Polyoxazolines with Cholesterol Lipid Anchor for Fast Intracellular Delivery

Due to the increasing challenges posed by the growing immunity to poly(ethylene glycol) (PEG), there is growing interest in innovative polymer-based materials as viable alternatives. In this study, the advantages of lipids and polymers are combined to allow efficient and rapid cytoplasmic drug delivery. Specifically, poly(2-methyl-2-oxazoline) is modified with a cholesteryl hemisuccinate group as a lipid anchor (CHEMSPOx). The CHEMSPOx is additionally functionalized with a coumarin group (CHEMSPOx-coumarin). Both polymers self-assembled in water into vesicles of approximate to 100 nm and are successfully loaded with a hydrophobic model drug. The loaded vesicles reveal high cellular internalization across variant cell lines within 1 h at 37 degrees C as well as 4 degrees C, albeit to a lesser extent. A kinetic study confirms the fast internalization within 5 min after the sample's addition. Therefore, different internalization pathways are involved, e.g., active uptake but also nonenergy dependent mechanisms. CHEMSPOx and CHEMSPOx-coumarin further demonstrate excellent cyto-, hemo-, and membrane compatibility, as well as a membrane-protecting effect, which underlines their good safety profile for potential biological intravenous application. Overall, CHEMSPOx, as a lipopolyoxazoline, holds great potential for versatile biological applications such as fast and direct intracellular delivery or cellular lysis protection. Poly(2-methyl-2-oxazoline) modified with a cholesteryl hemisuccinate group (CHEMSPOx) are explored as alternatives to poly(ethylene glycol) for drug delivery. CHEMSPOx, functionalized with lipid and coumarin groups, self-assembles into vesicles that efficiently deliver hydrophobic molecules into cells. These vesicles demonstrate rapid internalization across various cell lines and exhibit excellent biocompatibility, suggesting their potential for intracellular delivery and membrane protection in biological applications. image