A Novel Doxorubicin Prodrug with Controllable Photolysis Activation for Cancer Chemotherapy
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).
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.
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.
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.
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- A Novel Doxorubicin Prodrug with Controllable Photolysis Activation for Cancer Chemotherapy
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- 1. Department of Bioengineering, Moores Cancer Center, University of California San Diego, 3855 Health Sciences Dr. # 0815, La Jolla, California, 92093-0815, USA
- 2. Department of Physical Chemistry, Israel Institute for Biological Research, P.O. Box 19, Ness-Ziona, 74100, Israel
- 3. Moores Cancer Center, University of California at San Diego, La Jolla, California, 92093, USA
- 4. Department of Bioengineering, University of California at San Diego, La Jolla, California, 92093, USA
- 5. Department of Nanoengineering, University of California at San Diego, La Jolla, California, 92093, USA