Cleavable Micelles through Bioorthogonal Chemistry – NanoClick

Nanomedicine has sparked a rapidly growing interest as it promises to solve a number of crucial issues associated with conventional therapeutic strategies. Over the past decades, remarkable progresses have been made in the development of engineered nanoparticles able to transport and deliver effective drugs to treat pathologies more effectively. However, although nanotechnology-based targeted delivery has shown promising results in preclinical models, the translation into clinic remains problematic.
Among the possible reasons are uncontrolled release of the drug from nanocarriers and lack of specificity of targeted strategies. One alternative to this problem involves on-demand processes that allow for tailored drug release with spatial, temporal and dosage control. On-demand drug delivery has become feasible through the design of stimuli-responsive nanocarriers that react in a dynamic way in the targeted microenvironment through either enzymatic, pH or physical external stimuli such as temperature, light or ultrasounds for example. However, the difficulties to control endogenous triggers like pH and the lack of focusing and tissue-penetration depth of external stimuli limited the number of successful stories in that field.
The NANOClick project proposes a different strategy based on new designed responsive-micelles that can be cleaved by a biorthogonal activation process. Such micelles are constructed with cleavable bioorthogonal linkers allowing their controlled decomposition inside targeted tissues in a stringently controlled fashion through a bioorthognal chemical stimulus. In such approach, both reactants, i.e. the nanoparticle and the bioorthogonal trigger, are inert individually but, when localized at the same site, react together to provoke the destruction of the nanomaterial and the liberation of its content. One main advantage of such approach is the possibility to apply complementary targeted strategies to both reactants in order to concentrate them in one precise location while limiting their concomitant presence in other areas of the body. Thus, this double targeting strategy could lead to an unprecedented level of selectivity for drug delivery that is of great interest in the context of personalized medicine.