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

Hannah J Vaughan; Camila G Zamboni; Kathryn M Luly; Ling Li; Kathleen L Gabrielson; Laboni F Hassan; Nicholas P Radant; Pranshu Bhardwaj; Florin M Selaru; Martin G Pomper; Jordan J Green

doi:10.2147/IJN.S390384

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

Int J Nanomedicine. 2023 May 11:18:2525-2537. doi: 10.2147/IJN.S390384. eCollection 2023.

Authors

Hannah J Vaughan^{1

2}, Camila G Zamboni^{1

2}, Kathryn M Luly^{1

2}, Ling Li³, Kathleen L Gabrielson⁴, Laboni F Hassan^{1

2}, Nicholas P Radant^{1

2}, Pranshu Bhardwaj^{1

2}, Florin M Selaru³, Martin G Pomper^{1

5

6}, Jordan J Green^{1

2

6

7}

Affiliations

¹ Department of Biomedical Engineering and the Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Division of Gastroenterology and Hepatology, Department of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
⁴ Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
⁶ Department of Materials Science and Engineering and the Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁷ Departments of Neurosurgery, Oncology, Ophthalmology, and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Abstract

Purpose: 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: gene therapy; liver cancer; nanoparticle; poly(beta-amino ester); targeted.

MeSH terms

Animals
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / therapy
Chemoembolization, Therapeutic* / methods
Injections, Intra-Arterial
Liver Neoplasms* / genetics
Liver Neoplasms* / therapy
Polymers
Rats
Tissue Distribution

Substances

Polymers

Grants and funding

The authors thank the NIH for support (R01EB022148, R01CA228133, P41EB024495, P41EB028239). HV was supported by the NIH F31 Predoctoral Fellowship (F31CA250365).