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 diisocyanate, 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).

Polyurethane–polyurea (PUUa) reactive prepolymers with adjusted hydrophobic and hydrophilic dangling chains to achieve multiwalled sub-30 nm nanoparticles are presented. The combination of an amphiphilic and a hydrophobic prepolymer at the oil–water interface creates a stratified shell by hydrophobic interactions. These novel nanostructures enhance the encapsulation stability of lipophilic compounds compared to monowalled nanostructures and facilitate the selective and ordered functionalization along the multiwalled shell with bioactive motifs. As proof of concept, PUUa nanoparticles have been engineered with disulfide bonds and an α_vβ₃ integrin-selective cyclic RGD peptide (cRGDfK) providing our system with glutathione (GSH) triggered controlled release and cell targeting specificity to U87 tumor cells.

Aortic endothelial cell dysfunction is an early trigger of atherosclerosis, the major cause of the cardiovascular disease (CVD). Nanomedicines targeting vascular endothelium and lesions hold great promise as therapeutic solutions to vascular disorders. This study investigates the vascular delivery efficacy of polyurethane-polyurea nanocapsules (Puua-NCs) with pH-synchronized shell cationization and redox-triggered release. Fluorescent lipophilic dye DiI was encapsulated into Puua-NCs of variable sizes and concentrations. In vitro cellular uptake studies with human aortic endothelial cells showed that these Puua-NCs were taken up by cells in a dose-dependent manner. In apolipoprotein E-deficient mice fed a Western diet, a model of atherosclerosis, circulating Puua-NCs were stable and accumulated in aortic endothelium and lesions within 24 hours after intravenous administration. Treatment with thiol-reducing and oxidizing reagents disrupted the disulfide bonds on the surface of internalized NCs, triggering disassembly and intracellular cargo release. Ultimately, Puua-NCs are a potential redox-controllable cardiovascular drug delivery system.

Cancer is one of the leading causes of mortality worldwide due, in part, to limited success of some current therapeutic approaches. The clinical potential of many promising drugs is restricted by their systemic toxicity and lack of selectivity towards cancer cells, leading to insufficient drug concentration at the tumor site. To overcome these hurdles, we developed a novel drug delivery system based on polyurea/polyurethane nanocapsules (NCs) showing pH-synchronized amphoteric properties that facilitate their accumulation and selectivity into acidic tissues, such as tumor microenvironment. We have demonstrated that the anticancer drug used in this study, a hydrophobic anionophore named T21, increases its cytotoxic activity in acidic conditions when nanoencapsulated, which correlates with a more efficient cellular internalization. A biodistribution assay performed in mice has shown that the NCs are able to reach the tumor and the observed systemic toxicity of the free drug is significantly reduced in vivo when nanoencapsulated. Additionally, T21 antitumor activity is preserved, accompanied by tumor mass reduction compared to control mice. Altogether, this work shows these NCs as a potential drug delivery system able to reach the tumor microenvironment, reducing the undesired systemic toxic effects. Moreover, these nanosystems are prepared under scalable methodologies and straightforward process, and provide tumor selectivity through a smart mechanism independent of targeting ligands.

Encapsulation of water-soluble bioactive compounds for enabling specific accumulation in tumor locations, while avoiding premature clearance and/or degradation in the bloodstream, is one of the main hallmarks in nanomedicine, especially that of NIR fluorescent probes for cancer theragnosis. The herein reported technology furnishes water-dispersible double-walled polyurethane-polyurea hybrid nanocapsules (NCs) loaded with indocyanine green (ICG-NCs), using a versatile and highly efficient one-pot and industrially scalable synthetic process based on the use of two different prepolymers to set up the NCs walls. Flow cytometry and confocal microscopy confirmed that both ICG-loaded NCs internalized in monocyte-derived dendritic cells (moDCs). The in vivo analysis of xenograft A375 mouse melanoma model revealed that amphoteric functionalization of NCs’ surface promotes the selective accumulation of ICG-NCs in tumor tissues, making them promising agents for a less-invasive theragnosis of cancer.

Correction for ‘Multifunctionalized polyurethane–polyurea nanoparticles: hydrophobically driven self-stratification at the o/w interface modulates encapsulation stability’ by Pau Rocas et al., J. Mater. Chem. B, 2015, DOI: 10.1039/c5tb01345c.