An important feature of modular nanostructures for improved delivery of therapeutic and diagnostic agents in vivo is the ability to release their payload in the target tissutal or cellular compartment in a controlled fashion. To this end, activatable linkers that  undergo cleavage or extensive conformational change when specific stimuli (pH, light, enzymatic activity) occur may provide an ideal tool.

In the framework of the Nanomedicine Division, we aim at designing novel cleavable linkers for the conditional release of a desired payload. The project is focused on the development of environmentally-sensitive linkers, provided with excellent selectivity and efficiency, and derivatized with suitable handles for conjugation to biomolecules, nanoparticles, polymers, and peptidic sequences. The study takes advantage of ab initio simulations of electronic spectra line-shapes, which allow better understanding of experimental outcomes and in turn photophysical and photochemical properties of target systems. Research activity involves identification of suitable stimuli that promote cleavage of the linker, an extensive in silico screening of potential cleavable structures, the synthesis of the most promising derivatives and a final validation of the prepared structures in model systems.

Particular attention is devoted to the development of peptidic and peptidomimetic sequences containing non-natural amino acids, and able to cleave peptidic backbone or to release specific molecules covalently linked to the side chains of the amino acids. Furthermore, interaction of photocleavable molecules with metal nanoparticles will be investigated, in order to enhance photocleavage efficiency through surface plasmon resonance effect.

Fig.1: Ab initio simulations allow better understanding of experimental outcome and provide the basis for rational design of cleavable systems. This enables synthesis of efficient cleavable and photocleavable structures (uncaging at 561 nm of fluoresce in living cells).