Molecular self-assembly plays a crucial role in biology, in particular by controlling the formation of cell compartments and regulating the transport of materials within the body. It also offers attractive possibilities for the design of smart carrier systems to aid in therapeutic delivery for major diseases such as cancer, inflammation and infection. Recently, polymeric nanoparticles have come into focus as drug delivery vehicles due to their adaptable surface chemistry and high cargo loading. Internal or external stimuli have been explored as ways to selectively trigger cargo release.<br/>Here, we take inspiration from natural amphiphilic molecules to develop enzyme and temperature-dual responsive polymer nanostructures formed by molecular self-assembly. These particles are aimed at targeted and controlled delivery of biomolecules such as therapeutics. This work focuses on the development of thermo-responsive, self-assembled, peptide cross-linked polymer nanostructures that can be degraded by selected enzymes associated with certain disease conditions (e.g. MMP-13 in osteoarthritis and MMP-7 in cancer). Advantages of this particle system include fine control over the temperature of self-assembly, high loading efficiency, versatility of degradation mechanisms, structural stability and adaptable surface chemistry. By controlled reversible addition-fragmentation chain-transfer (RAFT) polymerization a library of thermo-responsive NIPAM and NCPAM-based triblock copolymers able to self-assemble across a range of temperatures was prepared. The morphology of the formed nanostructures was investigated by small angle neutron scattering (SANS) and cryogenic transmission electron microscopy (cryoTEM). By using copper-catalyzed click chemistry we have cross-linked these nanostructures with peptide substrates sensitive to specific proteases. This approach provides improved system stability and enables controlled and tunable drug release kinetics. Furthermore, the versatile surface chemistry of our designed polymer nanoparticles enables the introduction of fluorescent tags for the study of nanoparticle-cell interactions and tissue-specific targeting groups, such as antibodies, enabling delivery of therapeutic agents at diseased sites in a selective manner.

Adaptable thermo-responsive polymer nanostructures for enzyme-triggered biomolecule delivery

256th National Meeting (2018)

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