Fluoro-Crown Ether Phosphate as Efficient Cell-Permeable Drug Carrier by Disrupting Hydration Layer

Fast and direct permeation of drug molecules is crucial for effective biotherapeutics. Inspired by a recent finding that fluorous compounds disrupt the hydrogen-bonded network of water, we developed fluoro-crown ether phosphate ^CyclicFP-X. This compound acts as a fast cell-permeating agent, enabling direct delivery of various bioactive cargos (X) into cancer cells without endocytic entrapment. In contrast, its nonfluorinated cyclic analog (^CyclicP-X) failed to achieve cellular internalization. Although the acyclic fluorous analog ^AcyclicFP-X was internalized, this process occurred slowly owing to the involvement of an endocytic trapping pathway. Designed with a high fluorine density, ^CyclicFP-X exhibits compactness, polarity, and high-water solubility, facilitating lipid vesicle fusion by disrupting their hydration layers. Raman spectroscopy confirmed the generation of dangling -OH bonds upon addition of ^CyclicFP-OH to water. Furthermore, conjugating ^CyclicFP-X with fluorouracil (FU, an anticancer drug) via a reductively cleavable disulfide linker (^CyclicFP-SS-FU) demonstrated the general utility of fluoro-crown ether phosphate as a potent carrier for biotherapeutics.