Gemcitabine-coumarin-biotin conjugates: a target specific theranostic anticancer prodrug.

Abstract

We present here, the design, synthesis, spectroscopic characterization, and in vitro biological assessment of a gemcitabine-coumarin-biotin conjugate (5). Probe 5 is a multifunctional molecule composed of a thiol-specific cleavable disulfide bond, a coumarin moiety as a fluorescent reporter, gemcitabine (GMC) as a model active drug, and biotin as a cancer-targeting unit. Upon addition of free thiols that are relatively abundant in tumor cells, disulfide bond cleavage occurs as well as active drug GMC release and concomitantly fluorescence intensity increases. Confocal microscopic experiments reveal that 5 is preferentially taken up by A549 cells rather than WI38 cells. Fluorescence-based colocalization studies using lysosome- and endoplasmic reticulum-selective dyes suggest that thiol-induced disulfide cleavage of 5 occur in the lysosome possibly via receptor-mediated endocytosis. The present drug delivery system is a new theranostic agent, wherein both a therapeutic effect and drug uptake can be readily monitored at the subcellular level by two photon fluorescence imaging.

• Authors: Sukhendu Maiti, Nayoung Park, Ji Hye Han, Hyun Mi Jeon, Jae Hong Lee, Sankarprasad Bhuniya, Chulhun Kang, Jong Seung Kim
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 135 Issue 11 Pg. 4567-72 (Mar 20 2013) ISSN: 1520-5126 [Electronic] United States
• PMID: 23461361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Coumarins
• Fluorescent Dyes
• Prodrugs
• Sulfhydryl Compounds
• Deoxycytidine
• Biotin
• coumarin
• Gemcitabine

Topics

• Antineoplastic Agents (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Biotin (chemistry)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Coumarins (chemistry)
• Deoxycytidine (administration & dosage, analogs & derivatives, chemistry, pharmacokinetics, pharmacology)
• Drug Delivery Systems
• Fluorescent Dyes (chemistry)
• Humans
• Neoplasms (drug therapy)
• Prodrugs (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Sulfhydryl Compounds (chemistry)
• Gemcitabine