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 Mease; Il Minn; Stephany Y. Tzeng; Kathleen L. Gabrielson; Pranshu Bhardwaj; Xin Guo; David Francisco; Martin Pomper; Jordan J. Green

doi:10.1126/sciadv.abo6406

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 Mease, Il Minn, Stephany Y. Tzeng, Kathleen L. Gabrielson, Pranshu Bhardwaj, Xin Guo, David Francisco, Martin Pomper, Jordan J. Green

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	eabo6406
Journal	Science Advances
Volume	8
Issue number	29
DOIs	https://doi.org/10.1126/sciadv.abo6406
State	Published - Jul 2022

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Vaughan, H. J., Zamboni, C. G., Hassan, L. F., Radant, N. P., Jacob, D., Mease, R., Minn, I., Tzeng, S. Y., Gabrielson, K. L., Bhardwaj, P., Guo, X., Francisco, D., Pomper, M., & Green, J. J. (2022). Polymeric nanoparticles for dual-targeted theranostic gene delivery to hepatocellular carcinoma. Science Advances, 8(29), Article eabo6406. https://doi.org/10.1126/sciadv.abo6406

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title = "Polymeric nanoparticles for dual-targeted theranostic gene delivery to hepatocellular carcinoma",

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.",

author = "Vaughan, {Hannah J.} and Zamboni, {Camila G.} and Hassan, {Laboni F.} and Radant, {Nicholas P.} and Desmond Jacob and Ronnie Mease and Il Minn and Tzeng, {Stephany Y.} and Gabrielson, {Kathleen L.} and Pranshu Bhardwaj and Xin Guo and David Francisco and Martin Pomper and Green, {Jordan J.}",

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year = "2022",

month = jul,

doi = "10.1126/sciadv.abo6406",

language = "English (US)",

volume = "8",

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AU - Vaughan, Hannah J.

AU - Zamboni, Camila G.

AU - Hassan, Laboni F.

AU - Radant, Nicholas P.

AU - Jacob, Desmond

AU - Mease, Ronnie

AU - Minn, Il

AU - Tzeng, Stephany Y.

AU - Gabrielson, Kathleen L.

AU - Bhardwaj, Pranshu

AU - Guo, Xin

AU - Francisco, David

AU - Pomper, Martin

AU - Green, Jordan J.

PY - 2022/7

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N2 - 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.

AB - 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.

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

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