A Novel Doxorubicin Prodrug with Controllable Photolysis Activation for Cancer Chemotherapy

作者：Ibsen Stuart^*; Zahavy Eran; Wrasdilo Wolf; Berns Michael; Chan Michael; Esener Sadik

来源：Pharmaceutical Research, 2010, 27(9): 1848-1860.

DOI：10.1007/s11095-010-0183-x

• prodrug
• photocleavable
• photoactivatable
• doxorubicin
• toxicity

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.

• 出版日期2010-9