Non-Viral Gene Delivery to Hepatocellular Carcinoma via Intra-Arterial Injection

Hannah J Vaughan,1,2 Camila G Zamboni,1,2 Kathryn M Luly,1,2 Ling Li,3 Kathleen L Gabrielson,4 Laboni F Hassan,1,2 Nicholas P Radant,1,2 Pranshu Bhardwaj,1,2 Florin M Selaru,3 Martin G Pomper,1,5,6 Jordan J Green1,2,6,7 1Department of Biomedical Engineering and the Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Division of Gastroenterology and Hepatology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA; 4Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA; 6Department of Materials Science and Engineering and the Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA; 7Departments of Neurosurgery, Oncology, Ophthalmology, and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USACorrespondence: Jordan J Green, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 400 N Broadway, Smith 5017, Baltimore, MD, 21231, USA, Tel +1 410 614-9113, Email [email protected]: Hepatocellular carcinoma (HCC) has limited treatment options, and modest survival after systemic chemotherapy or procedures such as transarterial chemoembolization (TACE). There is therefore a need to develop targeted therapies to address HCC. Gene therapies hold immense promise in treating a variety of diseases, including HCC, though delivery remains a critical hurdle. This study investigated a new approach of local delivery of polymeric nanoparticles (NPs) via intra-arterial injection for targeted local gene delivery to HCC tumors in an orthotopic rat liver tumor model.Methods: Poly(beta-amino ester) (PBAE) nanoparticles were formulated and assessed for GFP transfection in N1-S1 rat HCC cells in vitro. Optimized PBAE NPs were next administered to rats via intra-arterial injection with and without orthotopic HCC tumors, and both biodistribution and transfection were assessed.Results: In vitro transfection of PBAE NPs led to > 50% transfected cells in adherent and suspension culture at a variety of doses and weight ratios. Administration of NPs via intra-arterial or intravenous injection demonstrated no transfection of healthy liver, while intra-arterial NP injection led to transfection of tumors in an orthotopic rat HCC model.Conclusion: Hepatic artery injection is a promising delivery approach for PBAE NPs and demonstrates increased targeted transfection of HCC tumors compared to intravenous administration, and offers a potential alternative to standard chemotherapies and TACE. This work demonstrates proof of concept for administration of polymeric PBAE nanoparticles via intra-arterial injection for gene delivery in rats.Keywords: nanoparticle, gene therapy, liver cancer, poly(beta-amino ester), targete