Multisensitive drug-loaded polyurethane/polyurea nanocapsules with pH-synchronized shell cationization and redox-triggered release

An industrially scalable and versatile method to prepare amphiphilic and amphoteric multifunctionalized polyurethane/polyurea nanocapsules (NCs) is presented. Firstly, a prepolymer is prepared from a diiso-cyanate, which reacts with different functional diols and diamines, leading to a self-emulsifiable reactive product. Secondly, this prepolymer is used to nanoemulsify the desired hydrophobic drug under aqueous conditions. In this step, the prepolymer generates a self-organized drug/water interface driven by its hydrophilic-lipophilic balance (HLB) and allows stable and size-controlled nanoemulsion without external surfactants. Finally, the process is completed with the addition of a crosslinker, which converts the nanodroplets into robust nanocapsules. The process allows chemical versatility, high encapsulation yields and remarkable drug loading contents. The nanocapsules have a monomodal particle size distribution, a roughly round shape and amphoteric properties, which make the nanocapsules very sensitive to small pH changes occurring between blood or extracellular fluids of normal cells and the extracellular tumor microenvironment. Such an effect is intended to increase the stealthiness of the nanocapsule through a neutral hydrophilic corona under physiological conditions and also to enhance cell internalization in tumor cells via surface self-cationization. Fluorescence studies show prolonged stability under physiological conditions and specific degradability through a redox-triggered process involving reduced L-glutathione (L-GSH)