A timescale-guided microfluidic synthesis of tannic acid-Fe network nanocapsules of hydrophobic drugs.

Many drugs are poorly water-soluble and suffer from low bioavailability. Metal-phenolic network (MPN), a hydrophilic thin layer such as tannic acid (TA)-Fe network, has been recently used to encapsulate hydrophobic drugs to improve their bioavailability. However, it remains challenging to synthesize nanocapsules of a wide variety of hydrophobic drugs and to scale up the production in a continuous manner. Here, we present a microfluidic synthesis method to continuously produce TA-Fe network nanocapsules of hydrophobic drugs. We hypothesize that nanocapsules can continuously be formed only when the microfluidic mixing timescale is shorter than the drug's nucleation timescale. The hypothesis was tested on three hydrophobic drugs - paclitaxel, curcumin, and vitamin D with varying solubility and nucleation timescale. The proposed mechanism was validated by successfully predicting the synthesis outcomes. The microfluidically-synthesized nanocapsules had well-controlled sizes of 100-200 nm, high drug loadings of 40-70%, and a throughput of up to 70 mg hr per channel. The release kinetics, cellular uptake, and cytotoxicity were further evaluated. The effect of coating constituents on nanocapsule properties were characterized. Fe content of nanocapsules was reported. The stability of nanocapsules at different temperatures and pHs were also tested. The results suggest that the present method can provide a quantitative guideline to predictively design a continuous synthesis scheme for hydrophobic drug encapsulation via MPN nanocapsules with scaled-up capability.