd2016@gmail.com (M.C. Debnath). Contents lists available at ScienceDirect Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb https://doi.org/10.1016/j.colsurfb.2021.111778 Received 28 December 2020; Received in revised form 30 March 2021; Accepted 17 April 2021