Development of a folate receptor (FR)-targeted indenoisoquinoline using a pH-sensitive N-ethoxybenzylimidazole (NEBI) bifunctional cross-linker.
This Communication describes the synthesis and evaluation of a folate-conjugated drug delivery system (DDS) that incorporates an acid-sensitive N-ethoxybenzylimidazole (NEBI) bifunctional linker and a novel imidazole-containing indenoisoquinoline. Indenoisoquinolines are a class of TOP1 inhibitors that exhibit broad anticancer activity. Here, we examined whether a DDS that comprised an indenoisoquinoline attached to a folate moiety could help target activity to cancer cells that naturally overexpress the folate receptor (FR), thereby increasing the specificity of these compounds. Evaluation of the DDS revealed an 11-fold increased toxicity in folate receptor (FR)-overexpressing cells compared to in FR-knockdown cancer cells. Microscopy studies demonstrate enhanced internalization and localization of the DDS in acidic lysosomal compartments of FR-overexpressing cells, supporting a receptor-mediated mechanism for uptake and activation. Together with control experiments, the results support that the cytotoxic activity of this DDS is dependent on both the presence of the folate group as well as the presence of the acid-sensitive hydrolyzable group. This work represents the first example of a cell receptor-targeted indenoisoquinoline, which could help pave the way for the use of this class of compounds in anticancer therapy.
Department of Chemistry and Biochemistry, University of California , San Diego, 9500 Gilman Drive, La Jolla California 92093-0358, United States.
Yuchen
Y
Cao
Jerry
J
Yang
D003432:Cross-Linking Reagents / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D058975:Folate Receptor 1 / Q000037:antagonists & inhibitors*; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000737:chemistry*; D007192:Indenes / Q000737:chemistry* / Q000494:pharmacology*; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D007624:KB Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D003432:Cross-Linking Reagents; C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D007093:Imidazoles; D007192:Indenes; D007546:Isoquinolines; C000596191:N-ethoxybenzylimidazole; C510007:norindenoisoquinoline; C029899:imidazole; D005492:Folic Acid