Polypept(o)ide-based nanostructures for therapeutic and diagnostic application
Nanoparticles exhibit a number of adjustable properties, e.g., their size, shape, and surface and core chemistry, which can be further diversified with different functional moieties. This opens a broad field for application in diagnostic and therapy. In this respect, the use of a polymeric hybrid material, such as polypept(o)ides, combines the stealth-like hydrophilic part polysarcosine, and the functionality of polypeptides in the nanoparticle core.
- Gabriela Schäfer
My PhD project covers the synthesis and characterization of different polypept(o)ide architectures, namely polymeric micelles (PeptoMicelles) based on amphiphilic block copolymers and polymer brushes (PeptoBrushes), which are graft copolymers. Nuclear imaging techniques are essential to guide the development and achieve patient stratification in a clinical setting, which can reduce the failure rate and enable the development of personalized drugs. The use of radioisotopes and nuclear imaging techniques (SPECT or PET) enables the visualization of target accumulation, e.g., in solid tumors or infected tissues, which is a key requirement for any therapy. The slow pharmacokinetics of most nanomedicines, however, leads to high activity in the blood streams leading to low imaging contrast. To overcome this challenge, accumulation at the target site and the imaging step can be separated using pre-targeted nuclear imaging. In pretargeted imaging the balance between stability and reactivity of functional groups for in vivo click chemistry is essential. The Barz lab has developed PeptoBrushes consists of a poly(L- glutamic acid) backbone modified with trans-cyclooctenes (TCO) and polysarcosine side chains. In this particular polymer architecture the attached TCO-moieties are more stable towards enzymes but display even enhanced reactivity (rate constant is enhanced by 2 orders of magnitude) towards tetrazines allowing the efficient attachment of imaging agents in a bioorthogonal inverse electron demand Diels-Alder reaction.
My second project is the use of amphiphilic block copolypept(o)ides, namely polysarcosine block poly(g-benzyl-L-glutamic acid) copolymers, to prepare PeptoMicelles. The polymers are easily accessible by controlled living nucleophilic ring-opening polymerization (ROP) of corresponding a-amino acid N-Carboxyanhydrides (NCAs). PeptoMicelles are stabilized in their hydrophobic core by p-p interactions, allowing the efficient encapsulation of aromatic drugs to enhance the bioavailability of drugs. For the use in tuberculosis therapy, I use such systems to stablish micellar formulations containing multiple antituberculosis drugs, which are studied primary human cells, zebra fish larvae or mouse models of tuberculosis.