Polypept(o)ides represent a novel class of copolymers that combine the diverse functionality of polypeptides with the shielding properties of polypept(o)ids (e.g. polysarcosine). Polypept(o)ides can be conveniently synthesized by controlled sequential ring-opening polymerization of the respective α-amino acid N-carboxyanhydrides (NCAs) or N-substituted N-carboxyanhydrides (NNCAs), yielding polymers with narrow and symmetrical molecular weight distributions (PDI &lt; 1.2). In addition to functionality and the formation of reactive poly(amino acids), the polypeptide block can be exploited for the tendency to grow secondary structures (e.g. α-helix, β-sheet) that provide an additional parameter for nanoscale self-assembly. Consequently, cylindrical or spherical polymeric micelles (Dh 30-100 nm) were prepared by secondary structure-directed self-assembly of identical poly(sarcosine)-block-poly(S-alkylsulfonyl-L-cysteine) copolymers, depending on the formation or suppression of anti-parallel β-sheets mediated by chaotropic thiourea. Independent from the previously adjusted morphology, these micelles were then converted into core cross-linked polymeric micelles by addressing the S-alkylsulfonyl groups with dithiols in a chemoselective manner. This technique not only stabilizes the micelle and prevents disintegration upon dilution, but also allows for a tailored core polarity, which can be specifically adjusted. For this reason, a library of liponamide-based cross-linkers (logP 7.30 (hydrophobic) to -2.87 (hydrophilic)) has been developed and employed to tune or even invert core polarity. In addition, complex pro-drugs of active pharmaceutical ingredients were synthesized and bio-reversibly attached to the micellar core. In summary, this platform uniquely enables to generate a library of functional core cross-linked carriers that can be customized to the desired application in a simple but controlled manner.

Secondary structure-driven self-assembly of reactive polypept(o)ides for cross-linked polymeric micelles with defined core polarity and function

256th National Meeting (2018)

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