Norepinephrine-Transporter-Targeted and DNA-Co-Targeted Theranostic Guanidines

J Med Chem. 2020 Mar 12;63(5):2051-2073. doi: 10.1021/acs.jmedchem.9b00437. Epub 2019 Jul 3.

Abstract

High risk neuroblastoma often recurs, even with aggressive treatments. Clinical evidence suggests that proliferative activities are predictive of poor outcomes. This report describes syntheses, characterization, and biological properties of theranostic guanidines that target norepinephrine transporter and undergo intracellular processing, and subsequently their catabolites are efficiently incorporated into DNA of proliferating neuroblastoma cells. Radioactive guanidines are synthesized from 5-radioiodo-2'-deoxyuridine, a molecular radiotherapy platform with clinically proven minimal toxicities and DNA-targeting properties. The transport of radioactive guanidines into neuroblastoma cells is active as indicated by the competitive suppression of cellular uptake by meta-iodobenzylguanidine. The rate of intracellular processing and DNA uptake is influenced by the agent's catabolic stability and cell population doubling times. The radiotoxicity is directly proportional to DNA uptake and duration of exposure. Biodistribution of 5-[125I]iodo-3'-O-(ε-guanidinohexanoyl)-2'-deoxyuridine in a mouse neuroblastoma model shows significant tumor retention of radioactivity. Neuroblastoma xenografts regress in response to the clinically achievable doses of this agent.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • DNA / metabolism*
  • Drug Delivery Systems / methods*
  • Female
  • Guanidines / administration & dosage
  • Guanidines / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism*
  • Theranostic Nanomedicine / methods*
  • Xenograft Model Antitumor Assays / methods

Substances

  • Guanidines
  • Norepinephrine Plasma Membrane Transport Proteins
  • DNA