Polymeric nanoparticles for dual-targeted theranostic gene delivery to hepatocellular carcinoma

Hannah J Vaughan; Camila G Zamboni; Laboni F Hassan; Nicholas P Radant; Desmond Jacob; Ronnie C Mease; Il Minn; Stephany Y Tzeng; Kathleen L Gabrielson; Pranshu Bhardwaj; Xin Guo; David Francisco; Martin G Pomper; Jordan J Green

doi:10.1126/sciadv.abo6406

Polymeric nanoparticles for dual-targeted theranostic gene delivery to hepatocellular carcinoma

Sci Adv. 2022 Jul 22;8(29):eabo6406. doi: 10.1126/sciadv.abo6406. Epub 2022 Jul 20.

Authors

Hannah J Vaughan^{1

2}, Camila G Zamboni^{1

2}, Laboni F Hassan^{1

2}, Nicholas P Radant^{1

2}, Desmond Jacob³, Ronnie C Mease³, Il Minn^{1

3}, Stephany Y Tzeng^{1

2}, Kathleen L Gabrielson⁴, Pranshu Bhardwaj^{1

2}, Xin Guo⁴, David Francisco^{1

2}, Martin G Pomper^{1

3

5}, Jordan J Green^{1

2

5

6}

Affiliations

¹ Department of Biomedical Engineering and the Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
² Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
³ Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
⁴ Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Department of Materials Science and Engineering and the Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21231, USA.
⁶ Departments of Neurosurgery, Oncology, Ophthalmology, and Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Abstract

Hepatocellular carcinoma (HCC) develops predominantly in the inflammatory environment of a cirrhotic liver caused by hepatitis, toxin exposure, or chronic liver disease. A targeted therapeutic approach is required to enable cancer killing without causing toxicity and liver failure. Poly(beta-amino-ester) (PBAE) nanoparticles (NPs) were used to deliver a completely CpG-free plasmid harboring mutant herpes simplex virus type 1 sr39 thymidine kinase (sr39) DNA to human HCC cells. Transfection with sr39 enables cancer cell killing with the prodrug ganciclovir and accumulation of 9-(4-¹⁸F-fluoro-3-hydroxymethylbutyl)guanine (¹⁸F-FHBG) for in vivo imaging. Targeting was achieved using a CpG-free human alpha fetoprotein (AFP) promoter (CpGf-AFP-sr39). Expression was restricted to AFP-producing HCC cells, enabling selective transfection of orthotopic HCC xenografts. CpGf-AFP-sr39 NP treatment resulted in 62% reduced tumor size, and therapeutic gene expression was detectable by positron emission tomography (PET). This systemic nanomedicine achieved tumor-specific delivery, therapy, and imaging, representing a promising platform for targeted treatment of HCC.

MeSH terms

Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / genetics
Cell Line, Tumor
Herpesvirus 1, Human*
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
Nanoparticles*
Polymers
Precision Medicine
alpha-Fetoproteins / genetics

Substances

Polymers
alpha-Fetoproteins

Abstract

MeSH terms

Substances

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