Exploring intracellular fate of drug nanocrystals with crystal-integrated and environment-sensitive fluorophores

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Formulating a poorly water-soluble drug substance into nanocrystals offers many advantages. Understanding of the in vivo fate of drug nanocrystals is however very limited. In this study, we utilized the hybrid nanocrystal concept and studied the kinetic process of dissolution in cancer cells. By taking advantage of aggregation-induced emission (AIE), hybrid paclitaxel (PTX) nanocrystals integrated with tetraphenylethene (TPE) enabled a novel way for estimating the intracellular dissolution process of the nanocrystals. When TPE is entrapped in a nanocrystal, fluorescence is emitted when the nanocrystal is optically excited. When an entrapped TPE molecule is released to a liquid medium due to the dissolution of the nanocrystal, its fluorescence is quenched. By monitoring the change in fluorescence, it is possible to quantify the dissolution of nanocrystals in a biological environment. Cellular uptake studies of hybrid nanocrystals were conducted with KB and HT-29 cell lines and characterized by confocal microscopy, flow cytometry, and HPLC. The results suggest that drug nanocrystals were taken up directly by the cells, and subsequently dissolved in the cytoplasm. The extent to which the drug nanocrystal dissolved was estimated according to the fluorescence measurement. The cellular uptake and intracellular dissolution could be influenced by drug concentration, incubation time, and surface coating, as well as the type of cell line.

Graphical abstract

Paclitaxel nanocrystals become fluorescent when aggregation-induced emission fluorophores are physically integrated in the crystal lattice. When the crystals dissolve, the released fluorophores lose their fluorescence-emitting capability.

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