Supramolecular Host–Guest Chemistry-Based Folate/Riboflavin Functionalization and Cancer Cell Labeling of Nanoparticles

[Image: see text] Nanoparticle-based cellular probes are commonly designed via covalent conjugation with affinity biomolecules. Those nanobioconjugates selectively interact with cell surface receptors and induce endocytosis followed by intracellular trafficking. However, this approach requires functional modification of biomolecules that may alter their biochemical activity. Here, we show that supramolecular host–guest chemistry can be utilized as an alternative approach in nanoparticle functionalization and selective cell labeling. We have used cyclodextrin-conjugated quantum dots (QDs) for supramolecular host–guest interaction-based functionalization with folate (QD-folate) and riboflavin (QD-riboflavin), where cyclodextrin acts as a host for the folate/riboflavin guest. We demonstrate that QD-folate and QD-riboflavin selectively label cells that have over-expressed folate/riboflavin receptors and induce the endocytosis pathway similar to covalently conjugated folate-/riboflavin-based nanoprobes. However, labeling is highly sensitive to the molar ratio of folate/riboflavin to cyclodextrin and incubation time. The presented functionalization/labeling approach is unique as it does not require covalent conjugation and may be extended for in vivo targeting application via simultaneous delivery of host and guest molecules.