A Ring‐Flippable Sugar as a Stimuli‐Responsive Component of Liposomes

For the development of a liposome that takes in and out a drug in response to stimuli, 2,4‐diaminoxylose (Xyl), which allows stimuli‐responsive conformational switches between ⁴C₁ and ¹C₄, was incorporated into a lipid structure: Xyl derivatives with C8 and C16 methylene chains at the 1,3‐positions (C8Xyl and C16Xyl) were synthesized. ¹H NMR spectroscopy indicates that the addition of Zn²⁺ and then H⁺ induces conformational switches from the chair (⁴C₁) to the reverse chair (¹C₄) and ¹C₄‐to‐⁴C₁, respectively, at Xyl; this leads to transformation of the lipids between linear and bent structures. Osmotic pressure and electron microscopy studies demonstrate that C8Xyl in water forms spherical solid aggregates (C8Xyl?Zn), which are converted into liposomes (C8Xyl+Zn) upon the addition of Zn²⁺, and C16Xyl forms liposomes regardless of the presence of Zn²⁺. The aggregates of C8Xyl±Zn incorporated a fluorophore and only C8Xyl+Zn released the content upon the addition of HCl. This study shows that Xyl could be a stimuli‐responsive component of a liposome.