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<p>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 <i>Escherichia coli</i> 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 (LNP<sup>IT</sup>), delivers mRNA that leads to PNP expression in vivo. Additionally, in tumor cells transfected with LNP<sup>IT</sup>, 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 LNP<sup>IT</sup>-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.</p>

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Nanoparticle delivery of a prodrug-activating bacterial enzyme leads to anti-tumor responses

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月12日

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  • Sebastian G. Huayamares,
  • Liming Lian,
  • Regina Rab,
  • Yuning Hou,
  • Afsane Radmand,
  • Hyejin Kim,
  • Ryan Zenhausern,
  • Bhagelu R. Achyut,
  • Melissa Gilbert Ross,
  • Melissa P. Lokugamage,
  • David Loughrey,
  • Hannah E. Peck,
  • Elisa Schrader Echeverri,
  • Alejandro J. Da Silva Sanchez,
  • Aram Shajii,
  • Andrea Li,
  • Karen E. Tiegreen,
  • Philip J. Santangelo,
  • Eric J. Sorscher,
  • James E. Dahlman

摘要

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.