Exploring the potential of polypeptide–polypeptoide hybrid nanogels for mucosal delivery

Amphiphilic nanoparticles with high drug loading capacity and mucus penetration properties are attractive for the delivery of potent hydrophobic drugs across the mucosal barrier in tumor therapy. In this study we report a facile strategy towards biocompatible and tumour microenvironment responsive nanogels, capable of controlling the mucosal delivery and release of a model dye. Polypeptide–polypeptoide hybrid nanogels were obtained by the chain extension of corona-forming poly(sarcosine) with N-carboxyanhydrides (NCA) of phenylalanine and cystine as a core crosslinker. The nanogels exhibited a suitable size range of around 100 nm and a spherical morphology as monitored by dynamic light scattering (DLS), transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). They further showed a reduction-responsive behaviour through the cleavage of the cystine disulfide core crosslinks by glutathione at concentrations present in the intracellular environment as well as a lack of cytotoxicity against both cancerous and non-cancerous cell lines. Lead nanogels facilitated an enhanced transport of a model hydrophobic dye across artificial mucus compared to the dye alone with a reduction sensitive release in the presence of glutathione. This work provides a facile strategy for the synthesis of responsive nanomedicines in anti-cancer therapy where mucosal barriers have to be overcome.