Design of cross-linkable polypept(o)ide-based AB3 miktoarm star polymers through advances in PeptoMiktoStar synthesis

Advances in polymer chemistry can provide convenient access to more complex polymeric architectures, such as miktoarm star polymers. In comparison to their linear counterparts, the physical properties of miktoarm star polymers can substantially differ. Their complex synthesis, characterization, and purification, however, makes it a challenging task to prepare well-defined structures with multiple arms of adjustable chemical nature. In this work, well-defined cross-linkable polypept(o)ide-based AB3 miktoarm star polymers were achieved, taking advantage of a novel asymmetric tetrafunctional initiator system with different orthogonal protecting groups. The first controlled living ring-opening polymerization (ROP) of sarcosine N-carboxyanhydride yields a three-armed polysarcosine (pSar) macroinitiator with low molecular weight dispersity (Đ ∼ 1.1), while a reactive polypeptide arm can be synthesized upon cleavage of the remaining protective group. The established reactive S-alkylsulfonyl protecting group bearing polypeptides poly(S-ethylsulfonyl-l-cysteine) (pCys(SO2Et)) and poly(S-ethylsulfonyl-l-homocysteine) (pHcy(SO2Et) were implemented into the asymmetric star architecture. The presence of the well-defined cross-linkable AB3 PeptoMiktoStars was verified through the characterization via 1H NMR, 1H DOSY, and SEC, revealing structures with dispersity indices of 1.1–1.2 and precise control over the degree of polymerization of each individual polymer chain. In aqueous solution, both types of PeptoMiktoStars form polymeric micelles. The size and morphology can be tuned by secondary structure directed self-assembly: the pHcy(SO2Et)20(pSar100)3 polymers form spherical micelles whilst the pCys(SO2Et)20(pSar100)3 assembled into worm-like micelles. Therefore, this synthetic methodology provides not only access to well-defined reactive miktoarm star polymers, but also allows for the engineering of polymeric micelles based on PeptoMiktoStars.