Simultaneous activation and release of a microtubule inhibitor from amphiphilic polymeric nanoparticles

Light addressable drug delivery systems offer opportunities to achieve spatiotemporal control over therapeutic activity while minimising off-target effects. Here we report the design, synthesis, and evaluation of a photocaged photostatin (proPST-1), in which the phenolic group of photostatin-1 (PST-1) was masked with an o-nitrobenzyl (ONB) photocage. Our strategy combines reversible photoswitching of the azobenzene unit with irreversible photolysis of the ONB group, affording active PST-1. Molecular docking studies suggested reduced predicted tubulin compatibility of proPST-1 due to the bulky ONB group relative to PST-1 thus silencing the dark state activity and enabling optical ON-switching. Encapsulation of proPST-1 within polymeric nanoparticles (PNs) formed from an amphiphilic polymer resulted in water soluble nanocarriers with high encapsulation efficiencies of proPST-1 (∼95%). Upon 365 nm irradiation, photolysis released the active cis-PST-1, weakening hydrophobic partitioning and promoting release from the nanoparticle core. In vitro tubulin polymerisation assays confirmed pronounced light-dependent inhibition, while cytotoxicity assays in cells validated concentration-dependent activity only after irradiation. This proof-of-concept study establishes a blueprint for integrating photocaging and photoswitching within nanocarriers to achieve dual activation and triggered release.