Nanoparticle delivery of a prodrug-activating bacterial enzyme leads to anti-tumor responses
Abstract
Abstract Most cancer patients diagnosed with late-stage head and neck squamous cell carcinoma are treated with chemoradiotherapy, which can lead to toxicity. One potential alternative is tumor-limited conversion of a prodrug into its cytotoxic form. We reason this could be achieved by transient and tumor-specific expression of purine nucleoside phosphorylase (PNP), an Escherichia coli enzyme that converts fludarabine into 2-fluoroadenine, a potent cytotoxic drug. To efficiently express bacterial PNP in tumors, we evaluate 44 chemically distinct lipid nanoparticles (LNPs) using species-agnostic DNA barcoding in tumor-bearing mice. Our lead LNP, designated LNP intratumoral (LNPIT), delivers mRNA that leads to PNP expression in vivo. Additionally, in tumor cells transfected with LNPIT, we observe upregulated pathways related to RNA and protein metabolism, providing insight into the tumor cell response to LNPs in vivo. When mice are treated with LNPIT-PNP, then subsequently given fludarabine phosphate, we observe anti-tumor responses. These data are consistent with an approach in which LNP-mRNA expression of a bacterial enzyme activates a prodrug in solid tumors.
Article Details
Authors (20)
Sebastian G. Huayamares
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology
Liming Lian
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine
Regina Rab
Yuning Hou
Afsane Radmand
Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology
Hyejin Kim
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine
Ryan Zenhausern
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine
Bhagelu R. Achyut
Melissa Gilbert Ross
Melissa P. Lokugamage
David Loughrey
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine
Hannah E. Peck
Elisa Schrader Echeverri
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology
Alejandro J. Da Silva Sanchez
Aram Shajii
Andrea Li
Karen E. Tiegreen
Philip J. Santangelo
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine and Georgia Institute of Technology
Eric J. Sorscher
James E. Dahlman
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine