Gemcitabine–Coumarin–Biotin Conjugates: A Target Specific Theranostic Anticancer Prodrug

We present here, the design, synthesis, spectroscopic characterization, and <i>in vitro</i> biological assessment of a gemcitabine–coumarin–biotin conjugate (<b>5</b>). Probe <b>5</b> 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 <b>5</b> 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 <b>5</b> 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

An Activatable Prodrug for the Treatment of Metastatic Tumors

Metastatic cancers have historically been difficult to treat. However, metastatic tumors have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H₂O₂), supporting the hypothesis that a prodrug could be activated by intracellular H₂O₂ and lead to a potential antimetastatic therapy. In this study, prodrug <b>7</b> was designed to be activated by H₂O₂-mediated boronate oxidation, resulting in activation of the fluorophore for detection and release of the therapeutic agent, SN-38. Drug release from prodrug <b>7</b> was investigated by monitoring fluorescence after addition of H₂O₂ to the cancer cells. Prodrug <b>7</b> activated by H₂O_2, selectively inhibited tumor cell growth. Furthermore, intratracheally administered prodrug <b>7</b> showed effective antitumor activity in a mouse model of metastatic lung disease. Thus, this H₂O₂-responsive prodrug has therapeutic potential as a novel treatment for metastatic cancer via cellular imaging with fluorescence as well as selective release of the anticancer drug, SN-38