Cancer Cell Penetration and Intracellular Localization of a Fluorescently Labeled Folate-calix[4]arene Conjugate

Site-specific delivery of therapeutic and imaging agents is a strategy to minimize undesired side effects and maximize therapeutic and diagnostic index in the treatment of tumors. In the search for targeted delivery systems, folic acid receptor is an important target. A variety of folate-conjugates have been synthesized,1 and successfully tested in clinical trials for diagnosis and therapy of human cancers. The clustered organization of the folic acid receptors, overexpressed on the cancer cell surface, has stimulated the design of multivalent folate-conjugates, and it has been noted that the principles of multivalency can be effectively employed to improve the tumor cell surface binding avidity.2 Figure 1. Fluorescent folate-calix[4]arene derivative(1) and confocal fluorescence microscopy image of the uptake by cancer HeLa cells. Here, we report that a fluorescently labeled multivalent folate-calix[4]arene (1) penetrates selectively cancer cells over healthy cells via folate receptor-mediated endocytosis. This result suggests that a folate-calixarene conjugate may be a viable candidate for delivering drugs or imaging agents to folate-receptor positive cancer cells. The ability to combine multiple targeting units with drugs and/or diagnostic agents by means of a calixarene skeleton opens perspectives for development of new constructs for targeted multidrug therapy and theranostic. 1 Vlahov, I. R.; Leamon, C. P. Bioconjugate Chem. 2012, 23, 1357-1369. 2 Silpe, J. E.; Sumit, M.; Thomas, T. P.; Huang, B.; Kotlyar, A.; van Dongen, M. A.; Banaszak Holl, M. M.; Orr, B. G.; Choi, S. K. ACS Chem. Biol. 2013, 8, 2063-2071.