A novel Doxorubicin prodrug with controllable photolysis activation for cancer chemotherapy.
OBJECTIVE
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.
Ibsen
Stuart
S
Department of Bioengineering, Moores Cancer Center, University of California San Diego, 3855 Health Sciences Dr. # 0815, La Jolla, California 92093-0815, USA. sibsen@ucsd.edu
Zahavy
Eran
E
Wrasdilo
Wolf
W
Berns
Michael
M
Chan
Michael
M
Esener
Sadik
S
D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000528:radiation effects; D001710:Biotin / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000528:radiation effects; D004339:Drug Compounding; D004355:Drug Stability; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015394:Molecular Structure; D010782:Photolysis; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000528:radiation effects; D012995:Solubility; D014466:Ultraviolet Rays
D000903:Antibiotics, Antineoplastic; D011355:Prodrugs; D001710:Biotin; D004317:Doxorubicin