A novel doxorubicin prodrug with controllable photolysis activation for cancer chemotherapy

Stuart Ibsen, Eran Zahavy, Wolf Wrasdilo, Michael Berns, Michael Chan, Sadik Esener

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Purpose: Doxorubicin (DOX) is a very effective anticancer agent. However, in its pure form, its application is limited by significant cardiotoxic side effects. The purpose of this study was to develop a controllably activatable chemotherapy prodrug of DOX created by blocking its free amine group with a biotinylated photocleavable blocking group (PCB). Methods: An n-hydroxy succunamide protecting group on the PCB allowed selective binding at the DOX active amine group. The PCB included an ortho-nitrophenyl group for photo cleavability and a water-soluble glycol spacer arm ending in a biotin group for enhanced membrane interaction. Results: This novel DOX-PCB prodrug had a 200-fold decrease in cytotoxicity compared to free DOX and could release active DOX upon exposure to UV light at 350 nm. Unlike DOX, DOX-PCB stayed in the cell cytoplasm, did not enter the nucleus, and did not stain the exposed DNA during mitosis. Human liver microsome incubation with DOX-PCB indicated stability against liver metabolic breakdown. Conclusions: The development of the DOX-PCB prodrug demonstrates the possibility of using light as a method of prodrug activation in deep internal tissues without relying on inherent physical or biochemical differences between the tumor and healthy tissue for use as the trigger.

Original languageEnglish (US)
Pages (from-to)1848-1860
Number of pages13
JournalPharmaceutical Research
Volume27
Issue number9
DOIs
StatePublished - Sep 2010

Keywords

  • doxorubicin
  • photoactivatable
  • photocleavable
  • prodrug
  • toxicity

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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