Oral Delivery of Photopolymerizable Nanogels Loaded with Gemcitabine for Pancreatic Cancer Therapy: Formulation Design, and in vitro and in vivo Evaluations

Abstract

Adi Yugatama,1,2,&ast; Ya-Lin Huang,1,&ast; Ming-Jen Hsu,3 Jia-Pei Lin,1 Fang-Ching Chao,4 Jenny KW Lam,5 Chien-Ming Hsieh1,5,6 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan; 2Department of Pharmacy, Sebelas Maret University, Surakarta, 57126, Indonesia; 3Department of Pharmacology, Taipei Medical University, Taipei, 11031, Taiwan; 4CNRS UMR 8612, Institut Galien Paris-Saclay, Université Paris-Saclay, Orsay, 91400, France; 5Department of Pharmaceutics, School of Pharmacy, University College, London, WC1N 1AX, UK; 6Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan&ast;These authors contributed equally to this workCorrespondence: Jenny KW Lam, Department of Pharmaceutics, School of Pharmacy, University College London, 29– 39 Brunswick Square, London, WC1N 1AX, UK, Email [email protected] Chien-Ming Hsieh, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan, Email [email protected]: Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients.Methods: We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug.Results: Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91± 7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07± 19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM’s AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙μg/mL) compared to oral free-GEM (19.04 hr∙μg/mL) after oral administration (p< 0.01), highlighting NGs’ efficacy in impeding rapid drug metabolism and enhancing retention.Conclusion: In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.Keywords: oral delivery, nanogel, gemcitabine, pancreatic cance