Combining Core Cross-Linking and π–π-Interactions in Polymer Micelles Based on Polypept(o)ide AB3 Miktoarm Star Polymers

Abstract

The lack of stability in nanocarriers, premature release of drugs in the bloodstream, and the resulting adverse effects have greatly hindered the advancement of nanomedicines by comprising their therapeutic effectiveness. In order to surpass these limitations and fully exploit the potential of polymeric micelles for targeted drug delivery, various physical and chemical strategies have been devised to improve micellar blood circulation time and improve drug retention. In this regard, the improved polymer density at the hydrophilic/hydrophobic interface in miktoarm star polymers based micelles is highly appealing and sets them apart from conventional linear block copolymers. Nonetheless, the often complex synthesis of asymmetric architectures hinders a broader application in the field of nanomedicine. In this study, we have designed novel dual-stabilizable PeptoMiktoStars by optimizing the orthogonal group strategy, introducing core cross-linkability and π–π-interactions. These polypept(o)ide miktoarm star polymers unify the polypeptide blocks of poly(S-ethylsulfonyl-l-cysteine) (pCys(SO₂Et))/poly(S-ethylsulfonyl-l-homocysteine) (pHcy(SO₂Et)) and poly(γ-benzyl-l-glutamate (pGlu(OBn))) with multiple arms of the polypeptoid polysarcosine (pSar) in an AB₃ architecture. By utilizing ¹H NMR, ¹H DOSY, and GPC, the formation of well-defined star polymers was confirmed. The obtained results showcased star structures with narrow molecular weight distributions, low dispersities (Đ = 1.16–1.18), and accurate control over the degree of polymerization. After successful core cross-linking and drug encapsulation, uniform micelles with hydrodynamic diameters ranging from 60 to 68 nm were observed by dynamic laser light scattering (DLS) and transmission electron microscopy (TEM), making these structures suitable for controlled intracellular drug release upon local or systemic administration.