Complexes of star-shaped block copolymers of poly(2-alkyl-2-oxazine)s and curcumin can affect lipid bilayers mimicking biomembranes

Abstract

Poly(2-alkyl-2-oxazine)s (PAlOz) are promising tools for developing delivery systems due to their high biocompatibility, resistance to enzyme hydrolysis, and ability to degrade in biological environments. Here, we investigated the effects of hexaaza[2₆]cyclophane (CPh6), poly(2-methyl-2-oxazine) (PMedOz), a block copolymer of poly(2-ethyl-2-oxazine) (PEtOz) and poly(2-isopropyl-2-oxazine) (PiPrOz), star-shaped block copolymers with six PAlOz arms and a CPh6 branching center (CPh6-PAlOz), and the complexes of all these macromolecules with curcumin on lipid bilayers mimicking the membranes of normal and cancer cells. Curcumin alone demonstrated a pronounced ability to reduce the boundary potential of lipid bilayers composed of phosphatidylcholine or phosphatidylserine, while PMedOz and PEtOz-b-PiPrOz copolymers exhibited either no or weak effects on the electrical properties of biomimetic model membranes. CPh6-PAlOz star-shaped block copolymers were able to interact with K⁺-nonactin. Differential scanning microcalorimetry of the gel-to-liquid crystalline phase transition of membrane lipids indicated that curcumin and all tested macromolecules had more pronounced effects on phosphatidylserine melting than on the phase behavior of phosphatidylcholine. A star-shaped block copolymer with a [PEtOz]/[PiPrOz] ration of 0.8 significantly decreased the melting point of phosphatidylserine. The disordering effects of complexes of curcumin with CPh6, PEtOz-b-PiPrOz copolymers, or the CPh6-PAlOz star-shaped block copolymer with a [PEtOz]/[PiPrOz] ratio of 5 on phosphatidylserine bilayers were less than the algebraic sum of the effects of the polymers and curcumin separately. These data indicate that the carrier cannot be considered an inert matrix that does not affect the biological activity of the transferred active compound, and this should be taken into account when assessing the biological consequences.