Polymeric micelles have been widely used to improve the bioavailability and pharmacokinetics of hydrophobic drugs, as well as to alter their biodistribution. Nevertheless, as micelles are not static structures, dynamic covalent bonds are considered the missing link to match stable circulation of polymeric micelles, an essential prerequisite for passive accumulation in angiogenic tissue, with stimuli-responsive drug release. In this context, ruthenium complexes combine the ability to bind to DNA with light-induced ligand exchange reactions, while disulfide bonds are known to be bioreversible. Polypept(o)ides that combine the shielding properties of polypeptoids (e.g. polysarcosine) with the diverse functionality of polypeptides have emerged as promising carrier material. 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). Bio-reversibly cross-linked polymeric micelles have been prepared from poly(sarcosine)-block-poly(S-alkylsulfonyl-L-cysteine) copolymers. Depending on the formation or suppression of anti-parallel β-sheets, cylindrical or spherical micelles (Dh 30-100 nm) were formed from directed self-assembly of identical polymers. Independent from the morphology, these micelles were then converted into core cross-linked nanostructures when the S-alkylsulfonyl groups were chemoselectively addressed with dithiols. In addition to bare stabilization of the polymeric carriers, this technique allows for tailored core polarity, which can be adjusted to the desired cargo by a set of liponamide-based cross-linkers (logP 7.30 to -2.87) and allows for bio-reversible conjugation of pro-drugs. Photocleavable core cross-linked polymeric micelles were prepared from poly(sarcosine)-block-poly(L-glutamic acid) copolypept(o)ides, which were modified with benzonitriles, yielding an amphiphilic nitrile-containing block copolymer (PSar-b-PGlu(CN)). Upon aggregation by solvent switch procedure, micelles were core cross-linked with ruthenium(II) complexes resulting in light-sensitive core cross-linked polymeric micelles (Dh = 45-90 nm).

Choose a trigger: pH, reduction potential, or light. Dynamic covalent bonds for in vivo stabilization of polypept(o)ide-based micelles

256th National Meeting (2018)

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