Stabilization and characterization of DOPE liposomes with a reduction-responsive polyethylenimine-α-lipoic acid ion pair

초록

Due to its packing-parameter characteristics, Dioleoylphosphatidylethanolamine (DOPE) typically requires a helper molecule to form stable liposomes. In this study, an ion pair between polyethyleneimine and alpha-lipoic acid was employed as a reduction-responsive amphiphilic helper molecule and applied to stabilize DOPE liposomes. The ion pair exhibited UCST-type behavior, and its phase transition temperature decreased from approximately 42.6 degrees C to 37.7 degrees C, 29.6 degrees C, and 22.9 degrees C upon treatment with 5, 10, and 20 mM dithiothreitol, respectively. DOPE liposomes prepared using the ion pair enabled calcein encapsulation, and the DOPE: IP mass ratio of 10:1 showed the highest quenching efficiency of 48.1% together with a low polydispersity index of 0.105, indicating uniform liposome formation. Transmission electron microscopy further confirmed the formation of multilamellar structures in DOPE liposomes incorporating the ion pair. In release experiments, Lip-CHEMS (10:1) exhibited negligible release regardless of DTT, whereas Lip-IP (10:1) showed a stepwise increase in release with increasing DTT concentration, reaching approximately 12% at 20 mM DTT. Within the temperature range of 25-45 degrees C, temperature elevation alone did not produce a clear additional increase in release. These results show that the PEI/ALA ion pair is not merely an alternative to conventional DOPE helper molecules, but a functional helper molecule that simultaneously enables bilayer stabilization and reduction-triggered modulation of membrane permeability. Therefore, this study provides a formulation strategy for reduction-responsive DOPE liposomes capable of selective release under reducing conditions relevant to the tumor microenvironment.Graphical AbstractSchematic representation of reduction-responsive ion pairs formed from polyethyleneimine and alpha-lipoic acid, and DOPE liposomes stabilized by the ion pairs.

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